2019 Mentored Investigator Grant Recipient — Haineng Xu, PhD

Project Summary

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.

Bio

Dr. Haineng Xu is a postdoctoral researcher at the Ovarian Cancer Research Center at the University of Pennsylvania. Dr. Xu graduated from Chinese Academy of Sciences, where his research focus was on designing and optimizing the conditionally replicated adenovirus to specially suppress liver cancer cells and lung cancer stem cells, utilizing small molecular drugs to target gastric cancer stem cells. Dr. Xu is currently working under the supervision of Dr. Fiona Simpkins to develop novel therapeutic strategies by exploiting the genetic vulnerabilities in ovarian cancer. Combination of WEE1 and ATR inhibition was explored to treat the PARP inhibitor- and platinum- resistant, CCNE1 overexpressing ovarian cancers. The novel orthotopic patient-derived xenograft models are utilized in the preclinical trials to evaluate the drug efficacy and the mice tolerability. Treatment schedule optimization of the combination of WEE1 and ATR inhibitors further improve its efficacy and drug tolerance of the mice. The ultimate goal is to identify new therapies for women with ovarian cancer in the lab and bring them to the clinic.