Exploiting Ferroptosis for the Treatment of RB1-Deficient Lethal Prostate Cancer
Abstract
Rationale/Objective/Aims: Prostate cancer is the second leading cause of cancer-related death in the United States. Despite the development of new-generation antiandrogens that significantly extended the survival time of prostate cancer patients, drug resistance inevitably developed over time. Therefore, there is an urgent need to develop novel therapies that specifically target treatment-resistant prostate cancer. Previous studies have revealed that the loss of the RB1 gene is one of the most crucial genetic events to promote therapy resistance and adverse prognosis of prostate cancer. Up to 33% of the adenocarcinoma castration-resistant prostate cancer (CRPC) and 70% of the more aggressive neuroendocrine CRPC tumors were found to harbor RB1 gene aberration. Importantly, up to 90% of neuroendocrine CRPC displays RB protein loss. Intriguingly, our present study found that RB1 gene deficiency sensitizes prostate cancer cells to a newly discovered type of programmed cell death called ferroptosis. We therefore hypothesize that ferroptosis is an emerging cancer vulnerability that could be harnessed as a novel therapeutic target for the treatment of a majority of lethal prostate cancer. In this proposed study, we aim to clarify how RB regulates ferroptosis and thus facilitate the translation of ferroptosis targeting therapies into the clinic. By conducting preclinical mouse studies and applying modern molecular and cell biology approaches, we propose to achieve the following specific aims in this study: Specific Aims: Aim 1. To determine the in vivo therapeutic potential of ferroptosis induction in the treatment of RB1-deficient lethal prostate cancer. Aim 2. To investigate the molecular mechanisms of RB-regulated ferroptosis. Aim 3. To determine the correlation between RB, ACSL4, and ferroptosis markers in mCRPC (metastatic CRPC) samples. Ultimate Applicability of the Research: The proposed study could potentially contribute to two of the FY21 PCRP Overarching Challenges: Develop treatments that improve outcomes for men with lethal prostate cancer and Define the biology of lethal prostate cancer to reduce death. Specifically, we anticipate that the ferroptosis-targeting therapy could be applied to those patients with RB1-deficient lethal prostate cancer. We expect that this novel therapeutic strategy can effectively prevent metastasis and tumor recurrence and ultimately eliminate the death of prostate cancer. We expect that the preclinical and mechanistic studies will provide valuable data to help to translate the ferroptosis-targeting therapy into clinics. Principal Investigator’s Career Goals in Prostate Cancer Research: My career goal is to become an independent and productive cancer biologist and dedicate my professional expertise and effort to the field of prostate cancer research. The ultimate goal of my research is to develop more effective therapies to improve the life quality of those who are suffering from lethal prostate cancer. The support of this award and mentorship from highly experienced researchers in the prostate cancer research field will not only provide me the essential knowledge and skills, but also help me to gain the capability of independence for my career development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211005
Entities
People
- Mu-En Wang
Organizations
- Duke University
- United States Army