We have previously verified that the SEOC GDA models respond to cisplatin or olaparib similarly to patients, with olaparib demonstrating efficacy only in BRCA deficient tumors and cisplatin is optimally effective in these tumors. The combination of these two drugs for BRCA deficient tumors is no more efficacious than cisplatin alone. We have completed evaluation of consolidated therapy for BRCA1-deficient GDA tumors in which mice are treated with cisplatin to de-bulk tumors followed by treatment with an FDA-approved drug demonstrated in compound library screenings to be effective at killing both human and mouse SEOC-derived cells in a 2-D cell culture treatment paradigm. With standard routes of introduction, the compound was not more effective than the vehicle control. We are now evaluating the efficacy of this drug when delivered by implanted continuous dosing pumps. Studies for all other objectives are currently in progress. We have also completed several studies in a CRADA-supported collaboration with a Big Pharma company to assess the biomarker environment and conduct efficacy studies with combined treatment regimen of a PARP inhibitor, a VEGFR inhibitor, and an immune checkpoint inhibitor. Additional follow-up studies have been designed, per Company's request, and currently conducted. These efficacy tests are performed in both BRCA-proficient and BRCA-deficient models. CAPR also embarked on a CCR Oversight Committee approved collaborative study with Dr. Yves Pommier's laboratory conducted evaluation of three topoisomerase inhibitors discovered by Dr. Pommier's team for tolerability and efficacy in the orthotopic ovarian cancer model derived from the Brca1-deficient GEM models. This project is largely completed and data reported back to the collaborating investigator. In collaboration with investigators from the Division of Cancer Prevention (Dr. Shoemaker's laboratory), CAPR scientists are establishing a tractable murine model for breast adenocarcinoma by employing intra-ductal induction technique to infuse recombinant viral vectors expressing Cre recombinase into animals pre-programmed to inactivate pRb, p53 and Brca1/2 signaling upon Cre-mediated recombination in Adeno-Cre/Lent-Cre infected mammary epithelium cells. To support recently established collaborative relations with another CCR investigator Dr. Brad St. Croix, CAPR provided ovarian cancer tissue histologic specimen collection to enable evaluation of expression for target biomarkers important for subsequent testing of Dr. St. Croix's antibody-drug conjugates with putative therapeutic properties against ovarian and pancreatic tumors. This project is ongoing with an outlook of planning the efficacy treatment experiments as soon as expression data become available and analyzed.
