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Clinical Research

Abstract 1764: Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids

Robert Alan Nagourney, Paula J. Bernard, Federico R. Francisco and Steven S. Evans
Robert Alan Nagourney
1Rational Therapeutics, Long Beach, CA.
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Paula J. Bernard
1Rational Therapeutics, Long Beach, CA.
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Federico R. Francisco
1Rational Therapeutics, Long Beach, CA.
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Steven S. Evans
1Rational Therapeutics, Long Beach, CA.
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DOI: 10.1158/1538-7445.AM10-1764 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

Introduction: Signal transduction pathways are targets for small molecule tyrosine and serine-threonine kinase inhibitors. Redundancy and cross talk between pathways can complicate the application of genomic signatures but proteomic and functional platforms may more closely approximate tumor phenotypes. We used EVA/PCD (ex vivo analysis of programmed cell death), a functional platform measuring both apoptotic & non-apoptotic events to examine the PI3K and EGFr pathways in human 1° culture micro-spheroids. Methods: 337 tumor specimens provided from the OR were mechanically and enzymatically disaggregated and exposed to EGFr (Gefitinib), AKT (B-15), PI3K (LY294002) & mTOR (Rapamycin) inhibitors with LC50 values interpolated from 5-point dose response curves. Synergy was assessed by median effect and correlation coefficients by Pearson Moment. Results: Parallel Pearson Moment analyses in 51 specimens by 2-tailed T, revealed LY vs. B15 (NS); LY vs. Rapa (P<0.02); B15 vs. Rapa (P<0.0025); Rapa vs. Gefitinib (P <0.001). Synergy analyses for Rapa & Gefitinib revealed synergy in 29%, additivity in 41%, sub-additivity in 13% and antagonism in 17%. Exploratory synergy analyses that combined Gefitinib & LY and Gefitinib & B-15, favored the Gefitinib& B-15 combination with 100% synergy in this small series. Conclusions: EVA/PCD analyses provide insights into cellular response to targeted therapies, alone and in combination. Correlative analyses identify points of commonality and/or disparity in downstream signaling that can be exploited in drug development and therapy. Synergy analyses reveal potentially important drug combinations. The EVA/PCD human tumor micro-spheroid platform provides a functional tool capable of streamlining drug development and cancer therapy. Supported by The Vanguard Cancer Foundation and the Nagourney Institute.

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 1764.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract 1764: Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids
Robert Alan Nagourney, Paula J. Bernard, Federico R. Francisco and Steven S. Evans
Cancer Res April 15 2010 (70) (8 Supplement) 1764; DOI: 10.1158/1538-7445.AM10-1764

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Abstract 1764: Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids
Robert Alan Nagourney, Paula J. Bernard, Federico R. Francisco and Steven S. Evans
Cancer Res April 15 2010 (70) (8 Supplement) 1764; DOI: 10.1158/1538-7445.AM10-1764
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Cancer Research Online ISSN: 1538-7445
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