2018 Ann and Sol Schreiber Mentored Investigator Award Recipient — Damayanti Chakraborty, PhD
Project Summary
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.