Ovarian cancer is the sixth leading cause of cancer death among women in developed countries. Clear cell ovarian cancer (CCOC) is a subtype of ovarian cancer that is mostly resistant to chemotherapy with limited treatment options. Investigating how CCOC are resistance to current therapies and developing new treatments with durable efficacy for CCOC is an unmet need and this proposal addresses this gap. ARID1A gene mutated in about 50% of CCOC leading to loss of functional ARID1A protein. ARID1A alters the DNA chromatin structure leading to the transcription of certain genes. We hypothesize that ARID1A loss increases the reliance on chromatin remodeling and DNA damage repair pathways for CCOC cell survival. We therefore propose that combination DNA damage inhibitor ATRi with BETi and other chromatin remodeling inhibitor will have better therapeutic effects in ARID1A mutant CCOCs in comparison to monotherapy. Through testing multiple drugs in a dug screen, our preliminary data revealed that BETi is the most active monotherapy in CCOC and combination BETi with ATRi is synergistic at lower dosing schedules in ARID1Amut (not ARID1A wildtype) CCOC. To further decrease the toxicity and increase the efficacy of combination, we propose the following Specific Aim 1: To identify the most active combination of DNA damage inhibitors with BET inhibitors and dosing schedule for CCOC with ARID1A loss. Specific Aim 2: To discover new chromatin modifier for ATRi combination to induce synthetic lethality in ARID1A mutated CCOCs by a using a novel technology called CRISPR-Cas9 screen in mutagenesis of functional protein domains. IMPACT: Our study may discover new and better therapies for CCOC with ARID1A loss. The goal is to move the most active combination treatment into clinical trial for patients.
This grant was made possible in part by a generous donation from The Lilly Family, in memory of Jennifer Lilly.
Dr. Haineng Xu received his B.S. degree from Anhui Normal University, China, and his Ph.D. from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Dr. Xu is currently a Research Associate in Ovarian Cancer Research Center, Department of Obstetrics and Gynecology at the University of Pennsylvania Perelman School of Medicine (Penn Medicine). During Ph.D. training, Dr. Xu focused on designing and optimizing the conditionally replicated adenovirus to specially replicated in and suppress lung and bladder cancer stem cells, overcoming drug resistance. In his prior postdoctoral training in the Department of Radiation Oncology at Penn Medicine, his main projects are overcoming drug resistance in glioma by targeting cancer microenvironment and glioma stem cells. Dr. Xu joined Dr. Fiona Simpkins laboratory in Penn ovarian Cancer Research Center to develop novel therapeutic strategies by exploiting the genetic vulnerabilities in ovarian cancer. He utilized the novel orthotopic patient-derived xenograft models in the preclinical trials to evaluate the drug efficacy and the mice tolerability. He explored that combination of WEE1 and ATR inhibition is effective in treating platinum- resistant ovarian and endometrial cancers and identified CCNE1 level as a biomarker for the treatment. He also discovered that the combination inhibition of PARP and ATR was able to overcome PARP resistance in ovarian cancers. Dr. Xu is currently discovering new treatments for ARID1A mutant clear-cell ovarian cancer (CCOC) by combination of DNA damage inhibitors with BET inhibitor. He is also exploring new chromatin modifiers for ATRi combination to induce synthetic lethality in ARID1A mutated CCOCs by a CRISPR-Cas9 screen in mutagenesis of functional protein domains. The ultimate goal is to identify new therapies for women with clear cell ovarian cancer in the lab and bring them to the clinic. Dr. Xu’s research has been supported by Ovarian Cancer Research Alliance (OCRA) and Kaleidoscope of Hope (KOH). He is a previous recipient of OCRA Ann and Sol Schreiber Mentored Investigator Award.