Therapeutic evaluation in ovarian and breast cancer GEM-GDA models

Division Of Basic Sciences - Nci

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Abstract

CAPR previously developed both GEM and orthotopic allograft models for serous epithelial ovarian cancer (SEOC). These models harbor genetic aberrations in the pathways that are most frequently perturbed in human patients (namely BRCA1, TP53 and RB) and closely resemble human disease on histological and molecular levels. The Brca1-deficient mouse ovarian tumors respond to current standard of care (cisplatin) and to the PARP inhibitor olaparib, recapitulating clinical data for patients deficient in BRCA1, and thus represent a valuable tool for preclinical testing of potential therapeutics. Dr. Pommier's laboratory identified the indenoisoquinolines LMP400, LMP744, and LMP776, as novel topoisomerase I (TOP1) inhibitors and selected them for clinical development to overcome the known limitations and toxicities of camptothecin drugs like irinotecan. To determine which of the idenoisoquinolines had the best in vivo properties and whether Brca1-deficient ovarian cancer represented an appropriate patient population for the Phase II clinical trials, Dr. Pommier proposed to test the activity of the three LMP compounds in CAPR's ovarian orthotopic allograft cancer model. We found that LMP400 exhibited the maximum efficacy at a dose that was well tolerated in mice. We also evaluated whether the combination treatment of LMP400 and olaparib was synergistic in the Brca1-deficient or Brca1-wildtype ovarian cancer models. Tumor growth in the Brca1-deficient model was delayed by the olaparib/LMP400 combination, which resulted in a greater increase in survival than with either drug alone, but no survival benefit was observed in the tumors without Brca1 deletion. These findings published in Clinical Cancer Research provided the rationale for developing Phase II clinical trials of LMP400 (indotecan), the most advanced indenoisoquinoline TOP1 inhibitor, in combination with PARP inhibitors such as olaparib and demonstrated the value of developing future non-camptothecin TOP1 inhibitors as anticancer agents for patients with SLFN11-expressing and BRCA1/homologous recombination deficient tumors. In the frames of another project, to expand our portfolio of autochthonous murine models for gynecologic malignancies, we have modeled breast cancer development in the mouse by directly inducing Brca1 or Brca2 loss, inhibition of proteins of the Rb family (pRb, p107 and p130), and Trp53 loss or mutation (R172H) in the adult mammary ductal epithelium without pre-selecting the cellular subtype. The most frequently used Cre transgenes in mouse models for breast cancer are driven by various mammary tissue-specific promoters that direct genetic aberrations into a specific cell type. Although these mammary specific Cre transgenes are widely used, they do not allow for temporal control of the Cre expression, often resulting in induction of genetic events before onset of adulthood. Moreover, many of the Cre transgenes are expressed also in other tissues besides mammary gland. We have developed models with different allele combinations that cooperate to produce hormone receptor (HR) positive or negative mammary tumors of the luminal or basal subtype, respectively. Mice with Brca1 and Trp53 loss develop basal HR-negative mammary tumors, and mice with inhibition of Rb and Trp53 loss or the combination of Rb, Trp53 and Brca1 aberrations develop luminal ductal carcinoma that is positive for ER, PR and Her2 expression, but endocrine resistant. We completed molecular characterization of key pathways and analyzed drug sensitivities in vitro. We found that endocrine-resistant models exhibit upregulation of PI3K signaling and sensitivity to pathway inhibition, presenting a platform for evaluation of targeted combinations to improve chemotherapeutic response in patients. Moreover, the induction of genetic events in adult mice bypassed dependence on promoters that may express very early in mouse mammary development in progenitor cells. Therefore, these models are ideal for evaluation of cancer prevention strategies, especially those targeted towards Brca1 mutation carriers. We are currently finishing a manuscript describing these models. Additionally, we have generated a novel GEM model for nongestational choriocarcinoma (NGCO), an ovarian malignancy with poor prognosis, that carries alterations in Brca2, Trp53, and RB. As reported in Veterinary Pathology, we also established syngeneic orthotopic mouse models for NGCO, and these metastatic models provide a platform for evaluating new treatment strategies in preclinical studies aimed at improving outcomes in choriocarcinoma patients.