Therapeutic evaluation in ovarian and breast cancer GEM-GDA models

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

CAPR ovarian program successfully completed a large-sale CCR Oversight Committee approved collaborative study with Dr. Yves Pommier's laboratory. In the frames of these collaborative efforts, CAPR scientists 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 has been completed in full and data reported back to the collaborating investigator to be included in a publication that appeared in October'2019 Clinical Cancer Research journal. 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. In another OC approved project, 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, docetaxel and paclitaxel, in vivo tolerance experiments have been conducted to compare adequate levels of single drug exposure not causing severe toxicity in experimental animals when the compounds are administered by different routes (e.g. intra-venous vs. intra-peritoneal injections), as well as interrogate animal tolerance to combination of birinapant with other therapeutic formulations, such as docetaxel and paclitaxel. Combinatorial efficacy studies are presently underway to examine in SEOC models the effects of co-administering birinapant compound with several taxane formulations already broadly used in cancer treatment practices, such as docetaxel, paclitaxel, and abraxane. Pursuing an internal new model development initiative, CAPR ovarian cancer researchers successfully accomplished a construction of an unmet need murine model for a rare cancer type ovarian nongestational choriocarcinoma (NGCO) and characterized this novel model at the histopathologic and molecular levels to demonstrate the selection of molecular determinants that are common and distinct between EEOC and NGCO as well as comparative metastatic potential of SEOC and NGCO tumors initially at the stage of autochthonous disease, and subsequently in passage I GEM-derived allograft tumors. As a additional more recently launched effort, CAPR ovarian cancer team has commenced an NCI CRADA-supported project with Dr. Jeremy Cheng's lab at the University California at Davis to evaluate novel therapeutic options developed in Dr. Cheng's lab using CAPR models for ovarian cancer malignancy.