Novel Targeted Therapeutics for Castration-Resistant Prostate Cancer
Abstract
The burden of prostate cancer (PC) is tremendous, accounting for approximately 220,800 new cases in the U.S. in 2015 alone. Therefore, development of curative therapeutic agents for the treatment of PC represents an urgent clinical need. Conventional anti-androgen therapeutics, such as abiraterone, enzalutamide, and galeterone, have shown prominent results in pre- and post-chemotherapy settings, prolonging the survival of PC patients. However, nearly all patients ultimately develop a hormone-resistant form of PC. Therapeutic failure is often accompanied by various alterations of the androgen receptor (AR) signaling, including AR overexpression, androgen-independent activation of the AR, and expression of constitutively active AR variants. Several recently concluded studies show clear promise of the poly(ADP-ribose) Polymerase 1 (PARP-1) inhibitors for the treatment of PC tumors harboring mutations in DNA damage-repair genes. Apart from its role in repairing DNA damage, PARP-1 serves as a potent modulator of gene transcription. Recent studies have established that PARP-1 plays a critical role in controlling AR function in PC cells. Thus, PC represents a particularly promising disease site for targeting PARP-1, given that both DNA repair and AR-mediated activity depend on PARP-1 function. Critically, anti-androgen agents target only androgen-mediated activation of AR, whereas PARP-1 inhibitors suppress AR transcriptional function and can therefore be effective against both androgen-dependent and -independent routes of AR activation. The therapeutic utility of known PARP-1 inhibitors is limited by their non-specific activity. These clinical setbacks can be explained by the fact that classical PARP-1 inhibitors were developed by targeting PARP-1 activation via interaction with Nicotinamide Adenine Dinucleotide (NAD). NAD is utilized by many proteins other than PARP-1. Therefore, inhibiting PARP-1 by competing with NAD tends to affect a number of other metabolic processes and results in multiple off-target effects. To address these limitations, we have developed a novel class of PARP-1 inhibitors by targeting the histone-dependent route of PARP-1 activation, a mechanism that is unique to PARP-1 (patent pending). Our preliminary studies demonstrate that histone-dependent PARP-1 inhibitors are highly specific for PARP-1 and do not affect the activity of other enzymes. Importantly, novel inhibitors demonstrate superior anti-tumor activity compared with clinically relevant PARP-1 inhibitors and anti-androgen agents in cell and animal models of PC. The overall objective of the current study is to develop effective anti-cancer therapeutics by examining the anti-tumor activity of a novel class of histone-dependent PARP-1 inhibitors. In addition, we plan to identify cancer-related genes targeted by PARP-1 in PC cells. Products of these genes can serve as biomarkers for PARP-1 inhibitors sensitivity in future clinical trials. To evaluate the therapeutic potential of novel PARP-1 inhibitors and explore the molecular mechanisms underlying their anti-tumor activity, we propose the following specific aims: (1) To identify histone-dependent PARP-1 inhibitors with the superior anti-tumor activity. (2) To investigate the molecular mechanism underlying PARP-1-dependent control of PC malignant growth. (3) To develop the optimal strategy for blocking histone-dependent activation of PARP-1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710169
Entities
People
- Alexei Tulin
Organizations
- United States Army
- University of North Dakota