Abstract 3614: Development of a contra-indicatory biomarker to predict drug resistance and treatment failure
Authors: Dai Donghai , Beck Brandon B. , Wang Xiaofang , Howk Cory L. 
Published: August 2012

The efficacy of a targeted therapy relies on the existence of a unique target, a molecular alteration necessary for tumor growth (oncogenic dependence). However, there is increasing evidence that some tumors may contain alterations in multiple oncogenic pathways. Furthermore, cancer cell subclones inside a tumor may harbor distinct oncogenic pathways critical for their growth, exhibiting an intra-tumor genetic heterogeneity. This genetic heterogeneity among cancer cells has important implications in tumor evolution and could adversely affect treatment outcomes. While conventional biomarkers are commonly used as an indication for drug efficacy, we sought to evaluate an overall assessment of genetic alterations in a tumor and investigate if it can predict a tumor's resistance to an agent, for use as a contra-indicatory biomarker. Our study has found that an individual patient tumor contains subclones with unique profiles of loss-of-heterozygosity (LOH). The gene expression profiles have shown a similar pattern. Using transcriptome sequencing, we identified unique profiles of genetic mutations among cancer cells and demonstrated several distinct oncogenic pathways that are differentially activated among subclones. Xenograft studies have shown that individual tumors and individual subclones within a tumor respond differentially to targeted agents, ranging from being sensitive to resistant. Specifically, xenografts created from cancer cell clones isolated from the culture of primary tumors may be sensitive even when isolated from a resistant tumor, and other xenografts may be resistant even when created from clones isolated from a sensitive tumor, indicating the heterogeneity in the original tumors. Longitudinal immunohistochemical analysis of estrogen receptor, epidermal growth factor receptor and vascular endothelial growth factor showed that the cancer cell populations of individual subclones evolve differentially when treated with agents targeting these factors. Our preliminary analysis based on the quantitative measurement of LOH among subclones in individual tumors indicates that a cutoff value can be used with good specificity to predict drug resistance and this prediction works equally well for several targeted agents, suggesting that intra-tumor heterogeneity may be a common mechanism of treatment failure for many targeted agents. We are currently working to validate the sensitivity and specificity of the heterogeneity score in more patient tumors in vivo. We have reported a contra-indicatory biomarker for targeted therapies to predict treatment failure and remove patients from unnecessary treatment. This biomarker can be used complementarily in targeted therapy to improve drug efficacy in clinical trials as well as to reduce morbidity associated with treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3614. doi:1538-7445.AM2012-3614