MSK Research Highlights, December 23, 2022

detail shot of laboratory slides

New research from Memorial Sloan Kettering Cancer Center (MSK) and the Sloan Kettering Institute — MSK’s experimental research arm — explores ways to limit heart damage from chemotherapy and radiation; examines genomic differences between primary and metastatic tumors in bladder cancer; aims to understand the safety of checkpoint inhibitor therapy for patients who are obese; and investigates a potential therapeutic approach against acute myeloid leukemia.

Limiting heart damage from chemotherapy and radiation

Chemotherapy and radiation therapy for cancer can cause serious, even fatal, heart damage. New research from the lab of MSK radiation oncologist Adam Schmitt, MD, identified that these DNA damaging cancer therapies elicit delayed cardiac inflammation driven by cGAS- and STING-dependent type I interferon signaling. Shutting down cGAS-STING signaling reduced heart damage and fatal cardiac events after chemotherapy or radiation in mice. “These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors,” the study authors write. Read more in the Journal of Experimental Medicine.

Genomic differences between primary and metastatic tumors in bladder cancer present a challenge for precision oncology

Identifying genomic mutations driving a patient’s cancer is the bedrock of precision oncology. Tumors, however, evolve over time. The lab of David Solit, MD, director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSK, performed genomic analyses of primary tumors, metastases, and plasma collected from individuals with urothelial cancer — and observed a 23% difference in actionable mutations between primary and metastatic sites. “Our findings indicate that the high degree of lesion-to-lesion genomic heterogeneity may be a barrier to precision oncology approaches for bladder cancer and that circulating tumor DNA profiling may be preferred to tumor sequencing for a subset of patients,” the study authors write. Read more in Cell Reports.

While obesity is a risk factor for many types of cancer, it has, paradoxically, also been associated with improved outcomes for patients receiving immune checkpoint inhibitors. To better understand the safety of immunotherapies in obese patients, a multi-institution team led by MSK medical oncologist Robert Motzer, MD, and Jennifer McQuade, MD, of MD Anderson Cancer Center, analyzed adverse events for 3,700 patients with advanced cancer who received nivolumab, or nivolumab in combination with ipilimumab. The study found obesity to be associated with an increased incidence of mild to moderate side effects among patients treated with nivolumab alone, and with higher grade adverse events in female patients. The findings suggest a need for increased monitoring of patients at higher risk. MSK epidemiologist Helena Furberg, PhD, MSPH, was also a co-author. Read more in JAMA Oncology.

Study suggests new strategy to improve venetoclax-based treatments

Targeted therapies like venetoclax have improved outcomes for acute myeloid leukemia (AML), but most patients’ cancers still develop resistance to them. A team co-led by MSK’s Omar Abdel-Wahab, MD, chair of the molecular pharmacology program at the Sloan Kettering Institute, Eric Wang, PhD, of the Jackson Laboratory, and Robert Bradley, PhD, of Fred Hutchinson Cancer Center, performed CRISPR-Cas9 screening across a broad range of AML therapies to better understand the genomic determinants of drug response. The research uncovered a unique genetic relationship between the response to venetoclax and the function of particular RNA splicing factors. They identified a number of splicing factors whose loss promotes cell death when used with venetoclax, but which aren’t important for normal blood cell production — suggesting a potential therapeutic approach. In mouse models, the study identified a compound that enhanced venetoclax response by modulating RNA splicing. Read more in Cancer Cell.