Cancer immunotherapies such as drugs targeting the immune inhibitory molecules known as PD-1 and PD-L1 have shown benefit across a number of cancers. Unfortunately, in ovarian cancer, only a small fraction of patients responds to such treatments. It is thus necessary to identify the mechanisms that allow ovarian tumors to resist immunotherapy and to develop novel approaches that can target such mechanisms.
The biomarkers of response to immunotherapy in ovarian cancer remain unknown. Our preliminary data indicate that biomarkers that can predict response to PD-1 in other cancer types (such as high number of mutations or expression of a protein called PD-L1) appear not to work in ovarian cancer. In our studies we have found that mutations in genes encoding proteins that are involved in DNA remodeling (known as SWI/SNF complex proteins) seem to influence response to immunotherapy. The mechanisms underlying this effect are unknown. Understanding of such mechanisms may lead to a better selection of patients for clinical trials with immunotherapy and for development of drugs specifically targeting these pathways.
We hypothesize that changes in SWI/SNF genes in cancer lead to structural changes in the DNA that can lead to activation of pathways that promote or block recognition of cancer cells by the immune system.
To formally evaluate this, we have developed a number of mouse cancer cell lines that are either deleted for the specific SWI/SNF proteins or express them at high levels. Our preliminary data indicate that some of these changes can indeed influence recognition by the immune system and increase responses to PD-1 blockade in mice. Our research will aim to:
1.Characterize the mechanisms by which this immune recognition occurs
2.Using mouse models, determine whether drugs targeting chromatin remodeling, namely BET inhibitors, can improve responses to immunotherapy in cancers carrying such mutations.
The results of the study will also help us understand the mechanisms of response and resistance to immunotherapy and may help with selection of patients that are more appropriate for immunotherapy. In addition, the results of this work may lead to development of novel immune treatments for ovarian cancer and possibly other cancer types.
This grant was made possible in part by a generous donation from Torrid via a grant from the Torrid Foundation. These funds were raised through customer round-ups and donations in Torrid stores nationwide and online at torrid.com during Ovarian Cancer Awareness Month in September 2019.
Dmitriy Zamarin, MD, PhD is an Assistant Attending Physician and Translational Research Director in the Gynecologic Medical Oncology Service at the Memorial Sloan Kettering Cancer Center. Dr. Zamarin graduated Summa Cum Laude with a BS degree in Biology from Manhattan College. He obtained his MD and PhD degrees from the Mount Sinai School of Medicine in New York, where he was focused on the studies of influenza virus pathogenesis under the mentorship of Dr. Peter Palese. He completed residency in Internal Medicine at the Mount Sinai Hospital in New York and fellowship in Hematology/Oncology at the Memorial Sloan Kettering Cancer Center, where he worked under the mentorship of Dr. James Allison and Dr. Jedd Wolchok, studying the mechanisms of response and resistance to immunomodulatory antibody therapy and virus-based therapeutics.
Dr. Zamarin is currently a principal investigator and a translational chair on several institutional and cooperative group clinical trials exploring novel immunotherapy combinations in gynecologic cancers. In the laboratory, his research is focused on understanding of the mechanisms by which ovarian cancers are recognized by the immune system and on identification of biomarkers predictive of response and resistance to immunotherapy. His laboratory in addition uses mouse models to explore the mechanisms of tumor-immune system interactions and to develop novel therapeutics, with particular focus on oncolytic viruses and targeted therapies. His current work is focusing on understanding how alterations in SWI/SNF chromatin remodeling components affect tumor recognition by the immune system and the use of epigenetic drugs to promote tumor immunogenicity. For his work, Dr. Zamarin has received numerous awards, including Damon Runyon Foundation Fellowship Award, Young Investigator Award from the Conquer Cancer Foundation, Judith Liebenthal Robinson Ovarian Cancer Foundation Award, GOG Foundation Scholar Investigator Award, and the Ovarian Cancer Academy Grant from the Department of Defense.