Epithelial ovarian cancer (EOC) is uniformly fatal once resistance to platinum based therapy (Pt) is observed. Innate resistance is observed in approximately 25% of the nearly 22,000 annual cases of EOC, where the cancer is intrinsically refractory to Pt therapy. The remaining 75% of women have Pt sensitive disease and will respond with remission lasting up to 5 years. However, the majority of these women will ultimately develop a recurrent, Pt-resistant cancer and succumb to the disease. These courses of disease progression result in an overall 5 year survival rate of 46%. To impact this continuing and significant clinical problem, we will exploit both the mechanism of Pt-therapy and the biology of EOC in a novel treatment strategy targeting genome stability and maintenance. Cisplatin and carboplatin both impart their chemotherapeutic effect by the formation of Pt-DNA adducts which block DNA replication and transcription culminating in apoptosis. Repair of Pt-DNA adducts via nucleotide excision repair (NER) or homologous recombination repair (HRR) reduces the effectiveness of Pt therapy. Both intrinsically and acquired resistant EOC often display alterations in DNA repair or damage tolerance and thus inhibition of DNA repair pathways holds the potential to sensitize these cells to Pt treatment. We anticipate that both direct mechanisms of action on the repair pathways and synthetic lethal interactions can be exploited for therapeutic benefit. Towards this end we will pursue the development and analysis of small molecule inhibitors (SMIs) of the human single-strand DNA binding protein replication protein A (RPA). Our approach is to target the protein-DNA interaction which holds the potential for significant impact to allow an entire new class of interactions to be targeted. In addition to essential roles in NER and HRR which provides the rationale for Pt-sensitization, RPA is also essential for S-phase DNA replication providing a validated target for rapidly dividing EOC cells. Our data demonstrate that RPA inhibition with small drug-like molecules elicits anti-cancer activity in cell culture models of both lung and ovarian cancer. Preliminary data also demonstrate no overt toxicity in mice and potent anti-tumor activity in human cancer xenografts. We will pursue two specific aims that exploit our recently identified lead RPA SMIs NERX-505X and NERX-313E, and advance these molecules for the treatment of EOC. We will therefore;1) Determine the efficacy of lead RPA SMIs as single agents and in conjunction with cisplatin in Pt- sensitive and resistant ovarian cancer cell lines and in normal human surface ovarian epithelial cells and 2) Determine the in vivo pharmacokinetic properties of lead RPA SMIs and assess toxicity and efficacy xenograft studies using combination regimens which include platinum compounds. Successful completion of these studies will support a phase II STTR application to pursue Investigational New Drug (IND)-enabling studies, including expanded safety, toxicity, and efficacy studies.
The research proposed in this application is directly relevant to public health in that we are developing novel therapies for the treatment of ovarian cancer. Successful completion of this work had the potential to impact the over 22,000 women diagnosed with epithelial ovarian cancer (EOC) each year. Providing a more effective treatment regimen is essential to increase overall survival and enhance quality of life for those diagnosed with EOC.
|Pawelczak, Katherine S; Gavande, Navnath S; VanderVere-Carozza, Pamela S et al. (2018) Modulating DNA Repair Pathways to Improve Precision Genome Engineering. ACS Chem Biol 13:389-396|
|Gavande, Navnath S; VanderVere-Carozza, Pamela S; Hinshaw, Hilary D et al. (2016) DNA repair targeted therapy: The past or future of cancer treatment? Pharmacol Ther 160:65-83|
|Mishra, Akaash K; Dormi, Silvana S; Turchi, Alaina M et al. (2015) Chemical inhibitor targeting the replication protein A-DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer. Biochem Pharmacol 93:25-33|