Abstract
Abstract Altered phosphoinosotide metabolism is a hallmark of many human malignances. The phosphoinsotide kinases (PI3K) of which there are several sub-classes, have been explored as targets for cancer therapy. Beyond the first generation pan-PI3K inhibitors Wortmannin & LY294002, new, clinically active agents with subclass specificity and/or dual inhibitory functions (PI3K & mTOR) have been developed, including BEZ235 (PI3K/mTOR), GDC0941(αβδ), BYL719(α) & Idelalisib (δ). To examine the activity of these agents we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, R et al Anticancer Res., 2012)to human tumor microspheroids, isolated directly from surgical specimens. Lethal concentrations (LC50's) interpolated from 5-point dose response curves were compared for activity and for correlation by Pearson Moment. Results: Micro-molar activity favored BEZ > BYL > LY. Correlation coefficients reveal BYL vs. BEZ (N=15, R =0.69, P< 0.01); BYL vs. LY (N=7, R=0.74, P=0.1); BEZ vs. LY (N=61, R=0.52, P<0.001). A comparison of activity for hematologic (Heme) vs. Solid tumors (solid) for LY: Heme > Solid; BEZ: Solid > Heme; BYL: Heme > Solid with preliminary evidence for Idelalisib showing Heme > Solid. Conclusions: The PI3K inhibitors are active in both Heme and Solid tumors, with relative concordance between agents, but some evidence of disease specificity. Additional comparisons with GDC 0941 and drug combination studies are being conducted to further characterize the clinical activity and combinatorial potential of this class of agents. EVA/PCD analyses, conducted in human tumor primary cultures, have the capacity to evaluate drug activity, synergy and sequence dependence offering clinically relevant insights into novel drug applications. Citation Format: Robert Alan Nagourney, Paula J. Bernard, Federico Francisco, Steven S. Evans. A comparative analysis of PI3K inhibitors in human tumor primary culture microspheroids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4245. doi:10.1158/1538-7445.AM2014-4245
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