Ovarian cancer is the deadliest of all gynecologic cancers. It ranks fifth as a cause for cancer deaths among women. Up to 80% of ovarian cancer patients eventually develop resistance to standard chemotherapy with unclear mechanisms. Such drug resistance has been linked to the gain of a specific regions of our genome, 1q12-1q21. Cisplatin causes DNA damage during DNA replication, is the first line treatment option for ovarian cancer patients and has been shown to promote 1q21 gains which have been implicated in cancer associated genomic gains and drug resistance. KDM4A, an enzyme, is amplified and overexpressed in ovarian cancer. The KDM4A amplification was associated with a faster time to death in these patients. Interestingly, those gained genomic regions were co-amplified with KDM4A. Low oxygen tensions also known as hypoxia, stimulates site specific copy number gains of these genomic regions, driven by KDM4A. These copy number gains can be correlated to enriched amplifications in hypoxic primary tumor samples. Tumor hypoxia has been identified as a major determinant of drug resistance in ovarian cancer, associated with features of tumor aggressiveness. In this proposal, we will study the role of KDM4A in copy number gains and cisplatin response in ovarian cancer under normoxic and hypoxic conditions to understand ovarian cancer cell behavior and drug resistance. These studies will bridge molecular mechanisms with clinical outcomes and help us to design novel therapeutic targets for ovarian cancer treatment.
Dr. Damayanti Chakraborty is a postdoctoral fellow in Dr. Johnathan Whetstine’s laboratory at Massachusetts General Hospital Cancer Center. She got her PhD in Reproductive Biology from University of Kansas Medical center, where she conducted her research on epigenetic regulation of trophoblast stem cell maintenance and differentiation, working on the molecular basis of cell fate heterogeneity along with studying reproductive hormonal axis in transgenic animal models.
Dr. Chakraborty is interested in understanding epigenetic regulation of DNA copy number gains and tumor heterogeneity in ovarian cancers. Her postdoctoral research will focus on mechanisms by which histone demethylases regulate these site specific copy amplifications under influence of stressors like low oxygen signaling. The identification and characterization of those mechanisms will enable a better understanding of tumor cell heterogeneity and acquisition of drug resistance. Dr. Chakraborty has received prestigious Society for Study of Reproduction (SSR) trainee research award in 2015 annual meeting, a Lalor Foundation merit award for outstanding abstract in SSR annual meeting 2015, a NIH merit award in International Federation of Placenta Associates 2016 meeting. She also received fellowship from American Heart Association and Biomedical Research Training grants from University of Kansas Medical Center.