Ovarian cancer is the sixth leading cause of cancer mortality among women in developed countries. Cyclin E (CCNE1) is overexpressed in 25% of high grade serous ovarian cancers (HGSOC), 48% of clear cell ovarian carcinomas (CCOC), and correlates with chemoresistance and survival. Developing effective therapies leading to durable responses for Cyclin E overexpressing ovarian cancers is a critical need and this proposal addresses this gap.
Cyclin E promotes cell cycle progression. Overexpression of Cyclin E leads to an increased reliance on cell cycle checkpoint regulators, such as WEE1 and ATR. WEE1 specially regulates cell cycle progression by inhibiting both CDK2 and CDK1, thereby inhibiting cell cycle progression at two critical checkpoints, respectively. ATR kinase protects the DNA replication fork from collapse thereby inhibiting cell cycle progression so DNA can repair. Combination inhibition of WEE1 (WEE1i) and ATR (ATRi) is thus a rational strategy to target Cyclin E overexpressing ovarian cancers.
We hypothesize that DNA replication stress caused by Cyclin E overexpression can be further increased to toxic levels by dual inhibition of WEE1 and ATR, thus promoting ovarian cancer cell death and complete tumor suppression. To address this, we have developed primary tumor cultures and ovarian cancer patient-derived xenograft (PDX) models with Cyclin E overexpression. Our preliminary data show that combination of WEE1i with ATRi (WEE1i-ATRi) decreases cell viability, increases cell death in Cyclin E overexpressing HGSOC cells. WEE1i-ATRi significantly decreases transcription regulator, BRD4. Finally, WEE1i-ATRi treatment is not toxic and it improved survival rate 4 times in comparison with chemotherapy or monotherapy in one CCNE1 overexpressing HGSOC PDX model.
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.