Abstract 1801: Predictive diagnostics for the PI3 kinase inhibitor GDC-0941 in breast and ovarian cancer

Abstract

Abstract The class I phosphatidylinositol 3’ kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting the PI3K pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. GDC-0941 is a pan-inhibitor of all 4 isoforms of class 1 PI3K that is currently undergoing testing in the clinic. The PI3 kinase pathway is generally regarded as the most frequently altered pathway in cancer, and an attractive hypothesis is that these alterations will help identify tumors where the pathway is particularly active and hence patients who are likely to receive benefit from treatment with a PI3 kinase inhibitor. We used a large panel of breast and ovarian cancer cell lines as well as in vivo xenograft models to evaluate candidate predictive biomarkers for GDC-0941. The approach involved pharmacogenomic profiling as well as analysis of gene expression datasets from tumor cells profiled at baseline or after GDC-0941 treatment. We found that models harboring key pathway alterations were generally sensitive to the anti-tumor effects of GDC-0941. We found that a number of models that do not harbor these alterations also showed sensitivity, suggesting alternative explanations for sensitivity and thus a need to identify additional diagnostic hypotheses. Gene expression studies identified a small number of genes whose expression appears to be intimately linked to pathway activation that may also be useful diagnostic markers. 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 1801.