Integrated genomics and avatar mouse models for personalized cancer treatment.

Abstract

2511 Background: Every cancer has its unique set of molecular changes and the knowledge of such alterations is enabling an individualized approach to cancer treatment. The great intellectual challenge lies in linking confirmed mutations to protein function. Methods: Using massive parallel sequencing we performed whole exome sequencing analysis of 30 patients (pts) with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. We used 2 in silico methods (Polyphen and SIFT) to estimate the functional significance of a given confirmed mutation. Avatar models generated by direct engraftment of tumor samples from the patients into immunocompromised mice were used as an in vivo platform to test proposed treatment strategies. Results: Successful exome sequencing analyses has been obtained for 28 pts. Tumor specific mutations (Muts) and copy number variations were identified ranging from 5 to 952 and 0 to 956 respectively. All samples profiled contained relevant genomic alterations. Some of the most relevant actionable alterations were: CHEK1, FGFR2, IGF1R, MET, BRCA1, XPC, NOTCH, CREB3LB, GNA11, SMAD4, NF1, PTPRC, PI3KA, DDR2 and EGFR. An Avatar model was generated for 15 patients. In occasions actionable alterations such as muts in NF1, PTPRC, PI3KA and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and accordingly treatment of the pts with these drugs was not effective. So far 13 pts have received a personalized treatment: two, as expected based on the avatar model, did not response; 5 resulted in durable partial remissions. Eight pts are currently on treatment with at least disease stabilization. Bench testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in patients with no actionable mutations. Conclusions: The use of full genomic analysis for cancer care is promising but presents important challenges that will need to be solved for broad clinical application. Avatar models are a powerful investigational platform for therapeutic decision making and help to guide cancer treatment in the clinic. While limitations still exist, this strategy should be tested in prospective randomized clinical trials.