First line treatment of ovarian cancer includes combination therapy with a platinum drug (Pt), either cisplatin or carboplatin (1). A major impediment to the successful treatment of epithelial ovarian cancer (EOC) is resistance to Pt-based chemotherapeutic agents (3). Even in EOCs that initially respond to treatment, most will recur and will be Pt resistant; with an extremely poor prognosis as second line therapies are largely ineffective. The difficulties in providing effective treatment of EOC highlights the importance of tailoring therapies based on the biology of the individual disease. Recent advances in our understanding of the homologous recombination (HR)/BRCA pathway in breast and ovarian cancer (4;5) and the common alteration of HR in these cancers has led to targeting poly-ADP-ribose polymerase (PARP) by exploiting the concept of synthetic lethality. While PARP inhibitors have had some success in single agent studies in BRCA mutant cancers, combination of PARP inhibitors with Pt therapy has been considerably less effective. Pt agents impart their therapeutic effect by the formation of Pt-DNA adducts, which block DNA replication and transcription. Repair of Pt-DNA adducts reduces the efficacy of platinum-based treatment and contributes to cellular resistance. Importantly, repair of Pt-DNA damage is catalyzed by the PARP-independent pathways, nucleotide excision repair (NER) and homologous recombination repair (HRR). Thus, in HRR deficient cancers, targeting NER would be expected to have a significant impact on sensitivity to Pt therapy. Germ line mutations in BRCA1 or 2 predispose women to hereditary breast and ovarian cancer which are HRR deficient. Therefore we will address the hypothesis that synthetic lethal interactions can be exploited targeting the NER pathway with small molecules in HRR deficient cancers and, when combined with cisplatin will provide increased efficacy with minimal toxicity. Cisplatin treatment, in combination with an NER inhibitor, will differentially alter the repair capacity of different cells dependent on their HRR status. Non-cancerous, HRR proficient cells can repair or tolerate the cisplatin damage via HRR and thus will have reduced toxicity compared to the HRR deficient cancer cells which are unable to repair the cisplatin damage via either pathway. To address our hypothesis we will employ our recently discovered NER inhibitors targeting the xeroderma pigmentosum group A (XPA) protein (6) and replication protein A (RPA) (7-9) in two specific aims.
Aim 1 will develop and characterize novel inhibitors of the XPA protein and assess efficacy in combination with cisplatin in cell culture models of HRR proficient and deficient human ovarian and breast cancers. We will then determine the impact of XPA inhibition in combination with cisplatin therapy on cytotoxicity, DNA damage signaling and repair of cisplatin-DNA damage in cell culture and xenograft models of breast and ovarian cancer.
In aim 2 we will determine the mechanism by which small molecules targeting the RPA protein inhibit the RPA-DNA binding interaction, achieve single agent activity and synergize with cisplatin and etoposide in BRCA1 deficient cancers. Our previous data identified two classes of RPA inhibitors, both of which decrease

Public Health Relevance

Targeting DNA repair is a validated mechanism to sensitize cancer cells to cisplatin- based therapy. This research investigates a biology-based mechanism of chemical synthetic lethality to target BRCA1 mutant ovarian and breast cancers in a cisplatin- combination regimen via inhibition of nucleotide excision repair. This information will provide important chemical, biochemical and cellular information necessary to therapeutically exploit the DNA repair defects in many cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA180710-04
Application #
9117467
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kondapaka, Sudhir B
Project Start
2013-09-30
Project End
2018-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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; Mishra, Akaash K et al. (2017) Design and Structure-Guided Development of Novel Inhibitors of the Xeroderma Pigmentosum Group A (XPA) Protein-DNA Interaction. J Med Chem 60:8055-8070
Sears, Catherine R; Cooney, Sean A; Chin-Sinex, Helen et al. (2016) DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer. DNA Repair (Amst) 40:35-46
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
Woods, Derek S; Sears, Catherine R; Turchi, John J (2015) Recognition of DNA Termini by the C-Terminal Region of the Ku80 and the DNA-Dependent Protein Kinase Catalytic Subunit. PLoS One 10:e0127321
Turchi, John J; Woods, Derek S; VanderVere-Carozza, Pamela (2014) Testing the metal of ERCC2 in predicting the response to platinum-based therapy. Cancer Discov 4:1118-9