Genome-Scale Synthetic Lethal Screens in Prostate Cancer Cells by CHRISPR -Cas9 System
Abstract
Prostate cancer is the most common solid tumor among men in Western countries and the second leading cause of cancer-related death in American men after lung cancer. Despite the increasing knowledge of this disease during several recent decades, there is still no ideal therapy for localized or metastatic advanced prostate cancer, which usually exhibits poor responsiveness to androgen deprivation therapy. Progression into such hormone-refractory castration-resistant prostate cancer often heralds the onset of lethal form of disease and lacks effective curative treatments. The mechanism of progression remains elusive. In this proposal, by using a cutting-edge genome-editing tool called CRISPR, I aim to identify effective precision medicines that specifically target prostate cancer cells with tumor suppressor loss-of-function mutations and leave normal cells unharmed, as well as discover novel therapeutic targets for treatment of castration-resistant prostate cancer. According to our preliminary data and others reports, loss of TP53 or PTEN genes in androgen-dependent prostate cancer cells will result in the cells resistant to androgen deprivation therapy (ADT). We hypothesize this tumor suppressors may repress their targets that play important roles for ADT resistance, and double knockout of the tumor suppressors and its targets in these prostate cancer cells would be synthetic lethal upon ADT. This project has both biological and clinical significance to understand the mechanism of castration resistance and identify novel therapeutic targets combined with ADT for future precision prostate cancer medicine. My career goal is to become a leading research scientist in the field of prostate cancer, deciphering the code of cancer progression and developing promising therapies for fighting this notorious disease. As a postdoctoral trainee at the Dana-Faber Cancer Institute and Harvard Medical School, I am co-mentored by two excellent prostate cancer and cancer genomics experts -- Dr. Myles Brown and Dr. Xiaole Shirley Liu. I believe that in a training environment as such, I will obtain all the support and guidance that I need to satisfactorily complete the proposed project and to ultimately achieve my career goal. The completion of this study will greatly extend our knowledge of the mechanism of castration resistance during prostate cancer progression and open a door to novel therapeutic targets in the clinical practices for fighting prostate cancer in the near future, especially against those tumors with resistance to current ADT.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610409
Entities
People
- Tengfei Xiao
Organizations
- Dana–Farber Cancer Institute
- United States Army