Abstract 2389: Efficacy of ABT-737 against c-Myc-induced mammary adenocarcinomas in transgenic and syngrafted mouse tumor models

Abstract

Traditional preclinical discovery methods and models only poorly predict drug efficacy in clinical trials. It has been reasoned that present cultured tumor cell line and xenotransplantation-based in vivo models are too reductionist, failing to recapitulate tumour heterogeneity, tumor-microenvironment interactions and tumor microevolutionary trajectories. The genetically engineered mouse models (GEMMs) hold promise as next generation preclinical models, but the caveat is that GEMMs are not straightforward suitable for preclinical cohort studies. Here we hypothesized that mammary tumors from tumor-prone WAP-Myc mice retain their molecular characteristics and authentic drug responses when recreated as syngrafts in the mammary fat pads of recipient mouse. This platform would allow rapid and non-laborious pilot cohort studies with GEMM tumors. We are testing the hypothesis by determining tumor markers and apoptotic efficacy of BH3-mimetic ABT-737 against c-Myc-induced mammary adenocarcinomas and pulmonary metastases in both transgenic and syngraft models. In the WAP-Myc mice c-Myc is induced in the luminal mammary epithelial cells during late pregnancy resulting in development of endogeneous mammary adenocarcinomas in nearly 100% of multiparous animals. We observe that the tumors are transplantable as cells suspensions (25 000 cells/gland) with approximately 90% success rate. While the transgenic WAP-Myc tumors develop with an average of 3.5 months latency, the syngrafted tumors develop within 3-4 weeks post-transplantation. However, in contrast to 20% rate of pulmonary metastases in the transgenic WAP-Myc mice, syngrafted animals need to be sacrificed prior to metastasis formation. Our preliminary results suggest that the tumor histopathology does not significantly change and the tumor heterogeneity is preserved in the syngrafted tumors. To investigate the response of tumors to ABT-737, animals bearing either endogenous or transplanted tumors were treated with 100mg/kg of ABT-737 for 21 days. ABT-737 reduced primary tumor growth and lung metastases as well as enhanced caspase-3 activity in the transgenic WAP-Myc tumors. Also the syngrafted tumors respond to ABT-737 and the data comparing effects in transgenic versus syngrafted tumors will be presented. Our results demonstrating feasibility of the syngraft platform may help to alleviate many shortcomings of GEMMs in preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2389. doi:10.1158/1538-7445.AM2011-2389