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. CAPR has initiated a study with Dr. Annunziata's clinical program to evaluate SMAC mimetic compounds in combination with taxane chemotherapeutics in a subset of CAPR allograft murine models for SEOC cancer that are dependent on defective Rb and p53 signal transduction but are proficient for Brca1 expression. For several candidate compounds, such as birinapant, in vivo tolerance experiments have been conducted to compare acceptable levels of drug exposure when the compound is administered by different routes (e.g. intra-venous vs. intra-peritoneal injections), as well as interrogate animal tolerance to combination of birinopant with other therapeutic formulations, such as docetaxel and paclitaxel. As an internal new model development initiative, CAPR successfully accomplished a construction of an unmet need murine model for a rare cancer type ovarian choriocarcinoma. Additionally, CAPR oversees a breeding of several models that are anticipated to develop mammary malignancies or ovarian malignancies originating in the fallopian tube/oviduct part of the female reproductive system, broadly believed to house cells of origin for the serous epithelial ovarian malignancies.
