A Comparison Of Nvp-Auy-922 (Auy) And Geldenamycin (G) In Human Tumor Primary Culture Microspheroids

Introduction: Molecular chaperone heat shock protein 90 (HSP 90) maintains the stability and function of client proteins essential for malignant transformation. The ansamycin Geldenamycin (G) and its derivative 17-AAG are potent HSP90 inhibitors with activity observed in human tumors. The resorcinol-based HSP90 inhibitor AUY offers advantages with regard to solubility u0026 DT-diaphorase independence. To evaluate and compare the activity of AUY u0026 G we conducted ex vivo analysis of programmed cell death (EVA/PCD™) on microspheroids isolated from fresh human tumor specimens. Methods: The EVA/PCD™ method as previously reported (Nagourney, RA Anticancer Res. 2012) isolates microspheroids of desired size by mechanical u0026 enzymatic disaggregation followed by precise density centrifugation. Drug activity is measured by delayed loss of membrane integrity u0026 ATP content (luciferase). Lethal concentration (LC50) values are interpolated from 5-point dose response curves and compared by modified Z-Score. Concentrations ranges for AUY were 6.25-100 uM and for G 1.25-20 uM. Results: AUY and G activity compared in 22 parallel analyses by Pearson Moment revealed a correlation coefficient R = 0.59 (p Sarcoma u003eMelanoma u003eOvaryu003eNSCLCu003eBreast. ERBB2 (+) breast appeared more sensitive as did several EGFr mutation (+) NSCLC specimens. Metachronous assays conducted in 3 EGFr (+) NSCLC pts revealed activity for G following Erlotinib failure. Additional studies with AUY alone and in combination are underway. Conclusions: i) HSP-90 inhibitors are active in human tumor primary cultures ii) AUY and G activity correlate iii) HSP90 inhibitor activities reveal disease u0026 patient-specific profiles iv) EVA/PCD™ analyses could facilitate the development of clinical strategies for the use of HSP90 inhibitors. Supported by The Vanguard Cancer Foundation u0026 The Nagourney Institute. NVP-AUY-922 was the kind gift of Novartis AG. Citation Format: Robert Alan Nagourney, Paula J. Bernard, Federico Francisco, Meghan Cule, Ryan Wexler, Steven S. Evans. A comparison of NVP-AUY-922 (AUY) and Geldenamycin (G) in human tumor primary culture microspheroids. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2418. doi:10.1158/1538-7445.AM2015-2418