2022 Recipient — Melica Brodeur, MD

Dr. Melica Brodeur

Melica Brodeur, MD

Exploiting SMARCA4 Alterations for New Therapeutics in Ovarian Cancers

Project Summary

Ovarian cancer (OC) is the most lethal gynecological cancer. Immune checkpoint blockade (ICB), a type of immunotherapy that blocks proteins called checkpoints made by immune and cancer cells, has achieved remarkable responses in cancer types that were once fatal. ICB successes have brought new hope to OC patients; however, the latest OC clinical trials have shown overall disappointing responses. Tumors with mutations in genes that code for a protein complex, called mSWI/SNF, are likely to be more amenable to ICB. The mSWI/SNF complex is made up of many different proteins that dictate whether important genes, such as tumor-promoting genes, are turned on or off. Over half of OCs have mutations in one of these mSWI/SNF proteins. A critical subunit is SMARCA4, which is found to be mutated in 7% of OCs. Mutations in genes coding for the mSWI/SNF proteins can activate genes that are normally turned off, such as endogenous retroviruses (ERVs). When ERVs are turned on, they in turn activate inflammatory pathways. As a result of the immune effects this has in the tumor, the immune cell landscape of cancers driven by mSWI/SNF deficiencies, like SMARCA4, is described to be more favorable to ICB. Bromodomain and extraterminal proteins (BETs) are a related class of proteins to the mSWI/SNF complex as they provide an anchor for its components, such as SMARCA4, and help co-activate or -repress genes. They are also responsible for turning on checkpoint genes that are important for immune tolerance in the tumor environment. Targeting BETs could thus indirectly restore imbalances created from SMARCA4 mutations and ultimately influence whether genes are activated or suppressed. BET inhibitors (BETi) are a class of drugs that are already known to decrease important immune-suppressive checkpoint markers in tumor and immune cells. Based on these findings, combination treatment of BETi with ICB is a logical therapeutic strategy given the potential complementary immune targets. BETi could decrease the expression of checkpoint markers that create immune tolerance and ICB would block checkpoints and allow immune cells to kill cancer cells better. The central idea of our project is that SMARCA4 mutations influence immune-stimulatory genes, immune cell activation/recruitment and, ultimately, the tumor immune landscape, unmasking a vulnerability to targeted combination therapies. The proposed studies will help us to understand the mechanistic basis underlying the tumor-immune cell interactions and to help overcome the current limitations of immunotherapy in SMARCA4-mutated OCs. These studies could justify future more intensive evaluations of this approach leading to new therapeutic strategies. These results also generate data to explore these treatment combinations in OCs with other types of mSWI/SNF mutations.

This grant was made possible in part by a generous donation by The Wasily Family Foundation.

Areas of Research:


Dr. Melica Nourmoussavi Brodeur is currently a postdoctoral research fellow at the Memorial Sloan Kettering Cancer Center under the mentorship of Drs Britta Weigelt and Dmitriy Zamarin. Her research interests involve uncovering potential molecular vulnerabilities in ovarian cancers using novel preclinical models to develop personalized approaches to ovarian cancer treatment. Dr. Brodeur is a trained Canadian gynecologic oncologist. She obtained her Doctorate of Medicine from McGill University in Montreal after which she completed her residency in Obstetrics & Gynecology at the University of British Columbia in Vancouver. She then completed a four-year training in the Gynecologic Oncology and the Clinician-Investigator Programs at the Université de Montréal during which she completed her Master’s degree in Biomedical Sciences. Under the direction of research supervisor Dr. Anne-Marie Mes-Masson, her thesis focused on the comparison and utility of ovarian cancer preclinical models for treatment response assessment. Her research endeavors have earned her awards to support her research training and work including a multi-phase clinician-scientist trainee bursary from the Fonds de recherche du Québec – Santé (FRQS), the Canadian Institutes of Health Research (CIHR) – Canada Graduate Scholarship – and research excellence bursaries from the Montreal Cancer Institute. She is also among the prestigious alumni of the NCI-funded AACR Molecular Biology in Clinical Oncology Workshop. With OCRA’s support, Dr. Brodeur is interested in understanding the mechanistic basis underlying the tumor-immune cell interactions in ovarian cancers with SWI/SNF gene alterations, in particular SMARCA4-altered cancers. These studies could highlight new therapeutic strategies for these subtypes of ovarian cancer.

Researcher Spotlight: Meet a Scientist

Dr. Melica Brodeur, of Memorial Sloan Kettering Cancer Center, is a 2022 recipient of OCRA's Mentored Investigator Grant. With her project, "Exploiting SMARCA4 Alterations for New Therapeutics in Ovarian Cancer," Dr. Brodeur is investigating a genetic mutation, found in more than half of ovarian cancers, that is associated with relatively high presence of active immune cells within the tumor and may mean the tumors are more primed for immunotherapies.

OCRA-funded scientists are paving the way to a brighter tomorrow for everyone diagnosed with ovarian cancer. Donate today to enable more discoveries.

What initially sparked your interest in science?

During my first year of medical school, I participated in the Summer Research Program at McGill University. It was during this time that I discovered my interest in addressing knowledge gaps and unmet needs in cancer care. Later, I sought additional training to practice basic science research that allows me to perform bench-to-bedside work.

What drew you to the field of ovarian cancer research?

It was during my obstetrics and gynecology residency that I was faced with this devastating disease. At the time, only chemotherapy was available to patients and even though initial responses were good, most patients returned with recurrent disease and eventually died from their cancer that no longer responded to chemotherapy. 

Dr. Melica Brodeur standing in research lab between two colleagues, all smiling

It was also difficult to give patients a diagnosis for which I knew had a poor prognosis. I was not satisfied with the status quo and set out to try and make a difference for ovarian cancer patients. I truly believe that as a surgeon-scientist, my duty is to challenge and improve upon the standard of care — whether it be for prevention, early detection, treatment, quality of life or any of the many other important aspects that encompass cancer care.

Can you explain your research project?

It has always been a mystery how cancer cells find a way to evade our robust immune system (our line of defense). Recently, a new class of drug treatment, which is called immunotherapy, has had numerous success stories for different cancer types. Put simply, immunotherapy aims to reactivate our immune system and to fight against cancer cells. 

Unfortunately for ovarian cancer patients, immunotherapy has overall had disappointing results. Understanding what is different in ovarian cancers that do respond to immunotherapy will be important to the development of new treatment strategies for ovarian cancer patients.

More than half of ovarian cancers have some form of genomic alteration (meaning a problem with the DNA coding sequence) in genes making up the chromatin remodeling complex called SWI/SNF. The SWI/SNF complex is made up of almost 30 genes and is in part responsible for turning gene transcription on or off. 

Our research group had observed that ovarian cancer cases with a mutation in one of these SWI/SNF genes, which is known as SMARCA4, had more immune cells present and activated in the tumor environment. Other research groups found similar findings with other SWI/SNF gene mutations in other cancer types. With this preliminary evidence, we have set out to understand what makes these tumors more immune primed and how we may be able to harness this in the form of new therapeutic strategies.

What motivates you to persist in your research?

As a surgeon-scientist, I have the privilege to engage with two teams (clinical and research) that share the same passion to improve the lives of cancer patients. 

I am inspired by patients' experiences, and I am motivated by the idea that in some way (small or big) I may be able to contribute to the advancement of their (or future patients') care.

What is your hope for the field of ovarian cancer research?

First of all, I hope to bring more awareness of this lethal disease which has traditionally been underfunded and underexposed. I also hope to see how innovative and cutting-edge research can translate into real change for ovarian cancer patient outcomes.

If you had the opportunity to personally thank someone from the OCRA community who supported your work, what would you say?

I want to thank the OCRA members that saw merit in our research ideas and believe in our project and the work we are doing. It is truly an honor and privilege to be supported by this community. I also want to thank those who work hard to fundraise for this initiative, those who take the time to review all the submitted projects, as well as all the people that donate to this important cause. From our whole team, thank you!

Dr. Brodeur’s grant was made possible in part by a generous donation from The Wasily Family Foundation.

See more OCRA-funded research projects focused on immunotherapy.