latest research in cancer

FDA approves groundbreaking treatment for advanced melanoma

The Food and Drug Administration on Friday approved a new cancer therapy that could one day transform the way a majority of aggressive and advanced tumors are treated.

The treatment, called Amtagvi, from Iovance Biotherapeutics , is for metastatic melanoma patients who have already tried and failed other drugs. It’s known as TIL therapy and involves boosting the number of immune cells inside tumors, harnessing their power to fight the cancer.

It’s the first time a cellular therapy has been approved to treat solid tumors. The drug was given a fast-track approval based on the results of a phase 2 clinical trial. The company is conducting a larger phase 3 trial to confirm the treatment’s benefits. The therapy’s list price — the price before insurance and other potential discounts — is $515,000 per patient. 

“This is going to be huge,” said Dr. Elizabeth Buchbinder, a senior physician at Dana-Farber Cancer Institute in Boston. Melanoma is “not one of those cancers where there’s like 20 different” possible treatments, she said. “You start running out of options fast.” 

Friday’s approval is only for melanoma, the deadliest form of skin cancer , but experts say it holds promise for treating other solid tumors, which account for 90% of all cancers. 

“It is our hope that future iterations of TIL therapy will be important for lung cancer, colon cancer , head and neck cancer, bladder cancer and many other cancer types,” said Dr. Patrick Hwu, chief executive of the Moffitt Cancer Center in Tampa, Florida. Moffitt has been involved with Iovance’s clinical trials of TIL therapy.

TIL stands for tumor-infiltrating lymphocytes, which are immune cells that exist within tumors . But there are nowhere nearly enough of those cells to effectively fight off cancer cells. TIL therapy involves, in part, extracting some of those immune cells from the patient’s tumor and replicating them billions of times in a lab, then reinfusing them back into the patient. 

It’s similar to CAR-T cell therapy, where healthy cells are taken out of a person’s body and then modified in a lab to fight cancers. That’s usually used for hard-to-treat blood cancers such as leukemia and lymphoma. With TIL therapy, the cells used are already programmed to recognize cancer — no lab modifications needed — they just need a boost in numbers to fight it. 

Like CAR-T, TIL therapy is a one-time treatment, though the entire process can take up to eight weeks. The TIL cells are first harvested from the tumor through a minimally invasive procedure and then grown and multiplied in the lab, a process that takes 22 days, according to Iovance. 

While that’s happening, patients are given chemotherapy to clear out their immune cells to make room for the billions of new melanoma-fighting TIL cells. Once the TIL cells are reinfused back into the body, patients get a drug called interleukin-2 to further stimulate those cells. 

Hwu said that most side effects in patients undergoing TIL therapy are not from the reinfusion of cells, but from the chemotherapy and the interleukin-2. These can include nausea and extreme fatigue, and patients are also vulnerable to other illnesses because the body is depleted of disease-fighting white blood cells. 

Putting billions of cells back into the body is not entirely risk-free, however, said Dr. William Dahut, chief scientific officer of the American Cancer Society. It’s possible that the body’s immune system could overreact in what’s known as a cytokine storm, which can cause flu-like symptoms, low blood pressure and organ damage.   “There are risks for immune-related side effects, which could be serious,” he said.

Common side effects associated with Amtagvi can include abnormally fast heart rate, fluid buildup, rash, hair loss and feeling short of breath, the FDA said.

Those side effects can be managed, said Dr. Steven Rosenberg, chief of the surgery branch at the National Cancer Institute. “They’re a small price to pay for a growing cancer that would otherwise be lethal.”

Overall, Dahut said the approval of TIL therapy is “meaningful.”

“What’s nice about this is that patients will receive a wide variety of tumor fighting lymphocytes that will be able to have the capacity to overcome resistance and actually be a living therapy over time, too, to target additional cancer cells should they develop,” Dahut said.

In addition to melanoma, Dahut said that TIL therapy is most likely to be useful in cancers that respond to drugs that “take the brakes off the immune system,” called checkpoint inhibitors .

“Those would be things like non-small cell lung cancer, kidney cancer, maybe bladder cancer, that we know are responsive to immune-based therapies to begin with,” he said. “Many of those patients relapse, so another immune-based therapy that works in a different way, seems to me, the most likely way for this to be effective.”

Much more research is needed, and it may be years before TIL therapy is approved for other types of cancer.

One of Iovance’s clinical trials investigating TIL therapy for non-small cell lung cancer was forced to pause when a participant died. While the death is under investigation, the company said it may have been the result of either chemotherapy or interleukin 2 — therapies meant to knock down each patients’ immune system before they can get the reinfusion of their TIL cells. 

The therapy is not expected to work for every metastatic melanoma patient. Clinical trial data that Iovance submitted to the FDA showed that tumors shrank in about a third of patients who received TIL therapy. 

Of those patients, about half saw their tumors shrink for at least one year, Dr. Friedrich Graf Finckenstein, chief medical officer of Iovance Biotherapeutics. “Some of these patients even had their tumor completely disappear,” he said. 

Another study, conducted in the Netherlands , did a head-to-head analysis of TIL therapy and another form of immunotherapy, called ipilimumab. Twenty percent of the patients who received TIL had complete remissions, compared with 7% of patients who got ipilimumab. Iovance was not involved with the Dutch trial.

The goal of the therapy, Hwu said, “is to get rid of the cancer and have it stay away. These immune cells stay in the body and live in the body for decades.”

The technology has been in development and studied for nearly 40 years. It was Rosenberg who pioneered TIL therapy — first describing how it could shrink melanoma tumors in the New England Journal of Medicine in 1988 .

“I’ve been waiting for a very long time to see this given to patients, because I know that it can cure some patients that have metastatic melanoma that cannot be affected by any other treatment,” Rosenberg said.

It’s worked so far for Dan Bennett, 59, of Clermont, Florida. Bennett was diagnosed with melanoma in 2011 after his daughter noticed a suspicious mole on his neck that had changed color. 

Despite surgery, chemotherapy and radiation, his cancer kept returning. In 2014, his doctors at Moffitt recommended he try TIL therapy.

“At first, we were pretty leery about it because it was unproven,” Bennett said. Ten years later, Bennett is convinced the TIL therapy is the reason he has survived so long with stage 4 melanoma, which usually has a five-year survival rate of 22.5% . 

“I would recommend any experimental drug if it’s your last opportunity,” he said. “You owe it to yourself and your family to do whatever you can to stay alive and to be a productive member of society.”

Buchbinder, the Dana-Faber doctor, was not involved with Iovance’s TIL therapy trial for melanoma, but she is scheduled to begin similar trials with other drugmakers. 

“We literally have patients right now waiting for approval because they are hoping they’ll be able to go on it,” Buchbinder said. “It is definitely a practice-changing therapy.”

Erika Edwards is a health and medical news writer and reporter for NBC News and "TODAY."

Anne Thompson is NBC News’ chief environmental affairs correspondent. 

Marina Kopf is an associate producer with the NBC News Health and Medical Unit.

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Cancer research highlights from 2023

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By Mayo Clinic staff

Researchers at Mayo Clinic Comprehensive Cancer Center spent 2023 studying the biology of cancer and new ways to predict, prevent, diagnose and treat the disease. Their discoveries are creating hope and transforming the quality of life for people with cancer today and in the future. Here are some highlights from their research over the past year:

Mayo Clinic researchers link ovarian cancer to bacteria colonization in the microbiome.

A specific colonization of microbes in the reproductive tract is commonly found in people with ovarian cancer, according to a study from the Mayo Clinic  Center for Individualized Medicine . Published in  Scientific Reports  and led by  Marina Walther-Antonio, Ph.D. , a Mayo Clinic researcher, and Abigail Asangba, Ph.D., the discovery strengthens the evidence that the bacterial component of the microbiome — a community of microorganisms that also consists of viruses, yeasts and fungi — is an important indicator for early detection, diagnosis and prognosis of ovarian cancer . The study also suggests that a higher accumulation of pathogenic microbes plays a role in treatment outcomes and could be a potential indicator for predicting a patient's prognosis and response to therapy.  Read more .

Artificial intelligence is forging a new future for colorectal cancer and other digestive system diseases.

Colonoscopy remains the gold standard in detecting and preventing colorectal cancer , but the procedure has limitations. Some studies suggest that more than half of post-colonoscopy colon cancer cases arise from lesions missed at patients' previous colonoscopies. In 2022, Michael Wallace, M.D. , a Mayo Clinic gastroenterologist, published the results  of an international, multicenter study testing the impact of adding artificial intelligence (AI) to routine colonoscopies. His team, including James East, M.D. , a Mayo Clinic gastroenterologist, and other researchers from the U.S., the U.K., Italy, Germany and Ireland, found that incorporating AI into colonoscopies reduced the risk of missing polyps by 50%.  Read more .

A big step forward: Bringing DNA sequencing data to routine patient care.

The Tapestry study , an extensive genomic sequencing clinical research study, aims to complete exome sequencing (sequencing the protein-coding regions of a genome) for 100,000 Mayo Clinic patients. The results will be integrated into patients’ electronic health records for three hereditary conditions, and the amassed data will contribute to a research dataset stored within the Mayo Clinic Cloud on the Omics Data Platform. The overall hope of Tapestry is to accelerate discoveries in individualized medicine to tailor prevention, diagnosis and treatment to a patient's unique genetic makeup. It is poised to advance evidence that exome sequencing, when applied to a diverse and comprehensive general population, can proficiently identify carriers of genetic variants that put them at higher risk for a disease, allowing them to take preventive measures.  Read more .

Patients with multiple tumors in one breast may not need a mastectomy.

Patients who have multiple tumors in one breast may be able to avoid a mastectomy if surgeons can remove the tumors while leaving enough breast tissue, according to research led by the  Alliance in Clinical Trials in Oncology  and  Mayo Clinic Comprehensive Cancer Center . Patients would receive breast-conserving therapy — a  lumpectomy  followed by whole-breast  radiation therapy — rather than mastectomy . The study is published in the  Journal of Clinical Oncology . Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, says  Judy Boughey, M.D. , lead author, Mayo Clinic breast surgical oncologist and the W.H. Odell Professor of Individualized Medicine. Read more .

Staging pancreatic cancer early with minimally invasive surgery shows positive results in patient prognosis.

A study published in the  Journal of the American College of Surgeons  reveals that performing a minor surgical procedure on patients newly diagnosed with  pancreatic cancer  helps to identify cancer spread early and determine the stage of cancer. The researchers add that the surgery ideally should be performed before the patient begins chemotherapy. "This is an important study because it supports that staging laparoscopy may help determine a patient's prognosis and better inform treatment so that patients avoid unhelpful or potentially harmful surgical therapy," says  Mark Truty, M.D. , a Mayo Clinic surgical oncologist who led the research.  Read more .

Mayo Clinic study reveals proton beam therapy may shorten breast cancer treatment.

In a trial published in  The Lancet Oncology , Mayo Clinic Comprehensive Cancer Center researchers uncovered evidence supporting a shorter treatment time for people with breast cancer . The study compared two separate dosing schedules of pencil-beam scanning proton therapy , known for its precision in targeting cancer cells while preserving healthy tissue to reduce the risk of side effects. The investigators found that both 25-day and 15-day proton therapy schedules resulted in excellent cancer control while sparing surrounding non-cancerous tissue. Further, complication rates were comparable between the two study groups. "We can now consider the option of 15 days of therapy for patients based on the similar treatment outcomes observed," says  Robert Mutter, M.D. , a Mayo Clinic radiation oncologist and physician-scientist. Read more .

Harnessing the immune system to fight ovarian cancer.

Mayo Clinic research is biomanufacturing an experimental, cell-based ovarian cancer vaccine and combining it with immunotherapy to study a "one-two punch" approach to halting ovarian cancer progression. This research begins with a blood draw from people with advanced  ovarian cancer  whose tumors have returned after standard surgery and chemotherapy. White blood cells are extracted from the blood, biomanufactured to become dendritic cells and returned to the patient. Dendritic cells act as crusaders that march through the body, triggering the immune system to recognize and fight cancer. "We're building on an earlier phase 1 clinical trial  that showed promising results  in terms of survival after the dendritic cell-based vaccine," says  Matthew Block, M.D., Ph.D. , co-principal investigator and Mayo Clinic medical oncologist. "Of the 18 evaluable patients in the phase 1 study, 11 had cancer return, but seven of them — 40% — have been cancer-free for almost 10 years. We typically expect 90% of patients in this condition to have the cancer return."  Read more .

New gene markers detect Lynch syndrome-associated colorectal cancer.

Researchers from Mayo Clinic Comprehensive Cancer Center and Mayo Clinic Center for Individualized Medicine have discovered new genetic markers to identify Lynch syndrome-associated colorectal cancer with high accuracy. Studies are underway to determine if these genetic markers are in stool samples and, if so, how this could lead to a non-invasive screening option for people with  Lynch syndrome . The research was published in Cancer Prevention Research , a journal of the American Association for Cancer Research. "This is an exciting finding that brings us closer to the reality that clinicians may soon be able to offer a non-invasive cancer screening option to patients with the highest risk of getting cancer," says  Jewel Samadder, M.D. , co-lead author of the paper and a Mayo Clinic gastroenterologist. Read more .

Mayo Clinic prepares to biomanufacture a new CAR-T cell therapy for B-cell blood cancers.

Mayo Clinic research has developed a new type of  chimeric antigen receptor-T cell therapy (CAR-T cell therapy)  aimed at killing B-cell blood cancers that have returned and are no longer responding to treatment. This pioneering technology, designed and developed in the lab of  Hong Qin, M.D., Ph.D. , a Mayo Clinic cancer researcher, killed B-cell tumors grown in the laboratory and tumors implanted in mouse models. The preclinical findings are published in  Cancer Immunology, Immunotherapy . "This study shows our experimental CAR-T cell therapy targets several blood cancers, specifically chronic lymphocytic leukemia," says Dr. Qin. "Currently, there are six different CAR-T cell therapies approved for treatment of relapsed blood cancers. While the results are impressive, not everyone responds to this treatment. Our goal is to provide novel cell therapies shaped to each patient's individual need."  Read more .

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AACR Cancer Progress Report Details Exciting Advances in Cancer Research and Treatment

Report includes call to action outlining steps congress must take to maintain momentum against cancer for all patients.

PHILADELPHIA – Today, the American Association for Cancer Research (AACR) released the 13th edition of its annual Cancer Progress Report , which chronicles how basic, translational, and clinical cancer research and cancer-related population sciences—primarily supported by federal investments in the National Institutes of Health (NIH) and the National Cancer Institute (NCI)—remain vitally important to improving health and saving lives.

In addition to providing the latest statistics on cancer incidence, mortality, and survivorship, the AACR Cancer Progress Report 2023 offers detailed updates and important context regarding the latest research in cancer etiology, early detection, diagnosis, treatment, prevention, and survivorship. Throughout the report, the personal stories of patients who have benefited from innovative, recently approved anticancer therapeutics highlight the real-world impact of cancer research.

This comprehensive report also features a spotlight on cancer immunotherapy and addresses persistent challenges in cancer research, including cancer disparities, slow progress against certain types of cancer, and the physical, psychosocial, and financial hardships faced by cancer patients, survivors, and their caregivers. A closing call to action outlines steps Congress and other stakeholders must take to ensure that the U.S. maintains its momentum against cancer for the benefit of all patients.

“The advances in cancer research, particularly in the last two decades, have been breathtaking,” said AACR President Philip Greenberg, MD, FAACR, faculty member at Fred Hutchinson Cancer Center. “We are in an era of unparalleled opportunity to make even more breakthroughs for patients. For the cancer research community to achieve these breakthroughs, however, our representatives in Congress must continue to prioritize funding for biomedical research, from basic research to clinical trials. Through the AACR Cancer Progress Report 2023 , we are sharing with the public and policy makers the progress that has been made, how that progress has been delivered to patients, how it’s changed people’s lives, and the unparalleled opportunities that now exist from scientific and technologic advances, so they understand how crucial it is that we maintain this momentum through continued support of NIH and NCI.”

PROMISING TRENDS AND ADVANCES IN CANCER CARE

The medical research community—including researchers in academia and industry, physician-scientists, patient advocates, regulators, and many other stakeholders—has maintained impressive momentum against cancer in recent years. As outlined in the AACR Cancer Progress Report 2023 :

• A new gene therapy-based immunotherapeutic for certain patients with bladder cancer
• A first-in-class antibody drug conjugate for patients with ovarian cancer
• Four new T-cell engaging bispecific antibodies for a range of hematologic malignancies
• The first approval of an immune checkpoint inhibitor for pediatric and adult patients with a rare form of sarcoma
• Due in large part to advances in prevention, early detection, and treatment, the age-adjusted overall cancer death rate in the U.S. fell by 33% between 1991 and 2020— an estimated 3.8 million cancer deaths averted .
• Breast cancer mortality declined by 43% between 1989 and 2020 , leading to an estimated 460,000 fewer breast cancer deaths.
• The decrease in lung cancer mortality has accelerated from 0.9% a year between 1995 and 2005 to nearly 5% a year between 2014 and 2020. This rapid decline is the result of a steep reduction in the U.S. smoking rate as well as the development of numerous highly effective molecularly targeted therapeutics and immunotherapeutics.
• More and better treatment options have led to notable progress against many pediatric cancers as well. Among children (14 and younger) and adolescents (15-19), overall cancer death rates declined by 70% and 64%, respectively, between 1970 and 2020.

THE IMMUNOTHERAPY REVOLUTION

Immunotherapy has revolutionized cancer care. Breakthroughs in this field have contributed to much of the progress noted above, such as declines in the death rates for previously intractable cancers like advanced lung cancer and melanoma. The AACR Cancer Progress Report 2023 contains a spotlight on the history of cancer immunotherapy, the current state of this treatment modality, and the immense promise of the next generation of immunotherapeutics. Highlights include:

• Since 2011, the FDA has approved 11 immune checkpoint inhibitors , which release “brakes” on the surface of certain immune cells—called T cells—so that the T cells are able to destroy cancer cells. Many of these drugs are approved for more than one type of cancer, making immune checkpoint inhibitors a treatment option for 20 cancer types and any tumor with certain specific molecular characteristics.
• Since 2017, the FDA has approved six CAR T-cell therapies to treat a range of hematologic malignancies. CAR T-cell therapy is a type of adoptive cell therapy, which is designed to dramatically increase the number of cancer-killing immune cells a patient has.
• The field is expanding in exciting ways, with researchers combining the power of other cells in the immune system with recent advances in gene editing to develop more personalized and effective versions of adoptive cell therapy for treatment of solid tumors; developing mRNA-based vaccines and therapeutics to treat cancer; and targeting the gut microbiome to increase the efficacy of cancer immunotherapy, among many other innovative approaches.

DESPITE PROGRESS, CHALLENGES PERSIST

Despite the extraordinary scientific progress against cancer in recent years, this complex disease remains a significant threat to human health around the world. In the U.S., it is estimated that nearly 2 million new cases of cancer will be diagnosed and more than 609,000 people will die from the disease in 2023.

Indeed, cancer research and patient care face numerous challenges, as outlined in the AACR Cancer Progress Report 2023 :

• Cancer disparities are a pervasive public health problem, with racial and ethnic minorities and other medically underserved U.S. populations shouldering a disproportionally higher burden of cancer. While advances have been made in identifying, understanding, and addressing some of these disparities, more research and policy solutions are urgently needed to ensure equitable progress against cancer.
• There has been uneven progress against different cancer types. Few treatment options exist for patients diagnosed with pancreatic cancer or glioblastoma, for example, and 5-year relative survival rates for these cancers are extremely low.
• Incidence rates for some cancers are increasing, including for early-onset colorectal cancer, pancreatic cancer, and uterine cancer, in part due to the rising rate of obesity.
• Financial toxicity is widespread, exacerbated by the rising cost of cancer care. In 2019, U.S. cancer patients paid an estimated $16.2 billion in out-of-pocket cancer care costs and lost an additional $5 billion in “time costs.”

FEDERAL FUNDING ESSENTIAL FOR CONTINUED PROGRESS

To confront these and other challenges, the AACR Cancer Progress Report 2023 calls on Congress to support robust, sustained, and predictable annual funding growth for NIH and NCI by providing increases of at least $3.465 billion and $2.6 billion, respectively, in their fiscal year 2024 base budgets. This funding is crucial to continued progress for patients. From 2010 to 2019, NIH funding contributed to the development of 354 out of 356 new drugs, including many cancer drugs, approved by the FDA.

The AACR also urges Congress to:

• Provide $1.7 billion in dedicated funding for Cancer Moonshot activities in FY 2024 across NCI, FDA, and Centers for Disease Control and Prevention (CDC) with the assurance that Moonshot funding will supplement rather than supplant NIH funding in FY 2024.
• Appropriate at least $472.4 million in FY 2024 appropriations for the CDC Division of Cancer Prevention to support comprehensive cancer control, central cancer registries, and screening and awareness programs for specific cancers.
• Allocate $50 million in funding for the Oncology Center of Excellence at FDA in FY 2024 to allow regulators with the capable staff and necessary tools to conduct expedited review of cancer-related medical products.

“We are proud to release the 13 th annual AACR Cancer Progress Report ,” said AACR CEO Margaret Foti, PhD, MD (hc). “It is our hope that this comprehensive resource will help to increase knowledge about the myriad diseases we call cancer as well as the innovative research that is improving and extending lives. The findings in this report, along with the personal stories of the featured patients, underscore the enormous impact that robust, sustained, and predictable funding for cancer research has had on Americans’ health, and why that support must continue.”

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10 new breakthroughs in the fight against cancer

Medical advances are continuing to help the world fight cancer. Image:  Unsplash/National Cancer Institute

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This article was originally published in May 2022, and most recently updated in January 2024 .

• Cancer is one of the world’s biggest killers, with around 10 million deaths per year due to the disease.
• Scientists are using artificial intelligence, DNA sequencing, precision oncology and other technologies to improve treatment and diagnosis.
• The Centre for the Fourth Industrial Revolution India, a collaboration with the World Economic Forum, hopes to accelerate 18 cancer interventions.

Cancer kills around 10 million people a year and is a leading cause of death globally, according to the World Health Organization.

Breast, lung and colon cancer are among the most common. Death rates from cancer were falling before the pandemic . But COVID-19 caused a big backlog in diagnosis and treatment .

There is some good news, however. Medical advances are accelerating the battle against cancer. Here are 10 recent developments.

Test to identify 18 early-stage cancers

Researchers in the US have developed a test they say can identify 18 early-stage cancers. Instead of the usual invasive and costly methods, Novelna's test works by analyzing a patient's blood protein. In a screening of 440 people already diagnosed with cancer, the test correctly identified 93% of stage 1 cancers in men and 84% in women. The researchers believe the findings "pave the way for a cost-effective, highly accurate, multi-cancer screening test that can be implemented on a population-wide scale". It's early days, however. With such a small sample screening and a lack of information on co-existing conditions, the test is currently more of "a starting point for developing a new generation of screening tests for the early detection of cancer".

The seven-minute cancer treatment jab

England's National Health Service (NHS) is to be the first in the world to make use of a cancer treatment injection , which takes just seven minutes to administer, rather than the current time of up to an hour to have the same drug via intravenous infusion. This will not only speed up the treatment process for patients, but also free up time for medical professionals. The drug, Atezolizumab or Tecentriq, treats cancers including lung and breast, and it's expected most of the 3,600 NHS patients in England currently receiving it intravenously will now switch to the jab.

Precision oncology

Precision oncology is the “ best new weapon to defeat cancer ”, the chief executive of Genetron Health, Sizhen Wang, says in a blog for the World Economic Forum. This involves studying the genetic makeup and molecular characteristics of cancer tumours in individual patients. The precision oncology approach identifies changes in cells that might be causing the cancer to grow and spread. Personalized treatments can then be developed. The 100,000 Genomes Project, a National Health Service initiative, studied more than 13,000 tumour samples from UK cancer patients , successfully integrating genomic data to more accurately pin-point effective treatment. Because precision oncology treatments are targeted – as opposed to general treatments like chemotherapy – it can mean less harm to healthy cells and fewer side effects as a result.

Artificial intelligence fights cancer

In India, World Economic Forum partners are using emerging technologies like artificial intelligence (AI) and machine learning to transform cancer care. For example, AI-based risk profiling can help screen for common cancers like breast cancer, leading to early diagnosis. AI technology can also be used to analyze X-rays to identify cancers in places where imaging experts might not be available. These are two of 18 cancer interventions that The Centre for the Fourth Industrial Revolution India, a collaboration with the Forum , hopes to accelerate.

Greater prediction capabilities

Lung cancer kills more people in the US yearly than the next three deadliest cancers combined. It's notoriously hard to detect the early stages of the disease with X-rays and scans alone. However, MIT scientists have developed an AI learning model to predict a person's likelihood of developing lung cancer up to six years in advance via a low-dose CT scan. Trained using complex imaging data, 'Sybil' can forecast both short- and long-term lung cancer risk, according to a recent study. "We found that while we as humans couldn't quite see where the cancer was, the model could still have some predictive power as to which lung would eventually develop cancer," said co-author Jeremy Wohlwend.

Clues in the DNA of cancer

At Cambridge University Hospitals in England, the DNA of cancer tumours from 12,000 patients is revealing new clues about the causes of cancer, scientists say. By analyzing genomic data, oncologists are identifying different mutations that have contributed to each person’s cancer. For example, exposure to smoking or UV light, or internal malfunctions in cells. These are like “fingerprints in a crime scene”, the scientists say – and more of them are being found. “We uncovered 58 new mutational signatures and broadened our knowledge of cancer,” says study author Dr Andrea Degasperi, from Cambridge’s Department of Oncology.

Liquid and synthetic biopsies

Biopsies are the main way doctors diagnose cancer – but the process is invasive and involves removing a section of tissue from the body, sometimes surgically, so it can be examined in a laboratory. Liquid biopsies are an easier and less invasive solution where blood samples can be tested for signs of cancer. Synthetic biopsies are another innovation that can force cancer cells to reveal themselves during the earliest stages of the disease.

The application of “precision medicine” to save and improve lives relies on good-quality, easily-accessible data on everything from our DNA to lifestyle and environmental factors. The opposite to a one-size-fits-all healthcare system, it has vast, untapped potential to transform the treatment and prediction of rare diseases—and disease in general.

But there is no global governance framework for such data and no common data portal. This is a problem that contributes to the premature deaths of hundreds of millions of rare-disease patients worldwide.

The World Economic Forum’s Breaking Barriers to Health Data Governance initiative is focused on creating, testing and growing a framework to support effective and responsible access – across borders – to sensitive health data for the treatment and diagnosis of rare diseases.

The data will be shared via a “federated data system”: a decentralized approach that allows different institutions to access each other’s data without that data ever leaving the organization it originated from. This is done via an application programming interface and strikes a balance between simply pooling data (posing security concerns) and limiting access completely.

The project is a collaboration between entities in the UK (Genomics England), Australia (Australian Genomics Health Alliance), Canada (Genomics4RD), and the US (Intermountain Healthcare).

CAR-T-cell therapy

A treatment that makes immune cells hunt down and kill cancer cells was recently declared a success for leukaemia patients. The treatment, called CAR-T-cell therapy, involves removing and genetically altering immune cells, called T cells, from cancer patients. The altered cells then produce proteins called chimeric antigen receptors (CARs). These recognize and can destroy cancer cells. In the journal Nature, scientists at the University of Pennsylvania announced that two of the first people treated with CAR-T-cell therapy were still in remission 12 years on.

Fighting pancreatic cancer

Pancreatic cancer is one of the deadliest cancers. It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years. At the University of California San Diego School of Medicine, scientists developed a test that identified 95% of early pancreatic cancers in a study. The research, published in Nature Communications Medicine , explains how biomarkers in extracellular vesicles – particles that regulate communication between cells – were used to detect pancreatic, ovarian and bladder cancer at stages I and II.

Have you read?

Cancer: how to stop the next global health crisis, how to improve access to cancer medicines in low and middle-income countries, why is cancer becoming more common among millennials, a tablet to cut breast cancer risk.

A drug that could halve the chance of women developing breast cancer is being tested out by England's National Health Service (NHS). It will be made available to almost 300,000 women seen as being at most risk of developing breast cancer, which is the most common type of cancer in the UK . The drug, named anastrozole, cuts the level of oestrogen women produce by blocking the enzyme aromatase . It has already been used for many years as a breast cancer treatment but has now been repurposed as a preventive medicine. “This is the first drug to be repurposed through a world-leading new programme to help us realize the full potential of existing medicines in new uses to save and improve more lives on the NHS," says NHS Chief Executive Amanda Pritchard.

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Unlocking mRNA’s cancer-fighting potential

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What if training your immune system to attack cancer cells was as easy as training it to fight Covid-19? Many people believe the technology behind some Covid-19 vaccines, messenger RNA, holds great promise for stimulating immune responses to cancer.

But using messenger RNA, or mRNA, to get the immune system to mount a prolonged and aggressive attack on cancer cells — while leaving healthy cells alone — has been a major challenge.

The MIT spinout Strand Therapeutics is attempting to solve that problem with an advanced class of mRNA molecules that are designed to sense what type of cells they encounter in the body and to express therapeutic proteins only once they have entered diseased cells.

“It’s about finding ways to deal with the signal-to-noise ratio, the signal being expression in the target tissue and the noise being expression in the non-target tissue,” Strand CEO Jacob Becraft PhD ’19 explains. “Our technology amplifies the signal to express more proteins for longer while at the same time effectively eliminating the mRNA’s off-target expression.”

Strand is set to begin its first clinical trial in April, which is testing a self-replicating mRNA molecule’s ability to express immune signals directly from a tumor, triggering the immune system to attack and kill the tumor cells directly. It’s also being tested as a possible improvement for existing treatments to a number of solid tumors.

As they work to commercialize its early innovations, Strand’s team is continuing to add capabilities to what it calls its “programmable medicines,” improving mRNA molecules’ ability to sense their environment and generate potent, targeted responses where they’re needed most.

“Self-replicating mRNA was the first thing that we pioneered when we were at MIT and in the first couple years at Strand,” Becraft says. “Now we’ve also moved into approaches like circular mRNAs, which allow each molecule of mRNA to express more of a protein for longer, potentially for weeks at a time. And the bigger our cell-type specific datasets become, the better we are at differentiating cell types, which makes these molecules so targeted we can have a higher level of safety at higher doses and create stronger treatments.”

Making mRNA smarter

Becraft got his first taste of MIT as an undergraduate at the University of Illinois when he secured a summer internship in the lab of MIT Institute Professor Bob Langer.

“That’s where I learned how lab research could be translated into spinout companies,” Becraft recalls.

The experience left enough of an impression on Becraft that he returned to MIT the next fall to earn his PhD, where he worked in the Synthetic Biology Center under professor of bioengineering and electrical engineering and computer science Ron Weiss. During that time, he collaborated with postdoc Tasuku Kitada to create genetic “switches” that could control protein expression in cells.

Becraft and Kitada realized their research could be the foundation of a company around 2017 and started spending time in the Martin Trust Center for MIT Entrepreneurship. They also received support from MIT Sandbox and eventually worked with the Technology Licensing Office to establish Strand’s early intellectual property.

“We started by asking, where is the highest unmet need that also allows us to prove out the thesis of this technology? And where will this approach have therapeutic relevance that is a quantum leap forward from what anyone else is doing?” Becraft says. “The first place we looked was oncology.”

People have been working on cancer immunotherapy, which turns a patient’s immune system against cancer cells, for decades. Scientists in the field have developed drugs that produce some remarkable results in patients with aggressive, late-stage cancers. But most next-generation cancer immunotherapies are based on recombinant (lab-made) proteins that are difficult to deliver to specific targets in the body and don’t remain active for long enough to consistently create a durable response.

More recently, companies like Moderna, whose founders also include MIT alumni , have pioneered the use of mRNAs to create proteins in cells. But to date, those mRNA molecules have not been able to change behavior based on the type of cells they enter, and don’t last for very long in the body.

“If you’re trying to engage the immune system with a tumor cell, the mRNA needs to be expressing from the tumor cell itself, and it needs to be expressing over a long period of time,” Becraft says. “Those challenges are hard to overcome with the first generation of mRNA technologies.”

Strand has developed what it calls the world’s first mRNA programming language that allows the company to specify the tissues its mRNAs express proteins in.

“We built a database that says, ‘Here are all of the different cells that the mRNA could be delivered to, and here are all of their microRNA signatures,’ and then we use computational tools and machine learning to differentiate the cells,” Becraft explains. “For instance, I need to make sure that the messenger RNA turns off when it's in the liver cell, and I need to make sure that it turns on when it's in a tumor cell or a T-cell.”

Strand also uses techniques like mRNA self-replication to create more durable protein expression and immune responses.

“The first versions of mRNA therapeutics, like the Covid-19 vaccines, just recapitulate how our body’s natural mRNAs work,” Becraft explains. “Natural mRNAs last for a few days, maybe less, and they express a single protein. They have no context-dependent actions. That means wherever the mRNA is delivered, it’s only going to express a molecule for a short period of time. That’s perfect for a vaccine, but it’s much more limiting when you want to create a protein that’s actually engaging in a biological process, like activating an immune response against a tumor that could take many days or weeks.”

Technology with broad potential

Strand’s first clinical trial is targeting solid tumors like melanoma and triple-negative breast cancer. The company is also actively developing mRNA therapies that could be used to treat blood cancers.

“We’ll be expanding into new areas as we continue to de-risk the translation of the science and create new technologies,” Becraft says.

Strand plans to partner with large pharmaceutical companies as well as investors to continue developing drugs. Further down the line, the founders believe future versions of its mRNA therapies could be used to treat a broad range of diseases.

“Our thesis is: amplified expression in specific, programmed target cells for long periods of time,” Becraft says. “That approach can be utilized for [immunotherapies like] CAR T-cell therapy, both in oncology and autoimmune conditions. There are also many diseases that require cell-type specific delivery and expression of proteins in treatment, everything from kidney disease to types of liver disease. We can envision our technology being used for all of that.”

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Cancer signs could be spotted years before symptoms, says new research institute

Tests that can identify early changes in cells would give doctors more time to offer treatment, say Cambridge researchers

Scientists at a recently opened cancer institute at Cambridge University have begun work that is pinpointing changes in cells many years before they develop into tumours. The research should help design radically new ways to treat cancer, they say.

The Early Cancer Institute – which has just received £11m from an anonymous donor – is focused on finding ways to tackle tumours before they produce symptoms. The research will exploit recent discoveries which have shown that many people develop precancerous conditions that lie in abeyance for long periods.

“The latency for a cancer to develop can go on for years, sometimes for a decade or two, before the condition abruptly manifests itself to patients,” said Prof Rebecca Fitzgerald, the institute’s director.

“Then doctors find they are struggling to treat a tumour which, by then, has spread through a patient’s body. We need a different approach, one that can detect a person at risk of cancer early on using tests that can be given to large numbers of people.”

One example of this is the cytosponge – a sponge on a string – which has been developed by Fitzgerald and her team. It is swallowed like a pill, expands in the stomach into a sponge and is then pulled up the gullet collecting oesophagus cells on the way. Those cells that contain a protein, called TFF3 – which is found only in precancerous cells – then provide an early warning that a patient is at risk of oesophageal cancer and needs to be monitored. Crucially, this test can be administered simply and on a wide scale.

This contrasts with current approaches to other cancers, added Fitzgerald. “At present, we are detecting many cancers late and are having to come up with medicines, which have become incrementally more expensive. We are often extending life by a few weeks at a cost of tens of thousands of pounds. We need to look at this from a different perspective.”

One approach being taken by the institute – which is to be renamed the Li Ka-shing Early Cancer Institute after the Hong Kong philanthropist who has supported other Cambridge cancer research – focuses on blood samples. Provided by women as part of past screening services for ovarian cancer and kept in special stores, these samples have now been repurposed by the institute. “We have around 200,000 such samples and they are a goldmine,” said Jamie Blundell, a research group leader at the institute.

Using these samples, researchers have identified changes that differentiate those donors who have subsequently been diagnosed with a blood cancer 10 or even 20 years after they provided samples, with those who did not develop such conditions.

“We are finding that there are clear genetic changes in a person’s blood more than a decade before they start to display symptoms of leukaemia,” said Blundell. “That shows there is a long window of opportunity that you could use to intervene and give treatments that will reduce the odds of going on to get cancer.”

Cancers grow in stages and by spotting those with cells that have taken an early step on this ladder, it should be possible to block or hamper further developments. The crucial point is that at this early stage there is time for doctors to take action and avoid them having to deal with a cancer at a late stage when it has spread.

A similar strategy is being taken by Harveer Dev, another group leader, who has investigated men who have had their prostates removed. His team are now developing biomarkers that will provide better ways to pinpoint those who are likely to suffer poor outcomes from prostate cancer, one of the most common tumours in the UK.

“Our pilot data suggests that these tests may be much better than existing PSA tests and will be crucial in spotting those who with prostate cancer that is likely to progress,” said Dev.

Pinpointing those at risk of cancer – for example, people from families who have an inherited predisposition to tumours – will form a key part of the institute’s strategy. In addition, it will focus on finding ways to reduce cancer risks, as well as ensuring treatments can be widely administered.

A woman had, in her 80s, decided to leave the university £1m for cancer research, Fitzgerald said. “However, she lived until she was over 100 and only died recently, so we only just got that donation. We want to understand what makes some live into very old age while others get cancer, so more people can live as long as she did.”

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Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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One in five people with cancer participate in medical research studies

by Fred Hutchinson Cancer Center

Researchers from Fred Hutchinson Cancer Center, the American Cancer Society Cancer Action Network and peer institutions released new findings in the Journal of Clinical Oncology showing that when all types of cancer research studies are considered, at least one in five people with cancer, or 21.9%, participate in some form of clinical research.

The study evaluated all categories of cancer studies, such as treatment trials, biorepository studies and quality of life studies—the first time an estimate of participation in all types of cancer studies has been reported. Moreover, enrollment in cancer treatment trials was 7.1%, a notably higher participation rate than previous estimates of 2%–3%.

The study also found that enrollment in treatment trials was over five-fold higher at National Cancer Institute-designated cancer centers than at community sites (21.6% versus 4.1%), reflecting the impact that NCI funding for staff and infrastructure has on an institution's ability to offer trials and recruit patients.

Using deidentified accreditation data provided by the Commission on Cancer, the study updated decades-old estimates for participation in cancer research.

This expanded analysis includes more than 70% of people diagnosed with cancer in the U.S. each year who received care at a variety of clinical settings, from community hospitals and academic medical centers to NCI-designated comprehensive cancer centers. Additionally, the study reflects the broad spectrum of cancer research including different study types and those sponsored by industry, government and other sources.

"As we work to increase participation in cancer research studies and make them more accessible to patients, we need an inclusive, accurate assessment of current participation to inform these policies," said Joseph Unger, Ph.D., MS, a health services researcher and biostatistician at Fred Hutch and lead author of the study.

"While we knew that patients play a significant role in advancing all types of cancer research, now we better understand just how commonly people are participating in all types of cancer studies today."

While previous estimates of participation in cancer research studies were derived solely from government-sponsored trials, the study authors used patient data from a diverse range of trial sponsors and care settings for this analysis. Importantly, the data included settings such as community hospitals, where a majority of U.S. cancer patients receive care.

"We know that most patients with cancer will participate in a clinical trial if given the chance, and the level of enrollment we see at NCI-designated cancer centers shows what participation can be when patients are offered trials," stated Mark Fleury, Ph.D., a policy principle at ACS CAN and senior author of the study.

"These findings emphasize the need to offer more patients in community settings the chance to participate and that will require an investment in these sites that currently isn't there."

People with cancer enrolled in many different types of clinical studies. The study found the following participation rates in each type of clinical study: biorepository (12.9%), treatment (7.1%), registry (7.3%), genetic (3.6%), quality-of-life (2.8%), diagnostic (2.5%) and economic studies (2.4%).

Expanding the types of cancer clinical studies in this analysis demonstrates that there are a variety of ways people choose to participate in cancer research beyond the previous assessments, which were based only on participation in treatment studies.

"Cancer clinical research, in all of its forms, simply cannot be conducted without the contributions of people with cancer," emphasized Dr. Unger.

"These contributions are much more extensive than was previously recognized. Cancer clinical research is a true partnership between those with cancer and those who study and treat cancer."

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In the fight against breast cancer, researchers identify malignancy hibernation as the next battleground

Chemical engineers at the university find less than 1% of studies examine the phenomenon.

There is a surprising dearth of research about how breast cancer cells can go dormant, spread and then resurface years or even decades later, according to a new review of in vitro breast cancer studies conducted by researchers at the University of Massachusetts Amherst.

"[Our review found that] less than 1% of all these studies that combine cells with designer environments look at dormancy," says Shelly Peyton, Provost Professor of Chemical Engineering. "It's not enough. We just don't understand what's happening -- and it's killing patients."

Breast cancer dormancy is a phenomenon in which breast cancer cells metastasize -- or spread to different tissue sites throughout the body (typically the liver, lungs, brain or bones) -- but don't grow. "They're not detectable or symptomatic tumors," Peyton explains. "A patient will have their primary tumor removed and appear to be disease-free for months, years, even decades. And for reasons we don't understand, something changes about the environment that causes those cells to start regrowing, and then you have a deadly metastasis."

Patients with metastatic breast cancer have a 30% five-year survival rate, compared to a 99% survival rate for localized breast cancer. "Early detection is key, particularly in the Western world," says Peyton. "You can have lumpectomies, radiation, small surgeries. And women can survive. It's when that cancer has spread that it becomes much harder to treat."

This relapse in distant organs impacts 40% of early-stage breast cancer patients, and breast cancer dormancy is a contributing factor. But while metastasis has known biomarkers, dormant cancer cells are very hard to identify.

"When you have a single dormant breast cancer cell that's hiding in a distant tissue, it's really hard to detect that," says Nate Richbourg, lead author on the paper and postdoctoral researcher in the Peyton Lab. "And you don't want to do an invasive biopsy or prescribe toxic chemotherapy for something that might not be a problem."

With these challenges in mind, the review, published in Science Advances , aimed to identify gaps in the research, particularly focusing on in vitro studies, or research using benchtop-model environments instead of animal models or humans. In vitro studies allow for the precise control of the environment, which Peyton's research group says may play a deciding role in whether a cell remains dormant or reactivates into a deadly metastatic tumor.

"What can we control in these artificial environments that will give us insight into how breast cancer dormancy happens, and what we can do to treat it as well?" Richbourg asks, describing the importance of in vitro modeling. "When we create this artificial dormancy, we can see how many of those cells could turn back into proliferating and potentially deadly cells."

Their review highlights just how complex the role of the environment is. "If you have a [breast cancer] cell somewhere in the bone marrow, you're going to have other cells there, the physical factors in your environment, and the biochemical factors," Richbourg gives as an example. "We try to use reductive models to separate the thing that is influencing this behavior. But what we're seeing is that everything works together to create this breast cancer dormancy effect. The better we can create models that capture all that nuance, the better we're going to be able to understand it."

For Peyton, their work is also a call to action. "The paper is calling out to the field that we need to do more," she says. This includes being more creative with the materials that already exist and developing new materials; identifying ways to model the decades-long progression of dormancy that is impossible to recreate in a single study; and expanding the diversity of cell lines used for research (Richbourg points out that many of the studies they reviewed used the same cell line, MDA-MB-231, derived from one 40-to-50-year-old white woman).

Finally, the researchers have an eye to the ultimate goal: better treatments to save patients. "We see that that there are some clinical trials that are happening that are derived from some of those in vitro models," says Ninette Irakoze, graduate student in the Peyton Lab. "The paper gives hope that, with more development of these in vitro models, eventually we could find treatments to eradicate dormant cancer."

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• Nathan R. Richbourg, Ninette Irakoze, Hyuna Kim, Shelly R. Peyton. Outlook and opportunities for engineered environments of breast cancer dormancy . Science Advances , 2024; 10 (10) DOI: 10.1126/sciadv.adl0165

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Australian of the Year Richard Scolyer 'blown away' by success of radical new brain cancer treatment

World-first clinical trials of a groundbreaking treatment for aggressive brain tumours are likely to begin soon following "fantastic" results in the high-profile case of Australian of the Year, Professor Richard Scolyer.

Professor Scolyer, 57, was diagnosed with glioblastoma IDH wild-type in early June last year and became "patient zero" in a pioneering immunotherapy approach that has produced remarkable results: the tumour has not come back after 10 months.

"I'm blown away," Professor Scolyer tells Australian Story . "This is not what I expected. The average time to recurrence for the nasty type of brain cancer I've got is six months. So, to be out this far is amazing. Amazing."

Now, work is underway developing protocols for the start of clinical trials. If the results of those trials are strong, it could shake-up the current treatment regimen of surgery, chemotherapy and radiation that has not changed in 19 years.

"Hopefully, it'll transform into improved outcomes, not just for me, but for all brain cancer patients," Professor Scolyer says.

Professor Scolyer, a world-leading melanoma pathologist, shares the title of Australian of the Year with his colleague, medical oncologist Professor Georgina Long , for their life-saving work in the treatment of melanoma.

The duo are co-directors of Melanoma Institute Australia, which revolutionised the treatment of the deadly skin cancer by using combination immunotherapy before removing the melanoma.

When Professor Scolyer was diagnosed with the "the worst of the worst" type of brain cancer, Professor Long devised a plan adapting the extensive immunotherapy knowledge from their melanoma work to treat Professor Scolyer's brain cancer.

It was risky, with Professor Scolyer the "guinea pig" for the novel approach. But, given the aggressive brain cancer was going to kill him, Professor Scolyer says it took him "a millisecond to say, 'Yes, this is what I want to do'."

Medical and scientific authorities took a little longer to convince, though, because clinical trials had not been done. Professor Scolyer and his wife, Katie, also a pathologist, lobbied the authorities, emphasising that he was deeply familiar with the science involved and knew the risks. The go-ahead was eventually given.

So, how does it work? Professor Long targeted Professor Scolyer's specific brain tumour with a unique combination immunotherapy that was applied for 12 days before surgery. Professor Scolyer then underwent brain surgery to remove as much of the tumour as possible. He received radiation after the operation and continues to receive immunotherapy and a personalised vaccine.

Professor Long says a scientific paper about Professor Scolyer's treatment is undergoing peer review. "As a scientist and as a clinician, there is an absolute need to make sure that you do things properly and share that information in a peer-reviewed and standardised way," Professor Long says.

She says the release of that paper and the preparation of a clinical trial  protocol, which she is working on with neuro-oncologists from Australia and the US, will trigger important debate in the scientific community.

"The world can look at it, can discuss it, can criticise it, can love parts of it," Professor Long says. "Then we start the foundation of doing things differently and doing new trials in glioblastoma … and it's by doing that that we can develop the right treatments for the right patient, and then eventually they become a standard treatment, just like the current standard for Richard's tumour, which is now nearly 20 years old.

"We want to change that. But to change that, we have to show that this actually works in larger numbers of people."

Professor Long is careful not to put a time frame on the start of trials but says the process is moving as quickly as possible. 

Key findings so far are that if immunotherapies are to be used, they need to be used soon after diagnosis and that different tumours will require different immunotherapies.

Professor Long says some glioblastoma may not need the combination immunotherapy that Professor Scolyer is receiving. Some might need less.

Managing the toxicity of immunotherapies is another area of great interest to medical oncologists. "That can be very difficult and nuanced," Professor Long says. "Richard's been lucky enough to get through 10 months of pretty toxic treatment because of the experience of the team in managing [the delivery of immunotherapy] and [understanding] the nuance of toxicity."

Professor Scolyer's biggest battle since receiving treatment has been controlling seizures, which began in January. They now appear to be under control after "a bit of a journey" to get the right drugs and dosage.

A seizure is what led to his diagnosis. But Professor Scolyer says that even before the most recent encouraging scan, he wasn't worried the onset of more seizures meant the tumour had returned.

"I've had surgery, radiotherapy," Professor Scolyer says. "We well know that complications from that can cause seizures. So, I was comfortable that this is what was happening.

"I guess as time moves on, I'll become more anxious about the chances of it coming back," he says. "I don't feel quite there."

There have been other niggles, such as a cold and sinus issues, but the keen sportsman continues to exercise, recently riding about 450km in the cancer charity bike ride, Tour de Cure.

He made it without incident – unlike in the days before he was named Australian of the Year. At the ceremony, many people were concerned to see scars on his face. Professor Scolyer and Professor Long are keen to emphasise that the scars were not from the therapy but a bike riding accident.

"I stacked my bike a few days before the ceremony," Professor Scolyer says. "Just bad luck. Nothing too serious."

Professor Scolyer's optimistic attitude and willingness to share his progress on social media has garnered thousands of supporters who are barracking for him.

Along with being "incredibly thankful and grateful to my wife, Katie, my whole family, friends and many other colleagues", Professor Scolyer says he has been "blown away by so many people who I don't know who've been so kind and considerate".

Professor Scolyer says he accepts that the tumour is likely to return at some stage but for now, he's getting on with life.

"I can run and do the things I love doing and spending time with my wonderful family and enjoying life as best I can, given the circumstances," he says.

"I'm trying to enjoy life as I'd encourage all people to do: make the most of your life. You never know what's around the corner."

Watch Australian Story's Patient Zero on ABC iview .

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• Jean-Michel Carter

GAS41 modulates ferroptosis by anchoring NRF2 on chromatin

GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.

Oxygen-independent organic photosensitizer with ultralow-power NIR photoexcitation for tumor-specific photodynamic therapy

Conventional photodynamic therapy (PDT) is hindered by oxygen-dependent photosensitization pathways and high-power-density photoexcitation. Here, the authors develop polymer-based organic photosensitizers (PSs) through PS skeleton design and side-chain engineering to allow tumor-specific PDT under oxygen-free conditions using ultralow-power 808 nm photoexcitation.

• Yuanyuan Li

PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes

Blocking the mechanical sensor PIEZO1 in cytotoxic T lymphocytes strengthens their traction forces and augments their cytotoxicity against tumour cells.

• Ruiyang Pang

Generation of synthetic whole-slide image tiles of tumours from RNA-sequencing data via cascaded diffusion models

Cascaded diffusion models can be used to synthesize realistic whole-slide image tiles from latent representations of RNA-sequencing data from human tumours.

• Francisco Carrillo-Perez
• Marija Pizurica
• Olivier Gevaert

Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas

Cancer associated fibroblasts can shape the tumor microenvironment (TME) and modulate immune infiltration. Here the authors characterize the TME in preclinical models of softtissue sarcomas, identifying a subset of “glycolytic” cancer-associated fibroblasts that inhibit cytotoxic T cell infiltration into the tumor parenchyma.

• Marina T. Broz
• Emily Y. Ko
• Jlenia Guarnerio

Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer

TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.

• Yueyuan Zheng
• Yan-Yi Jiang

Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer

The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.

• Ashenafi Bulle
• Kian-Huat Lim

Allele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells

Quantifying the impact of copy-number alterations (CNAs) on gene expression at the subclone level in cancer remains a challenge. Here, the authors develop TreeAlign, a method that integrates sample-matched single-cell DNA and RNA sequencing data to infer the impact of CNAs on subclonal gene expression.

• Marc J. Williams
• Sohrab P. Shah

Transcription–replication conflicts underlie sensitivity to PARP inhibitors

Poly(ADP-ribose) polymerase 1 (PARP1) functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription–replication conflicts, and inhibiting PARP1 enzymatic activity may suffice for treatment efficacy in homologous recombination-deficient settings.

• Michalis Petropoulos
• Angeliki Karamichali
• Thanos D. Halazonetis

Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Hypoxia induces ·NO-dependent hydrogen sulfide (H 2 S) biogenesis by inhibiting the transsulfuration pathway. H 2 S oxidation promotes endothelial cell proliferation to support neovascularization in tissue injury and tumor xenograft models.

• Roshan Kumar
• Victor Vitvitsky
• Ruma Banerjee

A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche

A study reveals that Fusobacterium nucleatum subspecies animalis  is bifurcated into two distinct clades, and shows that only one of these dominates the colorectal cancer niche, probably through increased colonization of the human gastrointestinal tract.

• Martha Zepeda-Rivera
• Samuel S. Minot
• Christopher D. Johnston

The pleiotropic functions of reactive oxygen species in cancer

Papagiannakopoulos and colleagues discuss the roles of reactive oxygen species in cancer and the ways in which redox mechanisms may be exploited for cancer therapy.

• Katherine Wu
• Ahmed Ezat El Zowalaty
• Thales Papagiannakopoulos

Bone marrow inflammation in haematological malignancies

Haematological malignancies are associated with inflammation in the bone marrow. In this Review, the authors discuss how tumour-associated inflammation affects the normal functions of the bone marrow and supports the outgrowth and survival of malignant cells. Moreover, they describe how the inflammatory changes in the bone marrow differ in myeloid and lymphoid malignancies.

• Madelon M. E. de Jong
• Lanpeng Chen

Future direction of total neoadjuvant therapy for locally advanced rectal cancer

In this article, the authors discuss the use of total neoadjuvant therapy for locally advanced rectal cancer. They highlight ongoing trials and discuss future treatment options, including the potential use of multi-omics and artificial intelligence to facilitate treatment selection and prediction of response.

• Yoshinori Kagawa
• J. Joshua Smith
• Takayuki Yoshino

Targeting cuproplasia and cuproptosis in cancer

Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer.

• Daolin Tang
• Guido Kroemer

Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity

In this Review, Meier et al. discuss the molecular mechanisms of necroptosis, delineate how this form of immunogenic cell death activates antitumour immune responses and explore the opportunities and limitations of targeting necroptosis for anticancer therapy.

• Pascal Meier
• Arnaud J. Legrand

The present and future of bispecific antibodies for cancer therapy

Bispecific antibodies (bsAbs) can mediate therapeutic effects beyond those of natural monospecific antibodies. This Review provides an overview of recent developments in the field of bsAbs for cancer therapy and an outlook into next-generation bsAbs in earlier stages of development.

• Christian Klein
• Ulrich Brinkmann
• Roland E. Kontermann

Fungi in cancer

In this Viewpoint article, we asked three scientists working on the cancer mycobiome to provide their opinions on advancements and challenges and what the future holds for this exciting field of cancer research.

• Jessica Galloway-Peña
• Iliyan D. Iliev
• Florencia McAllister

Cancer burden in low-income and middle-income countries

In this Viewpoint, we asked four experts to discuss the increasing burden of cancer in low- and middle-income countries; they explore the changes that are necessary to improve cancer diagnosis, prevention and treatment within these nations.

• Sharmila Anandasabapathy
• Chite Asirwa
• Chemtai Mungo

The mechanisms of nanoparticle delivery to solid tumours

The mechanisms of nanoparticle delivery to solid tumours guide the engineering of nanoparticles for cancer applications. This Review discusses two contrasting nanoparticle delivery mechanisms, the enhanced permeability and retention effect and the active transport and retention principle, and their implications for the design of cancer nanomedicines.

• Luan N. M. Nguyen
• Warren C. W. Chan

Dendritic cells as orchestrators of anticancer immunity and immunotherapy

Dendritic cells (DCs) are antigen-presenting cells that function at the interface between innate and adaptive immunity, thereby acting as key mediators of antitumour immune responses and immunotherapy efficacy. In this Review, the authors outline the emerging complexity of intratumoural DC states that is being revealed through single-cell analyses as well as the contributions of different DC subsets to anticancer immunity and the activity of immune-checkpoint inhibitors. The authors also discuss advances in the development of DC-based cancer therapies and considerations for their potential combination with other anticancer therapies.

• Ignacio Heras-Murillo
• Irene Adán-Barrientos
• David Sancho

Molecular profile of bladder cancer progression to clinically aggressive subtypes

In this Review, the authors describe the molecular profile of bladder cancer progression associated with the subtypes of this disease and comment on their potential diagnostic, prognostic and therapeutic importance.

• Charles C. Guo
• Sangkyou Lee
• Bogdan Czerniak

Multiplex protein imaging in tumour biology

In this Review, de Souza et al. discuss how advances in the ability to image protein markers at high-plex, at single-cell and even subcellular resolution, are expanding our understanding of tumour biology and clinical outcomes, and outline the future promise of combining such multiplex protein imaging methods with other forms of spatial omics.

• Natalie de Souza
• Bernd Bodenmiller

The yin and yang of chromosomal instability in prostate cancer

Chromosomal instability is a hallmark of advanced prostate cancer. In this Review, the authors discuss the biological causes and paradoxical consequences of chromosomal instability, its potential clinical role in the stratification of prostate cancer aggressiveness and the development of novel treatment strategies.

• Marc Carceles-Cordon
• Jacob J. Orme
• Veronica Rodriguez-Bravo

Management of patients with muscle-invasive bladder cancer with clinical evidence of pelvic lymph node metastases

Muscle-invasive bladder cancer with clinically positive pelvic lymph nodes is a particular situation at the interface between localized and metastatic disease. In this Review, the authors discuss the advances and challenges of currently available strategies for the diagnosis and treatment of patients with muscle-invasive bladder cancer with clinically positive pelvic lymph nodes.

• Elisabeth Grobet-Jeandin
• Louis Lenfant
• Thomas Seisen

The complex interplay of modifiable risk factors affecting prostate cancer disparities in African American men

African American men are disproportionately affected by prostate cancer in the USA. In this Review, the authors discuss the complex interplay of modifiable risk factors that might underlie the glaring prostate cancer disparities observed.

• Jabril R. Johnson
• Nicole Mavingire
• Rick A. Kittles

Extrachromosomal DNA in cancer

Extrachromosomal DNA (ecDNA) is now accepted as a major contributor to cancer pathogenesis. In this Review, Yan, Mischel and Chang highlight the recent advancements in ecDNA research, providing new insights into the biogenesis and maintenance of ecDNA, as well as its role in altering gene expression and promoting tumour heterogeneity.

• Xiaowei Yan
• Paul Mischel
• Howard Chang

Natural killer cell therapies

This Review explores in detail the complexity of NK cell biology in humans and highlights the role of these cells in cancer immunity.

• Eric Vivier
• Lucas Rebuffet
• Valeria R. Fantin

Clinical and translational attributes of immune-related adverse events

Suijkerbuijk et al. summarize the clinical manifestation and classification of immune-related adverse events, discuss the immunopathogenesis of immune-related adverse events and provide key insights into their management and future therapeutic directions.

• Karijn P. M. Suijkerbuijk
• Mick J. M. van Eijs
• Alexander M. M. Eggermont

Translating p53-based therapies for cancer into the clinic

Although p53 was once considered undruggable, in this Review, Peuget et al. discuss the progress made in targeting p53 as a form of cancer therapy with approaches ranging from restoration of mutant p53 function to inhibition of the negative regulator of p53, MDM2, as well as newer strategies, including p53-based mRNA vaccines and antibodies.

• Sylvain Peuget
• Xiaolei Zhou
• Galina Selivanova

Aneuploidy and complex genomic rearrangements in cancer evolution

Van Loo and colleagues review the mechanistic underpinnings of large genomic alterations and their roles in tumor development and evolution.

• Toby M. Baker
• Peter Van Loo

FLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress

Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.

• Jessica D. Tischler
• Hiroshi Tsuchida
• Richard O. Adeyemi

BRAF — a tumour-agnostic drug target with lineage-specific dependencies

Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAF V600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF -mutant cancers.

• Aphrothiti J. Hanrahan
• David B. Solit

Lipids as mediators of cancer progression and metastasis

Schulze and colleagues discuss the latest advances in understanding the role of lipids in cancer progression and metastasis and reflect on opportunities to target lipid metabolism in tumors.

• Felix C. E. Vogel
• Adriano B. Chaves-Filho
• Almut Schulze

New immune cell engagers for cancer immunotherapy

Immune cell engagers — antibody-based molecules engineered to direct immune effector cells to recognize and kill cancer cells — represent a rapidly expanding approach in cancer therapy. Here, the authors bring us up to date with the targets, challenges and opportunities for harnessing the anticancer activities of T cells, natural killer cells and myeloid cells with immune cell engagers.

• Aurore Fenis
• Olivier Demaria
• Emilie Narni-Mancinelli

Metabolic heterogeneity in cancer

Demicco, Liu et al. discuss how metabolic adaptations in cancer contribute to tumour progression. These adaptations entail high spatial and temporal metabolic heterogeneity, based on local adaptations in different regions of the tumour microenvironment, as well as metabolic evolution over time as the tumour progresses and metastasizes.

• Margherita Demicco
• Xiao-Zheng Liu
• Sarah-Maria Fendt

Metabolic alterations in hereditary and sporadic renal cell carcinoma

Renal cell carcinoma is a metabolic disease linked to a variety of alterations in genes that regulate cellular metabolism. Here, the authors examine cell-intrinsic metabolic alterations in hereditary and sporadic renal cell carcinoma, and how they can be exploited to develop novel therapeutic interventions.

• Nathan J. Coffey
• M. Celeste Simon

News & Commentary

The death gaze of MEDUSA

Chemogenetic profiling can reveal genetic determinants that coordinate phenotypic responses to therapeutics, along with predicting potential pathways of resistance. A new analytical method for evaluating chemogenetic profiles reveals contributions from death-regulatory genes.

• Jesse D. Gelles
• Jerry Edward Chipuk

Mirvetuximab soravtansine has activity in platinum-sensitive epithelial ovarian cancer

• Diana Romero

Enhancing diagnostic precision in liver lesion analysis using a deep learning-based system: opportunities and challenges

A recent study reported the development and validation of the Liver Artificial Intelligence Diagnosis System (LiAIDS), a fully automated system that integrates deep learning for the diagnosis of liver lesions on the basis of contrast-enhanced CT scans and clinical information. This tool improved diagnostic precision, surpassed the accuracy of junior radiologists (and equalled that of senior radiologists) and streamlined patient triage. These advances underscore the potential of artificial intelligence to enhance hepatology care, although challenges to widespread clinical implementation remain.

• Jeong Min Lee
• Jae Seok Bae

IL-13Rα2-targeted CAR T cells show promise in patients with recurrent high-grade gliomas

• David Killock

Cutting-edge CAR-T cancer therapy is now made in India — at one-tenth the cost

The treatment, called NexCAR19, raises hopes that this transformative class of medicine will become more readily available in low- and middle-income countries.

• Smriti Mallapaty

A new standard of care for advanced-stage urothelial carcinoma

• Peter Sidaway

Identification of dynamic microbiota signatures in patients with melanoma receiving ICIs: opportunities and challenges

The composition of the gut microbiota has emerged as a tumour-extrinsic factor that modulates response to immune-checkpoint inhibitors (ICIs), although the lack of consistency in microbiota signatures across studies has limited their value as reliable biomarkers. Herein, we discuss a recent study in which longitudinal microbiome profiling identified several taxa that are persistently enriched in patients with melanoma and a favourable response to ICIs.

• Saman Maleki Vareki
• Diwakar Davar

‘Woah, this is affecting me’: why I’m fighting racial inequality in prostate-cancer research

Olugbenga Samuel Oyeniyi sought a career with a stronger public-health focus after learning that Black men are twice as likely as white men to get prostate cancer.

• Jacqui Thornton

Whittling down the bacterial subspecies that might drive colon cancer

Understanding the factors that drive formation of particular types of cancer can aid efforts to develop better diagnostics or treatments. The identification of a bacterial subspecies with a connection to colon cancer has clinical relevance.

• Cynthia L. Sears
• Jessica Queen

A waste product’s unexpected role in wasting

The mechanisms that drive cancer cachexia are unclear. Adipocyte activation of GPR81 by high levels of lactate is now shown to drive adipose tissue browning, thermogenesis and a loss of body weight in mouse models of cancer.

• Jack D. Sanford
• Marcus D. Goncalves

Why are so many young people getting cancer? What the data say

Clues to a modern mystery could be lurking in information collected generations ago.

• Heidi Ledford

Deadly brain cancer shrinks after CAR-T therapy — but for how long is unclear

Early studies with engineered immune cells show drastic but often short-lived results in glioblastoma, the most aggressive brain cancer.

Mechanisms of melanoma aggressiveness with age

The extracellular matrix is an essential component of the tumor microenvironment and affects cancer progression. Weeraratna and colleagues have now uncovered that age-related reductions in the level of hyaluronan and proteoglycan link protein 1 (HAPLN1) stimulate neoangiogenesis and compromise the vascular integrity of intratumoral blood vessels. These biological modifications converge to fuel distant melanoma metastasis.

• Corine Bertolotto

Engineered T cells call for back-up

• M. Teresa Villanueva

New pathogen on the block

Fu et al. provide data indicating a pathogenic role for Streptococcus anginosus in gastric cancer.

MEGA CRISPR rejuvenates exhausted CAR T cells

MEGA is a new CRISPR-based RNA-editing platform with the ability to enhance the fitness of CAR T cells; it may also overcome certain limitations of conventional DNA-targeting CRISPR–Cas9 systems.

• Karen O’Leary

First cell therapy for solid tumours heads to the clinic: what it means for cancer treatment

Therapy built on tumour-infiltrating lymphocytes is now being prepared for at least 20 people in the United States with advanced melanoma.

• Sara Reardon

FIRSTMAPPP prospectively charts the efficacy of sunitinib for phaeochromocytoma and paraganglioma

Enabling comparative gene regulatory network analysis on single-cell data with SCORPION

We present SCORPION, a computational tool to model gene regulatory networks based on single-cell transcriptomic data and prior knowledge of gene regulation. SCORPION networks can be modeled for specific cell types in individual samples, and are therefore suitable for conducting comparisons between experimental groups.

Improved identification of cancer mutational processes

Mutational signatures help to deconvolve the different processes that shape cancer genomes. A new tool now alleviates some of the persistent challenges in the field.

• Tom L. Kaufmann
• Roland F. Schwarz

Non-inferiority of simple versus radical hysterectomy in low-risk cervical cancer

Personalized cancer care can’t rely on molecular testing alone.

• James Larkin
• Chloe Beland
• Alexander R. Lyon

The future of precision cancer therapy might be to try everything

Researchers are blasting patients’ cancer cells with dozens of drugs in the hope of finding the right treatment.

• Elie Dolgin

Repurposing the dopamine transporter antagonist vanoxerine to treat colorectal cancer

Self-renewing cancer stem cells drive tumor initiation and progression and represent a major target for therapeutic development. A study now shows that vanoxerine, a dopamine transporter antagonist, precisely inhibits this cell population in colorectal cancer, which leads to attenuation of tumor initiation and increased infiltration by immune cells.

• Winnie Chen

Low risk of CAR T cells going rogue

• Maria Papatriantafyllou

Rare CTR9 variants and myeloid malignancies

Selenium abandons selenoproteins to inhibit ferroptosis rapidly

Selenium is usually incorporated into selenoproteins, with important functions in redox regulation. A new study in Nature Metabolism reveals a previously unappreciated role for selenium-based chemical species as direct electron donors to reduce ubiquinone, thus contributing to redox homeostasis by preventing lipid peroxidation.

• Ian G. Chambers
• Rajiv R. Ratan

Melanoma leverages local cues to promote liver-specific metastasis

Using CRISPR–Cas9 screens, we found that cancer-cell-intrinsic loss of Pip4k2c conferred liver-metastatic organotropism in melanoma through hypersensitization to insulin-mediated PI3K–AKT signaling via co-optation of distinct hepatic metabolic cues. Additionally, we showed that combinatorial therapies that abolished physiological and drug-induced changes in glucose and insulin levels specifically reduced liver metastasis.

Mitochondrial DNA mutation enhances sensitivity to immunotherapy in melanoma

Mitochondrial DNA mutations are present in over 50% of all cancers, and truncating mutations in several genes encoding components of complex I of the respiratory chain are most recurrent. We found that these mutations are a source of Warburg-like metabolic shifts that promote a pro-inflammatory immunological state, enhancing sensitivity to checkpoint blockade.

Why we need to rethink how we talk about cancer

Naming metastatic cancers after parts of the body could be holding up research and preventing people from accessing the best treatment

• Lucy Odling-Smee

PD-L2 expression in senescent cancer cells limits tumor clearance after chemotherapy

Senescent cancer cells, which are characteristically present in tumors after genotoxic therapies, upregulate the immune checkpoint ligand programmed cell death 1 ligand 2 (PD-L2). We show that genetic or pharmacological ablation of PD-L2 prevents the accumulation of intratumoral senescent cells, reducing the recruitment of immunosuppressive myeloid cells and facilitating tumor clearance by T cells.

Methods & Protocols

Engineering megabase-sized genomic deletions with MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements)

The authors introduce MACHETE (molecular alteration of chromosomes with engineered tandem elements), a clustered regularly interspaced short palindromic repeats directed Cas9-based system for the efficient deletion of megabase-sized genomic regions.

• Francisco M. Barriga
• Scott W. Lowe

CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction

CONIPHER is a computational framework for accurately inferring subclonal structure and the phylogenetic tree from multisample tumor sequencing, accounting for both copy number alterations and mutation errors.

• Kristiana Grigoriadis
• Ariana Huebner
• Nicholas McGranahan

Robust scoring of selective drug responses for patient-tailored therapy selection

This protocol presents a computational approach to scoring drug sensitivity that integrates multiple dose–response parameters into a single response metric and identifies differences in drug-response patterns between cancer cells and healthy control cells.

• Yingjia Chen
• Tero Aittokallio

INVADEseq to identify cell-adherent or invasive bacteria and the associated host transcriptome at single-cell-level resolution

Invasion–adhesion-directed expression sequencing adapts the 10x Genomics 5′ single-cell RNA sequencing protocol to enable generation of bacterial and eukaryotic DNA libraries to identify adherent or invasive bacteria and the associated host transcriptome at a single-cell level.

• Jorge Luis Galeano Niño
• Susan Bullman

Genome-wide pooled CRISPR screening in neurospheres

The authors present a protocol for genome-wide clustered regularly interspaced short palindromic repeat screening of three-dimensional neurospheres.

• Amy B. Goodale
• David E. Root

Newly diagnosed AML: quizartinib improves OS

Promising results for antisense RNA therapy in mouse models of diffuse midline glioma

• Caroline Barranco

Serum tumour markers for testicular cancer recurrence

The current serum tumour markers α-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase show limited value for testicular cancer relapse detection. A recent study highlights that false-positive elevations in follow-up monitoring are common and, conversely, many patients do not have elevations despite proven relapse. These findings highlight the potential for circulating microRNAs to be used as improved biomarkers for relapse detection.

• Matthew J. Murray
• Cinzia G. Scarpini
• Nicholas Coleman

Stress response in tumor-infiltrating T cells is linked to immunotherapy resistance

A newly composed single-cell transcriptomic atlas of tumor-infiltrating T cells across 16 cancer types revealed previously undescribed T cell states and heterogeneity. A unique T cell stress response state, T STR , was linked to immunotherapy resistance. Our high-resolution T cell reference maps, web portal, and annotation tool can assist efforts to develop T cell therapies.

CD4 + CAR T cells — more than helpers

Therapeutic products containing CD8 + and CD4 + T cells expressing CARs are effective at inducing remission in patients with cancer. How CD4 + CAR T cells contribute to the anti-tumor response has not been well established. A study uses syngeneic models and in vivo imaging to glean mechanistic insights into how CD4 + T cells target tumors.

• M. Eric Kohler
• Terry J. Fry

Venetoclax–obinutuzumab combinations are effective in fit patients with CLL

Taking the temperature of lung cancer antigens

Antigen presentation is fundamental to anti-tumor immunity, but our understanding of the physiological and molecular inputs to the process in different contexts remains limited. Two new studies explore the contribution of cell-intrinsic proteolytic mechanisms and cell-extrinsic hot and cold tumor microenvironments in shaping the antigenic landscape in lung cancer.

• Paul A. Stewart
• Alex M. Jaeger

A skull bone marrow niche for antitumour neutrophils in glioblastoma

A preprint by Lad et al. shows that tumour-associated neutrophils in glioblastoma originate from skull bone marrow and acquire an antigen-presenting cell phenotype intratumorally in the presence of local T cells.

• Austeja Baleviciute

Impaired RNA clearance

In this study, Insco et al. find patient-specific CDK13 mutations to impede RNA surveillance, leading to the accumulation and translation of prematurely terminated RNAs that drive malignancy in melanoma models.

• Gabrielle Brewer

Peptide-mediated CRISPR engineering of cells

An article in Nature Biomedical Engineering reports a simple and hardware-independent peptide-mediated delivery method for the CRISPR-mediated engineering of T cells.

• Nesma El-Sayed Ibrahim

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More Studies by Columbia Cancer Researchers Are Retracted

The studies, pulled because of copied data, illustrate the sluggishness of scientific publishers to address serious errors, experts said.

By Benjamin Mueller

Scientists in a prominent cancer lab at Columbia University have now had four studies retracted and a stern note added to a fifth accusing it of “severe abuse of the scientific publishing system,” the latest fallout from research misconduct allegations recently leveled against several leading cancer scientists.

A scientific sleuth in Britain last year uncovered discrepancies in data published by the Columbia lab, including the reuse of photos and other images across different papers. The New York Times reported last month that a medical journal in 2022 had quietly taken down a stomach cancer study by the researchers after an internal inquiry by the journal found ethics violations.

Despite that study’s removal, the researchers — Dr. Sam Yoon, chief of a cancer surgery division at Columbia University’s medical center, and Changhwan Yoon, a more junior biologist there — continued publishing studies with suspicious data. Since 2008, the two scientists have collaborated with other researchers on 26 articles that the sleuth, Sholto David, publicly flagged for misrepresenting experiments’ results.

One of those articles was retracted last month after The Times asked publishers about the allegations. In recent weeks, medical journals have retracted three additional studies, which described new strategies for treating cancers of the stomach, head and neck. Other labs had cited the articles in roughly 90 papers.

A major scientific publisher also appended a blunt note to the article that it had originally taken down without explanation in 2022. “This reuse (and in part, misrepresentation) of data without appropriate attribution represents a severe abuse of the scientific publishing system,” it said .

Still, those measures addressed only a small fraction of the lab’s suspect papers. Experts said the episode illustrated not only the extent of unreliable research by top labs, but also the tendency of scientific publishers to respond slowly, if at all, to significant problems once they are detected. As a result, other labs keep relying on questionable work as they pour federal research money into studies, allowing errors to accumulate in the scientific record.

“For every one paper that is retracted, there are probably 10 that should be,” said Dr. Ivan Oransky, co-founder of Retraction Watch, which keeps a database of 47,000-plus retracted studies. “Journals are not particularly interested in correcting the record.”

Columbia’s medical center declined to comment on allegations facing Dr. Yoon’s lab. It said the two scientists remained at Columbia and the hospital “is fully committed to upholding the highest standards of ethics and to rigorously maintaining the integrity of our research.”

The lab’s web page was recently taken offline. Columbia declined to say why. Neither Dr. Yoon nor Changhwan Yoon could be reached for comment. (They are not related.)

Memorial Sloan Kettering Cancer Center, where the scientists worked when much of the research was done, is investigating their work.

The Columbia scientists’ retractions come amid growing attention to the suspicious data that undergirds some medical research. Since late February, medical journals have retracted seven papers by scientists at Harvard’s Dana-Farber Cancer Institute . That followed investigations into data problems publicized by Dr. David , an independent molecular biologist who looks for irregularities in published images of cells, tumors and mice, sometimes with help from A.I. software.

The spate of misconduct allegations has drawn attention to the pressures on academic scientists — even those, like Dr. Yoon, who also work as doctors — to produce heaps of research.

Strong images of experiments’ results are often needed for those studies. Publishing them helps scientists win prestigious academic appointments and attract federal research grants that can pay dividends for themselves and their universities.

Dr. Yoon, a robotic surgery specialist noted for his treatment of stomach cancers, has helped bring in nearly $5 million in federal research money over his career.

The latest retractions from his lab included articles from 2020 and 2021 that Dr. David said contained glaring irregularities . Their results appeared to include identical images of tumor-stricken mice, despite those mice supposedly having been subjected to different experiments involving separate treatments and types of cancer cells.

The medical journal Cell Death & Disease retracted two of the latest studies, and Oncogene retracted the third. The journals found that the studies had also reused other images, like identical pictures of constellations of cancer cells.

The studies Dr. David flagged as containing image problems were largely overseen by the more senior Dr. Yoon. Changhwan Yoon, an associate research scientist who has worked alongside Dr. Yoon for a decade, was often a first author, which generally designates the scientist who ran the bulk of the experiments.

Kun Huang, a scientist in China who oversaw one of the recently retracted studies, a 2020 paper that did not include the more senior Dr. Yoon, attributed that study’s problematic sections to Changhwan Yoon. Dr. Huang, who made those comments this month on PubPeer, a website where scientists post about studies, did not respond to an email seeking comment.

But the more senior Dr. Yoon has long been made aware of problems in research he published alongside Changhwan Yoon: The two scientists were notified of the removal in January 2022 of their stomach cancer study that was found to have violated ethics guidelines.

Research misconduct is often pinned on the more junior researchers who conduct experiments. Other scientists, though, assign greater responsibility to the senior researchers who run labs and oversee studies, even as they juggle jobs as doctors or administrators.

“The research world’s coming to realize that with great power comes great responsibility and, in fact, you are responsible not just for what one of your direct reports in the lab has done, but for the environment you create,” Dr. Oransky said.

In their latest public retraction notices, medical journals said that they had lost faith in the results and conclusions. Imaging experts said some irregularities identified by Dr. David bore signs of deliberate manipulation, like flipped or rotated images, while others could have been sloppy copy-and-paste errors.

The little-noticed removal by a journal of the stomach cancer study in January 2022 highlighted some scientific publishers’ policy of not disclosing the reasons for withdrawing papers as long as they have not yet formally appeared in print. That study had appeared only online.

Roland Herzog, the editor of the journal Molecular Therapy, said that editors had drafted an explanation that they intended to publish at the time of the article’s removal. But Elsevier, the journal’s parent publisher, advised them that such a note was unnecessary, he said.

Only after the Times article last month did Elsevier agree to explain the article’s removal publicly with the stern note. In an editorial this week , the Molecular Therapy editors said that in the future, they would explain the removal of any articles that had been published only online.

But Elsevier said in a statement that it did not consider online articles “to be the final published articles of record.” As a result, company policy continues to advise that such articles be removed without an explanation when they are found to contain problems. The company said it allowed editors to provide additional information where needed.

Elsevier, which publishes nearly 3,000 journals and generates billions of dollars in annual revenue , has long been criticized for its opaque removals of online articles.

Articles by the Columbia scientists with data discrepancies that remain unaddressed were largely distributed by three major publishers: Elsevier, Springer Nature and the American Association for Cancer Research. Dr. David alerted many journals to the data discrepancies in October.

Each publisher said it was investigating the concerns. Springer Nature said investigations take time because they can involve consulting experts, waiting for author responses and analyzing raw data.

Dr. David has also raised concerns about studies published independently by scientists who collaborated with the Columbia researchers on some of their recently retracted papers. For example, Sandra Ryeom, an associate professor of surgical sciences at Columbia, published an article in 2003 while at Harvard that Dr. David said contained a duplicated image . As of 2021, she was married to the more senior Dr. Yoon, according to a mortgage document from that year.

A medical journal appended a formal notice to the article last week saying “appropriate editorial action will be taken” once data concerns had been resolved. Dr. Ryeom said in a statement that she was working with the paper’s senior author on “correcting the error.”

Columbia has sought to reinforce the importance of sound research practices. Hours after the Times article appeared last month, Dr. Michael Shelanski, the medical school’s senior vice dean for research, sent an email to faculty members titled “Research Fraud Accusations — How to Protect Yourself.” It warned that such allegations, whatever their merits, could take a toll on the university.

“In the months that it can take to investigate an allegation,” Dr. Shelanski wrote, “funding can be suspended, and donors can feel that their trust has been betrayed.”

Benjamin Mueller reports on health and medicine. He was previously a U.K. correspondent in London and a police reporter in New York. More about Benjamin Mueller

Stealing Strategies from Cancerous T Cells May Boost Immunotherapy

March 20, 2024 , by Sharon Reynolds

CAR T cells (yellow) may get a boost in cancer-killing abilities from the addition of mutations found in blood-cancer cells.

For some people with blood cancers like leukemia and lymphoma, CAR T-cell therapies have proven to be a transformative treatment. But for solid tumors like breast, colorectal, or pancreatic cancer, which make up about 90% of cancer cases, success with T-cell therapies has been harder to come by.

One big reason for these failures is that T cells , the immune system’s primary defense against infected and diseased cells, often become weakened and incapacitated in the toxic environment found within and around solid tumors. Researchers have been exploring many ways to help CAR T cells and other experimental T-cell therapies survive within these hostile surroundings, known as the tumor microenvironment .

In a new study, an NCI-funded research team showed the promise of one such tactic: looking to the genetic changes that cancerous T cells themselves use to stay alive and grow. Incorporating those genetic changes into T-cell therapies, the team found, may make them better cancer killers .

When tested in mice, T cells engineered to have one specific genetic alteration the team discovered in cancerous T cells gave the engineered cells “superpowers,” said Jaehyuk Choi, M.D., Ph.D., of Northwestern University, who co-led the study.

Adding the genetic change, a fusion of parts of two genes, helped the engineered T cells divide faster, kill more tumor cells, and survive for more than a year in the treated mice. And, importantly, it didn’t make the T cells behave like cancer cells, the researchers reported February 7 in Nature .

“When we added [this] single mutation, we didn’t see the sort of unrestrained [T-cell] growth [you see in cancer], but it gave [the engineered] T cells capabilities that they don’t naturally have,” explained the study’s other leader, Kole Roybal, Ph.D., of the University of California San Francisco.

The first two decades of T-cell therapy research focused on the basics, explained Rosa Nguyen, M.D., Ph.D., who studies cellular therapies in NCI’s Center for Cancer Research but was not involved in this study. That work included figuring out what molecules on cancer cells can be targeted by T cells and how to change T cells to better identify such targets, as is done in CAR T-cell therapies .

“Now people are getting super creative in coming up with different things [to add] to these cells to make them work better,” Dr. Nguyen said. “That’s what the field is moving toward now.”

Harnessing nature’s survival strategies

Any type of cell in the body has the potential to turn cancerous, even immune cells. As its name implies, the blood cancer called T-cell lymphoma starts in T cells.

These cancerous T cells have something many normal T cells often lack: the ability to thrive in the hostile environment of a tumor. That environment can include other immune cells that actually work to slow down or disable T cells, as well as other cells and molecules that make it hard for T cells to function.

First Cancer TIL Therapy Gets FDA Approval for Advanced Melanoma

The new treatment, lifileucel, was originally developed by NCI researchers and is the first cell therapy approved for a solid tumor.

Dr. Choi’s lab has been studying the survival traits of T-cell lymphomas for over a decade. “It’s … amazing how these T-cell cancers have developed ways to protect themselves,” he explained.

From the perspective of developing a T cell – based therapy, many of the mutations found in cancerous T cells provide an additional advantage, Dr. Choi explained: Any one of them, on its own, is not likely to direct a cell to become cancerous.

Their years of research clearly showed that “nature has already done this massive experiment to make [cancerous] T cells stronger,” he explained. So “we thought maybe [nature] can show us the way” to improve T-cell therapies.

Better, faster-acting, and safe T cells

Joining forces with Dr. Roybal’s lab, which specializes in T-cell engineering, the researchers first carefully analyzed a wide range of cancerous T cells from T-cell lymphomas, looking for genetic alterations that appeared to help them survive in that tumor microenvironment.

They initially found 71 candidate alterations. In further laboratory experiments, they engineered CAR T cells to have some of the most promising candidate alterations, and this achieved what the researchers had hoped: They increased the CAR T cells’ ability to kill cancer cells and keep creating more CAR T cells.

Additional work revealed what appeared to be the most promising alteration: a fusion of parts of two genes, CARD11 and PIK3R3.

“This single [fusion] activated many things that people have predicted would help [improve] T-cell therapies,” Dr. Choi explained. In experiments in mice, treating them with CAR T cells engineered to express this fusion gene increased the production of molecules that T cells need to survive and function.

And these improvements only occurred when the specific protein recognized by the T cells’ specialized receptor, their chimeric antigen receptor , was present. That is, these extra-engineered CAR T cells would only become supercharged where and when needed inside a tumor.

Improved T cell survival and persistence in solid tumors

The team tested the CAR T cells engineered to express the gene fusion in mouse models of different cancers, including solid tumors like mesothelioma and melanoma. Across those experiments, they found that the treatment was much more effective at shrinking tumors—and keeping them under control for longer—than CAR T cells without the fusion.

“Persistence, the ability to stick around in the tumor microenvironment, is the biggest problem [these cells] solved,” Dr. Choi said. While T cells without the fusion died within a few days, the ones with the fusion “seem to stick around for as long as needed,” he said.

The treatment was very effective even though the mice didn’t also get chemotherapy, Dr. Choi pointed out. That is important because currently, “almost everyone who gets treated with [T-cell therapies] needs to have what’s called conditioning chemotherapy beforehand,” Dr. Choi explained. But this chemotherapy can cause side effects, often severe enough that patients have to wait longer to get the T-cell treatment or possibly preventing them from doing so at all.

“If we ever want these sorts of therapies to be given in less specialized centers, or even in the outpatient setting, we need to get rid of these cumbersome techniques [like conditioning chemotherapy] that are toxic to patients,” added Dr. Roybal.

The researchers also engineered the fusion into a different type of T cell – based immunotherapy, called TCRs, and saw similar results.

One CAR T-Cell Therapy for Blood Cancers?

Using CRISPR, researchers have developed a potential “universal” immunotherapy for blood cancers like leukemia and lymphoma.

In a mouse model of melanoma, for example, TCR T cells with the fusion gene flowed into tumors in much greater numbers and killed tumor cells much more effectively than TCR T cells without the fusion gene. The TCR T cells with the fusion even showed this advantage at starting doses 20 to 100 times lower than TCR T cells without the fusion.

Being able to give a lower dose of a T-cell therapy would provide another safety advantage for patients, Dr. Roybal explained. Current CAR T-cell therapies, which are given in large doses, have the potential to cause a dangerous—or even fatal—immune system overreaction called cytokine release syndrome . That risk would likely be lower with a smaller dose that ramps up its activity over time, he added.

The researchers also tracked the T cells in the mice for more than 400 days after treatment. Though they initially multiplied rapidly to kill the tumors, their numbers then shrank back down and showed no signs of becoming cancerous themselves.

Testing supercharged T cells in people

The researchers have launched a biotechnology startup to move their CAR T-cell therapy with this gene fusion into human trials, although they are likely 2 to 3 years away from launching these studies, Dr. Roybal explained.

Eventually, researchers may want to try mixing and matching different ways to soup up T cells, Dr. Nguyen said. But these approaches first need to be tested one at a time to better understand how each one works. “We have to use a stepwise approach,” she said.

Drs. Roybal and Choi also want to keep exploring the dozens of other promising mutations their screen initially uncovered.

“We found a lot of different mutations … that could [potentially] be used” in T-cell therapies to treat “a variety of different types of cancer,” said Dr. Roybal.

“Maybe the [CARD11–PIK3R3] fusion protein will be good for [fighting] some subset of solid cancers. And one of the other [mutations] we found will be important for another subset,” he said. “This is the beginning [of this research], not the end.”

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