Researchers across MSK continued to make strides against cancer in 2023.
Researchers at Memorial Sloan Kettering Cancer Center (MSK) continued to make strides against cancer in 2023. Laboratory research teams across the institution investigated many fundamental biological questions to advance the global understanding of cancer and the development of new therapies.
“MSK is known for providing unparalleled care to our patients, but I also hope everyone understands that we have an equal commitment to cancer research,” says MSK President and CEO Selwyn M. Vickers, MD, FACS. “Every day, MSK scientists continue to make important foundational discoveries about human biology and cancer biology. And we apply what we learn in the lab to improve cancer treatment.”
MSK scientists are global leaders in the field, publishing their work frequently in leading scientific and medical journals, and presenting it at top national and international conferences.
Here are some of the most exciting scientific discoveries reported over the past year, in chronological order:
Getting Drugs Across the Blood-Brain Barrier Using Nanoparticles
Brain tumors are notoriously hard to treat. One reason is the challenge posed by the blood-brain barrier, a network of blood vessels that protects the brain but also prevents most drugs from getting to brain tissue.
An MSK team led by biomedical engineer Daniel Heller, PhD, in collaboration with Praveen Raju, MD, PhD, a pediatric neurologist at Mount Sinai Medical Center, may have found a way to carry drugs across the blood-brain barrier using nanoparticles — tiny objects with diameters one-thousandth that of a human hair. The method, which was published March 2 in Nature Materials, could potentially improve treatment for medulloblastoma, other brain tumors, and other brain diseases.
MSK Scientists Identify Potential New Strategy Against Metastasis
A team of scientists from the lab of Sloan Kettering Institute Director and MSK Chief Scientific Officer Joan Massagué, PhD, has identified the STING cellular signaling pathway as a key player in keeping dormant cancer cells from progressing into aggressive tumors months, or even years, after they’ve escaped from a primary tumor. The findings, which were published in Nature on March 29, suggest that drugs to activate STING could help prevent the spread of cancer to new sites throughout the body — a process known as metastasis.
Why Is Colorectal Cancer in African Americans Hard To Treat? One Reason Is Genetics
An MSK research team led by computational biologist Henry Walch, MS, found colorectal cancer patients of African ancestry are less likely to have tumors that respond well to two important classes of newer treatments: immunotherapy and targeted therapy. These treatments work better against tumors that have certain genetic mutations — or have a larger number of mutations overall. The research found that a smaller fraction of the Black patients whose tumors were sequenced at MSK had molecular profiles that could be targeted by these therapies.
“Our findings suggest that the type of molecular profiles observed in the tumors of patients with African ancestry could reduce the number of options that these patients have for treatment,” says Walch, who presented the findings April 17 at the American Association for Cancer Research annual meeting in Orlando, Florida. “They also underscore the urgent need to include racially diverse populations in cancer research and drug development studies.”
Expansion of Cell-to-Cell Communication Drives the Early Development of Pancreatic Cancer, New Research in Mice Finds
Interactions between genetic mutations and external factors, such as tissue injury that leads to inflammation, reshape both cells’ identities and their local environment in ways that foster cancer’s emergence and runaway growth.
In pancreatic cancer, these changes start to happen fast — within 24 to 48 hours after tissue damage. They happen predictably. And they greatly expand some cells’ ability to communicate and interact with nearby cells.
Those were the findings from a study published May 11 in Science by an international research team overseen by MSK investigators Scott Lowe, PhD, and Dana Pe’er, PhD. The research combined sophisticated genetically engineered mouse models and advanced computational methods to map the earliest cell states leading to pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer.
Potential Drug Shows Promise Targeting a Range of KRAS-Driven Cancers in the Lab
KRAS was one of the first cancer genes ever discovered, but for a long time the cancer-causing KRAS protein was considered “undruggable” with targeted therapy. That started to change in May 2021, when the Food and Drug Administration granted accelerated approval to sotorasib (Lumakras®) for lung cancers caused by a particular KRAS mutation, called KRAS G12C. The approval of sotorasib was based on years of lab research and clinical trials, much of that work led by physician-scientist Piro Lito, MD, PhD, and other investigators at MSK.
But G12C is only one of many mutations in KRAS (pronounced “kay-rass”) known to cause cancer, and lung cancer is only one of many cancers linked to these mutations. In a paper published May 31 in Nature, investigators led by Dr. Lito reported results for a new molecule that can block many more mutated forms of the KRAS protein. In the lab, the compound was effective at blocking the growth of multiple cancer cell lines, including lung cancer, colon cancer, and pancreatic cancer. It was also effective in mouse models of lung and colorectal cancers caused by KRAS.
MSK-Led Research Finds Unexpected Link Between Chromosomal Instability and Epigenetic Alterations
MSK study published June 7 in Nature found an unexpected link between chromosomal instability and epigenetic alternations, both of which are hallmarks of cancer — especially advanced, drug-resistant cancers. The study found that together these defects lead to differences between individual cancer cells within a tumor, a diversity that helps them survive and resist treatment. The work was co-supervised by Samuel Bakhoum, MD, PhD, whose research group studies how alterations in the number and structure of chromosomes drive cancer, and epigenetics expert Yael David, PhD. The discovery of this link between the two phenomena points to potential new therapeutic opportunities, as well as opening rich new areas of study.
New Design Could Make CAR T Cells a More Effective Immunotherapy for Solid Tumors
Chimeric antigen receptor (CAR) T cell therapy, an immunotherapy that uses genetically modified immune cells, has shown great promise for the treatment of blood cancers such as leukemia and lymphoma. However, this type of immunotherapy has so far been much less effective against solid tumors, which account for most cancers.
A big problem is that solid tumors have a surrounding ecosystem — called the tumor microenvironment — that inhibits attacking CAR T cells.
The lab of thoracic surgeon Prasad Adusumilli, MD, however, has developed a way to boost CAR T cells’ power and persistence by co-opting one of cancer’s own weapons: a genetic mutation in a gene called c-KIT. This mutation is critical to the ability of cancer cells to grow, multiply, and survive. The findings were published in the June 19 issue of Nature Cancer.
Researchers Discover Division of Labor in DNA Repair
DNA double-strand breaks (DSBs) are an especially toxic form of DNA damage, affecting both strands of the DNA double helix. This damage can cause mutations that accumulate as cells grow and divide, fueling cancer formation and progression. Repairing DSBs is essential for any organism, and several pathways have evolved to fix these breaks with minimal changes to DNA sequence. Now the laboratory of Sloan Kettering Institute molecular biologist Agnel Sfeir, PhD, has discovered a pathway that previously was considered to be a backup pathway actually has the final say. The findings were published July 13 in Science.
Shedding Light on Racial Disparities in Endometrial Cancer
While the incidence of endometrial cancer is similar in Black and white women, Black women are more likely to die of the disease. An MSK-led analysis of nearly 2,000 endometrial carcinomas published November 1 in Cancer Discovery revealed a higher prevalence of high-risk features in the cancers of Black patients compared with those of white patients. For example, the CN-H/TP53abn molecular subtype, which is associated with worse outcomes, was more frequent in Black patients, according to the research team, which was led by first author Britta Weigelt, PhD. Meanwhile, white women were more likely to have alterations that made their cancers more amenable to treatment with immunotherapy. The study revealed important biological differences in endometrial cancers from different racial groups, notes senior study author Carol Brown, MD, a gynecologic surgeon at MSK. The findings emphasize the importance of increasing the representation of diverse populations in clinical research in order to address these types of disparities.
Disrupting a Single Gene Could Improve CAR T Cell Immunotherapy, Study Shows
CAR T cell therapy, a powerful type of immunotherapy, has begun to revolutionize cancer treatment. Pioneered at MSK, the therapy involves engineering a patient’s T cells so they recognize and attack cancer cells. These CAR (chimeric antigen receptor) T cells are then multiplied in a lab and given back to the patient to be a continual fighting force against the cancer.
New research from the lab of physician-scientist Michel Sadelain, MD, PhD, shows that disrupting a single gene in the CAR T cells can make them more potent and able to fight tumors longer. In a paper published November 7 in Cancer Discovery, the team demonstrated that disrupting the gene SUV39H1 causes a ripple effect: It restores the expression of multiple genes that help sustain the T cells’ longevity. The researchers showed that this approach improved CAR T cell effectiveness against multiple cancers in mice.
Lung Cancer Cells’ ‘Memories’ Suggest New Strategy For Improving Treatment
Research from the lab of cancer biologist Tuomas Tammela, MD, PhD, shows that some lung cancer cells retain a “memory” of the healthy cell where they came from — one that might be exploited to make an emerging type of lung cancer treatment called KRAS inhibition more effective.
The team’s findings shed important light on lung cancer cells that linger after treatment with a KRAS inhibitor. Importantly, they suggest that separately targeting these cells alongside treatment with a KRAS inhibitor could help prevent recurrence. The study was published November 7 in Cancer Discovery.
Location, Location, Location: The Hidden Power of Intracellular Neighborhoods
Back in 2018, the lab of Christine Mayr, MD, PhD, introduced the world to a key cellular component that had been hiding in plain sight.
This year, the lab published important results that build on that discovery. New findings published December 21 in Molecular Cell provide details about the hidden organization of the cytoplasm — the soup of liquid, organelles, proteins, and other molecules inside a cell. The research shows it makes a big difference where in that cellular broth that messenger RNA (mRNA) get translated into proteins.
Overall, the work adds to an emerging body of research showing how the cytoplasm is “beautifully organized” and not just a big jumble of stuff. Not only do the findings shed new light on fundamental cellular biology, but the knowledge holds promise for increasing or altering the production of proteins in mRNA vaccines and therapies.