Abstract A11: Modeling drug response and resistance using patient-derived xenograft models.

Metastatic melanoma is a highly lethal type of cancer and is often refractory to all traditional chemotherapeutic agents. Melanoma is associated with a high burden of genetic alteration, e.g. BRAF, NRAS or NF1 mutation. In the clinic, BRAF inhibitors are used as a targeted therapy to treat melanoma patients, but thus far a single-agent approach is not capable of achieving a durable response for this lethal disease. Very often, patients rapidly develop resistance to BRAF inhibitors. In the current study, we propose a large scale in vivo screening using patient-derived xenograft models (PDXs) for compound profiling. Since these PDX melanoma models are derived from individual patient tumors and therefore represent the genetic heterogeneity of patient tumors, we propose a “one animal per model per compound” approach (mouse clinical trial) to understand the genetic factors that contribute to drug response. In addition, we use this approach to model drug resistance after long-term compound treatment. We find that the mouse clinical trial approach accurately predicts response of both cytotoxic chemotherapeutics as well as targeted therapies. In addition, this approach successfully recapitulates the resistance profile of a novel BRAF inhibitor LGX818 in melanoma. We also find that combination of LGX818 with other targeted therapy agents including PI3K and MEK inhibitors significantly increases the response rates and delays the development of resistance. Taken together, our findings suggest that the mouse clinical trial is a valid approach to model drug response and resistance, and can be used to predict patient response in the clinic. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A11. Citation Format: Guizhi Yang, John Green, Colleen Kowal, Shawn Cogan, Roberto Velazquez, John Monahan, Joshua Korn, Nicholas Keen, Juliet Williams, Hui Gao. Modeling drug response and resistance using patient-derived xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A11.