The Role of PARP2 in Prostate Cancer
Abstract
Introduction: One of the major barriers to effective prostate cancer (PCa) screening, prevention, and treatment is to distinguish aggressive from indolent disease, as currently, only one in two patients diagnosed have tumors are of minimal clinical consequence. Revealed by our recent genetic study, PARP2 was associated with risk for lethal disease with underlying mechanisms responsible for this phenotype largely unknown. PARP2 is a gene with enzymatic activity that is involved in many physiological and pathological process including cell proliferation, differentiation, and DNA damage repair. PARP2 belongs to a superfamily of enzymes consisting of 17 members that share similar protein structure and functions. The role of PARP family protein and rationale for its inhibition in cancer is primarily based on its DNA repair function. PARP inhibitors make cancer cells more vulnerable to chemotherapy and radiotherapy. Clinical trials with PARP inhibitors have also shown promising results in treatment of cancer patients who carry DNA repair gene mutations. While current PARP inhibitors target both PARP1 and PARP2, previous studies have been focused on PARP1 and the role of PARP2 in PCa has not been studied. We have discovered that (1) PARP2 is significantly overexpressed in aggressive prostate tumors compared to non-aggressive tumors; and (2) PARP2 inhibition has comparable inhibitory effect on PCa growth compared to PARP1 inhibition. This inhibitory effect is further enhanced when PCa cells are treated in combination with anti-androgen therapy (enzalutamide). (3) Inhibition of PARP2 also blocks PCa cell migration. (4) More important, PARP2 physically and functionally interacts with FOXA1, which is a critical factor modulating androgen receptor (AR) signaling in PCa. These results indicated that PARP2 plays an important role in PCa aggressiveness and PARP2 is a therapeutic target for advanced PCa. Objective/Rationale: This proposal is based on the hypothesis that (1) PARP2 enhances PCa growth and progression through regulating pioneer factor FOXA1 function and modulating AR-mediated gene expression and (2) selectively targeting PARP2 is sufficient to inhibit PCa growth and progression irrespective of DNA repair status. The objective of this application is to determine the oncogenic role of PARP2 in PCa, and establish the basis for therapeutic targeting of PARP2 in specific clinical settings. Aims of the Application: The specific aims are to determine (1) whether selective targeting PARP2 inhibits PCa growth and progression in PCa cell and mouse models and (2) the molecular mechanisms by which PARP2 promotes PCa growth and metastasis. Clinical Applicability: Our studies have shown that PARP2 (but not PARP1) is associated with aggressive PCa. This indicates PARP2 may possess more important biological functions in PCa than previously thought. Selective targeting PARP2 is sufficient to inhibit PCa growth through interfering AR signaling irrespective of DNA repair function of PARP. Because PARP2 is involved in AR signaling through interaction with pioneer factor FOXA1, selective PARP2 inhibitors may be applied for androgen-independent castration-resistant prostate cancer (CRPC), including enzalutamide or abiraterone-resistant CRPC. In addition, selective PARP2 inhibitors may have synergistic suppression effect on PCa tumor growth when combined with current antiandrogen therapies (abiraterone and enzalutamide) or general PARP inhibitors (Olaparib and Veliparib) that mainly target DNA repair function. In summary, the successful implementation of this project will not only greatly advance our mechanistic understanding of development of aggressive PCa, but also have important implications for development of prophylactic and therapeutic strategies by targeting PARP2 alone or in combination with either AR antagonists or DNA damage agents.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710251
Entities
People
- Jia Li
Organizations
- United States Army