MSK Research Highlights, July 17, 2023

Through-the-microscope view of a tissue sample

New research from Memorial Sloan Kettering Cancer Center (MSK) and the Sloan Kettering Institute — a hub for basic science and translational research within MSK — discovered a division of labor in DNA repair that suggests a possible therapeutic strategy for certain cancers; identified a way to reduce toxicity in CAR T cell therapy; developed a new method to enable imaging of two PET tracers simultaneously; found biomarkers that could help predict outcomes in HER2-positive metastatic esophagogastric cancer; and made progress toward improving options for patients with early-stage, potentially indolent cancers.

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.

Microhomology-mediated end joining (MMEJ) is the only DNA repair mechanism active when cells divide during mitosis; other pathways — homologous recombination (HR) and nonhomologous end joining (NHEJ) — are suppressed. “MMEJ is not just backup, but the last-ditch repair pathway, and it comes at the expense of fidelity,” Dr. Sfeir says. “Ultimately, it’s better for cells to fix the breaks than not fix them when cells commit to cellular division.” The team, which included postdoctoral researcher and co-corresponding author Alessandra Brambati, PhD, and research technician Olivia Sacco, also found that a protein called RHINO plays a critical role in confining MMEJ during mitosis. They showed that RHINO directs another protein, polymerase theta, to DNA breaks and fixes them.

The researchers note that the division of labor in DNA repair offers a possible therapeutic strategy for certain cancers. In people with BRCA mutations, cancer cells have disabled HR repair pathways. The new findings suggest combining PARP inhibitors with drugs that disable MMEJ, including inhibitors of polymerase theta and RHINO. Unable to repair their DNA, the cancer cells would die. Read more in Science.

Reducing neurotoxicity in CAR T cell therapy

CAR T cell therapy can sometimes cause neurotoxicity, which may include confusion, disorientation, seizures, and unconsciousness. An MSK team led by hematologic oncologist Jae Park, MD, used a drug called anakinra to reduce severe neurotoxicity in people with relapsed or refractory lymphoma treated with CAR T cells that target CD19. Anakinra works by blocking IL-1 signaling. The phase 2 clinical trial was a direct translation from research done by the laboratory of Michel Sadelain, MD, PhD, Director of MSK’s Center for Cell Engineering, which reported the effectiveness of anakinra in a mouse model in 2018 in Nature Medicine. In the new study, giving anakinra reduced severe neurotoxicity from a rate of 28%–38% usually seen with standard anti-CD19 CAR T treatment to only 9.7%. Together, all grades of neurotoxicity were reduced from 56%–64% to 19%. Dr. Park’s research team also confirmed that anakinra had made it into participants’ cerebrospinal fluid, providing evidence that the toxicity was reduced by the drug. Preventing neurotoxicity will make CAR T treatment safer, more available on an outpatient basis, and therefore more accessible to patients. Read more in Nature Medicine.

New method enables imaging of two PET tracers simultaneously

Positron emission tomography (PET) is one of the most widely used diagnostic tools in cancer care. PET scans show the location of a tumor, usually based on increased glucose intake, a hallmark of cancer cells. Now research led by MSK’s Sloan Kettering Institute and collaborators at the Complutense University of Madrid have developed a new method that allows for the imaging of two different PET tracers at the same time, thereby doubling the information depth of a single PET scan. The technique, dubbed multiplexed-PET, or mPET, could reduce the number of sequential scans patients will need to receive. It also has applications in preclinical research, says MSK’s Jan Grimm, MD, PhD, co-senior author of a new study describing mPET. In mouse model experiments, the researchers used mPET to noninvasively monitor dual drug delivery, simultaneously tracking each drug. They also imaged CAR T cells, used in immunotherapy, and their target, prostate-specific membrane antigen (PSMA) tumors, in the same animals simultaneously — which has not been possible previously. “This advance could help increase the molecular information attainable during a single scan, giving scientists and radiologists alike more timely information for a diagnosis and staging that could not be done with a biopsy,” Dr. Grimm says. Study first author Edwin Pratt, PhD, adds: “The beauty is that mPET is immediately clinically translatable; the approach can be done on most existing machines, with minimal modifications.” A clinical study based on the findings is planned. Read more in Nature Biomedical Engineering.

Biomarkers could help predict outcomes in HER2-positive metastatic esophagogastric cancer

About 20% of stomach and esophageal cancers have increased expression of the HER2 protein. For those patients, chemotherapy combined with trastuzumab (Herceptin®), an antibody that blocks HER2, has been standard treatment for more than a decade. In March 2022, the Food and Drug Administration approved the addition of a another drug to this combination: the immunotherapy pembrolizumab (Keytruda®). This approval was based on KEYNOTE 811, a multicenter clinical trial led by MSK medical oncologist Yelena Janjigian, MD, which found that this updated regimen resulted in a nearly 23% improvement in treatment response. Some people benefit more than others, however, and eventually resistance to the combination of chemotherapy, HER2 therapy, and immunotherapy treatment develops in most patients.

New research from Dr. Janjigian and MSK medical oncology Steven Maron, MD, MSc, sought to identify biomarkers that could explain this. The investigators used samples from MSK patients who participated in KEYNOTE 811. In the new study, analyses were aimed at improving the understanding of which patients will benefit most from this regimen, including circulating tumor DNA (ctDNA), whole exome sequencing, single-cell RNA sequencing, and HER2-PET scans before and during treatment. The studies revealed that amplification of the ERBB2 gene resulted in better long-term responses, while mutations in MYC and CDKN2A/B were associated with worse outcomes. The findings illustrate how liquid biopsies and HER2-PET studies can noninvasively help identify patients who will benefit the most from HER2-directed therapy and provide a more personalized treatment approach. Read more in Clinical Cancer Research.

Moving toward better options for patients with early-stage, potentially indolent cancers

MSK has a strong history developing new approaches to minimize unnecessary treatment for specific types of cancers that may be slow-growing or not likely to progress. Epidemiologists often call these “overdiagnosed” cancers because they don’t pose a significant threat to a person’s health. MSK’s Urology Service has been a leader in promoting active surveillance for people with nonaggressive prostate cancer, and MSK’s Head and Neck Cancer Surgery and Endocrinology services have been leaders in the same approach for thyroid cancer.

New research from an MSK team led by Luc G.T. Morris, MD, MSc, a surgeon and cancer genomics researcher, has provided new insights into why some cancers remain indolent — appearing to be in a state of immune equilibrium, a phenomenon that had previously only been observed in mice. Specifically, the team analyzed tumors of the thyroid, prostate, breast, and lung, as well as melanoma — cancer types in which some tumors have been overdiagnosed.

Small and localized tumors that remain indolent were more likely to be constrained by immune surveillance, and larger tumors showed evidence of immune escape. In contrast, in more aggressive cancer types, no evidence of immune equilibrium or escape was observed. “We believe that some indolent or overdiagnosed cancers can remain in a prolonged state of immune equilibrium, but more aggressive types of cancer probably escaped from immune equilibrium at a much earlier stage, possibly even before they were clinically apparent,” Dr. Morris notes. Further validation could assist with the development of prognostic biomarkers to inform clinical decision-making and more personalized treatment options for patients with early-stage, potentially indolent cancers, he notes. Read more in Cancer Cell.

Clinical and genomic features of response and toxicity to sotorasib in a real-world cohort of patients with advanced KRAS G12C-mutant non-small cell lung cancer

Sotorasib (Lumakras®) is a targeted therapy that has received accelerated approval for treating people with non-small cell lung cancer that has changes, or mutations, in the KRAS G12C gene. The drug works by halting the growth of cells that make an abnormal version of the KRAS protein. While the drug has helped many with this condition, it is unknown why some develop resistance or severe side effects to treatment.

MSK oncology/hematology fellow Rohit Thummalapalli, MD, and thoracic oncologist Kathryn C. Arbour, MD, led a retrospective study that examined medical records of 105 people with this condition who were treated with sotorasib outside of a clinical trial. Using next-generation sequencing, investigators found that people whose tumors had additional KEAP1 gene mutations experienced shorter progression-free survival and overall survival, meaning their cancer grew and spread more quickly after treatment and they died sooner, compared with those who did not have these mutations. Additionally, they discovered that people who recently received immunotherapy experienced more severe side effects than those who did not. These observations may help guide the use of sotorasib in the clinic and inform future clinical trials. Read more in JCO Precision Oncology.