Abstract 637: Filling the gap between preclinical and clinical oncology drug evaluation- Molecular profiling and PD biomarkers on HuPrimeTM tumors models

Abstract

Abstract Most anticancer drug candidates, currently in clinical trials, have clear targets in molecular and cellular systems. However, such molecular targets are not always affected (or not correlated with efficacious endpoints) when the candidate is evaluated in a clinical setting. The gap between preclinical and clinical drug evaluation remains the bottle neck for anticancer drug development. There is an urgent need to develop better biological tools and models to ease the transition between in vitro and in vivo, and between preclinical and clinical settings. In our translational platforms, 170 human primary tumor models (HuPrimeTM) have been established directly from tumor fragments of the patients with many cancer types. In order to pick the best models for evaluation of targeted therapeutics, we have conducted a comprehensive molecular profiling of our models. This profiling includes Affymetrix whole genome expression, Illumina 1400 SNP of cancer related cancer genes for amplification, deletion, and allelic imbalance. Methylation statuses for selected gene sets were also analyzed by SuperArray platform. Genomic amplifications were further confirmed with protein analysis by western blot or immunohistochemistry. The models selected in this way have facilitated pharmacodynamic (PD) biomarker strategies. We have developed a unique platform combining our novel HuPrimeTM xenograft models with molecular profiling and PD biomarker exploration. We have now validated immunohistochemistry (IHC) assays on many molecules covering most signaling pathways that are involved in proliferation, apoptotic, necrotic, and cell cycle regulation, G2M phase arrest, DNA damage response, etc. Additional markers including angiogenesis have also been validated for certain therapeutic compounds. To illustrate the usefulness of our platform, we have applied it to understand the pharmacodynamic changes (at the molecular level) which are associated with the activity of Sunitinib, Sorafenib and Tarceva in several HuPrimeTM models. The PD biomarkers validated in this approach have potential for clinical application and patient stratification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 637.