Abstract IA26: Dual functions of PARP1 in prostate cancer: mechanisms and implications for therapeutic intervention

Prostatic adenocarcinoma (PCa) is the 2nd leading cause of cancer death in US men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct AR antagonists, as PCa is exquisitely dependent on androgen receptor (AR) activity for survival. Furthermore, recent studies identified AR as a major effector of DNA repair, manifest through the ability of the receptor to regulate DNAPK expression and activity. While AR directed therapeutics effectively suppress the pro-proliferative, pro-survival, and pro-DNA repair functions of AR and result in tumor remission, relapse is common. Recurrent disease arises largely due to resurgent AR activity with 2-3 years, and there is no cure for this castration-resistant phase (CRPC, castration-resistant PCa). Thus, there is a significant need to develop new means for targeting recurrent AR activity or develop adjuvant therapies in advanced PCa.The function of PARP1 in DNA repair has been cultivated as a therapeutic target for tumors incurring alterations of specific DNA repair pathways. However, it is now clear that factors beyond DNA repair alterations play a role in the response to PARP1 inhibitors-- as noted in the TO-PARP trial, not all patients with DNA repair alterations responded to PARP1 inhibitors as single agents; conversely, a significant number tumors lacking BRCA1/2 or other DNA repair alterations show obj...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research