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.
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.