2020 Recipient — Dmitriy Zamarin, MD, PhD

Dmitriy Zamarin

Dmitriy Zamarin, MD, PhD

Chromatin Remodeling and Immunotherapy in Ovarian Cancer

Project Summary

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.

Areas of Research:


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. 

When a Virus is a Good Thing: Meet a Scientist

The COVID-19 pandemic left people around the world feeling scared, overwhelmed, exhausted and befuddled. But Dmitriy Zamarin, MD, PhD, adds “fascinated” to the list as he ponders the psychological and sociological implications of the Covid-19 pandemic.

Photo: Dr. Dmitriy Zamarin, smiling with arms crossed, in a research lab.

“This small amount of genetic material that has spread through the world and caused this chaos,” Dmitriy said, “puts life in a completely new perspective. Modern technological advances, the military, bombs … the amount of money being spent on that. And yet you have this tiny little thing that can beat us all.”

Dmitriy, an Assistant Attending Physician and Translational Research Director in the Gynecologic Medical Oncology Service at the Memorial Sloan Kettering Cancer Center, has good reason to be fascinated by what is happening in the world around us. For more than ten years, he has been studying how viruses can be used as therapeutics for cancer. 

As he explained, viruses don’t operate in a vacuum. They interact with cancer cells and with the immune system.

Good guys, bad guys, double agents

The specialized immune cells in our bodies, or T-cells, recognize and fight both virus infections and cancer cells. But what scientists like Dmitriy have learned is that cancer cells have certain mechanisms that they use to protect themselves, almost making them invisible to the T-cells.

“If we can overcome these mechanisms,” Dmitriy said, “we can activate the T-cells to recognize and kill cancer cells.”

He and his team are exploring what happens when you infect a cancer cell with a virus. Normally, a virus elicits an immune response which causes inflammation. So when the cancer cell becomes ‘infected’ with the virus, it causes inflammation, which in turn alerts the immune system to see this cancer cell where it wouldn’t have before.

“It sounds a bit crazy because we are giving somebody a virus,” Dmitriy said, “but these viruses are attenuated, meaning they don’t have a good ability to replicate in a human.”

They replicate primarily in the cancer cells. One way of looking at this process is that you have good guys who can’t get into where the bad guys are. So they introduce another bad guy (the virus) who “blows away the doors” allowing the immune cells to get in. A double agent, in essence.

The origins of Dr. Zamarin's career 

Dmitriy’s interest in science, specifically microbiology, goes back to his childhood. He was born and grew up in Uzbekistan in the former Soviet Union. His mother is a physician, and so he had always been somewhat exposed to the field of medicine. But when he was 10 or 11 years old, he developed a severe case of chickenpox that caused an inflammation of the brain, which landed him in the hospital for about a month.

“From that point on, I was very interested in doing something with viruses in the future,” Dmitriy said.

The experience of being hospitalized and having to learn how to walk again also impacted his career as a doctor, Dmitriy believes, for the better. “What it constantly reminds me of is the aspect of human interaction,” Dmitriy said. “It definitely gives you the perspective of the patient, despite having this happen so many years ago.”

Dmitriy and his family moved to the United States when he was a teenager, and he went to college in New York. It was then that he had the opportunity to work in a biology lab, where his fascination with viruses was solidified. While he got his PhD in virology, thinking he’d pursue a career in infectious diseases, he was drawn to oncology, specifically gynecological cancers.

“Ovarian cancer had not had much success with immunotherapy,” Dmitriy said, referring to the start of his career, and noting that it still doesn’t today. “I thought it would be the perfect opportunity to jump into a field that has a lot of therapeutic needs, and also needs a lot more scientific understanding.”

Waiting for the bus

Dmitriy reflected on what keeps him motivated, when it feels sometimes like 99% of his work is failure. “It’s like waiting for that bus. Is it going to come? Not going to come? Should I just not take it?”

But he refuses to look at the setbacks as failures. Rather, he sees them as challenges that he sets a goal to overcome. And it’s the possibility that he might be the first person in the world to have an answer, no matter how big or small the question may be, that keeps him at it.

“It may just be 1% of the time,” Dmitriy said. “But that 1% of knowing that you have contributed to the world’s knowledge? That’s probably the biggest motivation that keeps me going.”

Dr. Zamarin's 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.

Innovative research projects like Dr. Zamarin's are bringing us closer to ovarian cancer cures. Donate now to fund progress and save lives.

Photo: Dr. Dmitri Zamarin, smiling broadly as he stands in a lush green field with a woman and two children, all holding apples.