Ongoing efforts in our laboratory have been towards understanding the biology of ovarian cancer and identifying new treatments from which patients with ovarian cancer could benefit. Recent efforts have focused on exploring therapies that will target specific subgroups of patients with ovarian cancers with similar genetic alterations. These kinds of therapies are generally known as targeted therapies. In order to apply an appropriate targeted therapy to a specific ovarian cancer subtype, it is of essence to understand the biology of genes and mutations that define this subtype. The focus of our studies is to explore targeted therapies in an ovarian cancer subtype that has mutations in genes involved in the repair of damaged DNA.
DNA is constantly exposed to various damaging factors so it is vital for the cell to have functional DNA damage repair mechanisms, such as homologous damage repair (HDR). Some of the most common HDR genes that are mutated in advanced ovarian cancers are the BRCA1 and BRCA2 genes. Clinical trials have shown that ovarian cancers carrying mutations in these genes are extremely sensitive to PARP inhibitors, agents that are specifically targeting HDR-impaired cells. Recently, it has been suggested that ovarian cancer subtypes with intact BRCA genes but with mutations in other genes essential for HDR, might also respond to PARP inhibitors.
In our studies, we are exploring the biology of ovarian cancers with alterations in EMSY, a putative HDR gene, and testing how these cells respond to PARP inhibition in combination with other HDR-targeted agents. The mechanism of how EMSY suppresses DNA damage repair is unknown. We challenge the currently held impression that EMSY interacts with BRCA2 and propose a BRCA2-independent mechanism for EMSY’s role in HDR. Checkpoint kinase 1 (CHK1) activation is a critical component of the HDR pathway and it has been shown that PARP and CHK1 inhibitors can synergize in breast and pancreatic cancers. We are testing for the synergy between these inhibitors in EMSY-overexpressing and other HDR-impaired ovarian cancer cells. Our published work demonstrated that PARP inhibitors trigger CHK1 activation. We propose that maintaining lower CHK1 activity in EMSY-overexpressing and other HDR-impaired ovarian cancers could further sensitize these cancers to PARP inhibition. Therefore, PARP inhibitors could particularly benefit from combined treatment with CHK1 inhibitors.
Our work will unravel a novel BRCA2-independent mechanism for EMSY’s role in HDR. Demonstrating that EMSY-amplified and other HDR-impaired ovarian cancer patients may benefit from HDR-targeted therapies could have a noticeable impact on treating a substantial population of high-grade advanced ovarian cancer patients, accounting for almost 50% of all cases. The right combination targeted therapy could minimize toxicity, ensuring better quality of life for women with ovarian cancer and ultimately improve their chances for survival.
Dr. Petar Jelinic is currently a Research Associate in the Department of Surgery at Memorial Sloan Kettering Cancer Center (MSKCC). He earned his Diploma in Molecular Biology from the University of Zagreb, Croatia. In obtaining a PhD from the University of Lausanne, Switzerland, Dr. Jelinic’s research focused on studying a unique subset of genes, called imprinted genes, which are tightly regulated in a parent-of-origin fashion. Studying molecular mechanisms relevant to carcinogenesis remained the focus of his work after joining New York University Langone Medical Center as a postdoctoral fellow. In 2010, Dr. Jelinic joined the Gynecology Research Laboratory at MSKCC led by Dr. Douglas Levine where his current research focuses on DNA damage repair pathways in ovarian cancer and related targeted therapies. Dr. Jelinic was also a recipient of the Florence & Marshall Schwid Ovarian Cancer Research grant from the Foundation for Women’s Cancers in 2012.