Cotargeting Microenvironment Damage Responses to Enhance Prostate Cancer Therapy
Abstract
Prostate cancer (PCa) is the most frequently diagnosed tumor in men, accounting alone for 29% of incident cases. It is the second most common cause of death due to cancer in men after lung cancer. Irradiation is an important treatment modality for localized and locally advanced PCa, with high clinical responses. Although radiation and chemotherapy have been demonstrated to significantly prolong the survival of men with advanced metastatic prostate cancer, resistance to these agents is common and significantly limits their utility. As such, there is a great need to understand the mechanisms underlying de novo and acquired resistance to these agents. Beyond the resistance barrier lies even greater potential to significantly alter the natural course of human cancer. This proposal will focus on the mechanisms of treatment resistance and how to overcome it. Most studies of cancer treatment resistance to date focus on mechanisms intrinsic to the neoplastic cells themselves. In this proposal, I will focus on factors derived from the tumor microenvironment that have the potential to radically influence responses and resistance to radiation, chemotherapy, and potentially pathway-targeted agents. Prior studies from our group and others have shown that genotoxic damage to benign cells comprising the tumor microenvironment generate a DNA damage secretory program (DDSP) that includes a spectrum of growth factors and cytokines that can promote the resistance of surviving tumor cells to further cycles of treatment. In a search for regulators of the damage response that could be targeted by bioavailable drugs, we identified Poly ADT Ribose Polymerase (PARP) as a strong candidate. In this proposal, I will evaluate members of the PARP family as master regulators of the DDSP that could be co-targeted with conventional prostate cancer therapeutics to overcome resistance and improve treatment outcomes. As a principal investigator of this project, my goal is to define and rigorously test potential therapeutic targets that will contribute significantly in bypassing the acquired resistance to radio and chemotherapy. I will conduct a comparative study of the available PARP inhibitors currently under clinical evaluation to determine which most potently suppress the DDSP, define the mechanisms by which they do so, and confirm that suppressing the microenvironment DDSP by impairing PARP will improve tumor cell killing. I want to connect basic DNA repair pathway biology to the clinic so that ultimately it can be harnessed to improve patients survival by enhancing responses to treatment and reducing tumor growth in local and metastatic sites.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510535
Entities
People
- Payel Chatterjee
Organizations
- Fred Hutchinson Cancer Center
- United States Army