Histone-Dependent PARP-1 Inhibitors: A Novel Therapeutic Modality for the Treatment of Renal Cell Carcinoma
Abstract
Recent advances in cancer biology and drug discovery provided the foundation for the development of targeted agents. Targeted therapeutics act on specific molecular factors and pathways involved in tumor development and progression and, therefore, they selectively affect cancer cells while sparing normal cells and tissues. The clinical potential of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors has been increasingly recognized over the last years, prompting intensive research on their therapeutic applications. While PARP-1 plays a key role in repairing DNA damage in tumor cells, recent findings indicate that it also serves as a potent transcriptional modulator of various tumor-promoting genes. In clear cell renal cell carcinoma (ccRCC) PARP-1 regulates the expression of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), the most common driving factors in renal carcinogenesis. PARP-1 also functions as a transcriptional coactivator of nuclear factor-kappaB. Enhanced NF-kappaB activity is closely associated with ccRCC tumor progression, metastatic spread, and clinical drug resistance. However, the therapeutic utility of known PARP-1 inhibitors is limited by their non-specific activity. The clinical use of these agents is associated with frequently reported adverse events, including nausea, vomiting, diarrhea, fatigue, and headache. Hematological toxicities such as anemia, lymphopenia, and thrombocytopenia are the most common dose-limiting toxicities of conventional PARP-1 inhibitors. These clinical setbacks can be explained by the fact that all known 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. Importantly, all of the clinically relevant PARP-1 inhibitors such as olaparib, veliparib, and rucaparib, as well as those in exploratory stages of research elsewhere, also act by blocking the NAD binding site on PARP-1 and therefore display promiscuous inhibitory activity. 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, thus minimizing the off-target effects and ensuring greater specificity (patents US 2016/ 0097083 and WO 2016/054237 A3). 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 in vitro and in vivo antitumor activity compared with olaparib (FDA-approved PARP-1 inhibitor) and sunitinib (tyrosine kinase inhibitor approved for the treatment of advanced ccRCC). Our published and preliminary findings fortify the role of histone-dependent PARP-1 inhibitors as effective therapeutic agents for the treatment of kidney cancer. To evaluate the therapeutic potential of novel PARP-1 inhibitors and investigate the molecular mechanisms underlying their antitumor activity, we propose the following Specific Aims: (1) Evaluate the in vitro antitumor activity of histone-dependent PARP-1 inhibitors; (2) Examine ADME and PK properties of histone-dependent PARP-1 inhibitors; (3) Determine the in vivo efficacy of histone-dependent PARP-1 inhibitors using patient-derived xenograft models of human ccRCC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810449
Entities
People
- Vladimir Kolenko
Organizations
- United States Army