Abstract 1734: Preclinical study of HSP-90 inhibitor drug, AUY922 showed good efficacy in treatment of nasopharyngeal cancer
Authors: Timothy T.C. Yip, Roger K.C. Ngan, Wai-Tong Ng, Lewis T.C. Chan, William C.S. Tai, Wai-Wai Cheng, Victor W.S. Ma, Kwok-Wai Lo, Ya-Ping Li, Michael B.H. Yang, Eric C.H. Wong, Brigette B.Y. Ma, Nai-Ki Mak, George S.W. Tsao, Maria Li-Lung
Journal: Cancer Research (2015)

Abstract Introduction: Prognosis of patients with metastatic or recurrent nasopharyngeal cancer (NPC) is usually poor. Despite some good response to chemotherapy by cisplatin-containing regimen, long term remission in NPC patients is not common. Response rate to second line drug after failing cisplatin is poor. Heat shock protein-90 (HSP-90) is a molecular chaperone essential to the folding of a wide variety of oncogenic client proteins. Inhibition of HSP-90 can lead to a combinatorial blockage of signal transduction leading to cancer cell death. Here, we reported a successful preclinical study showing good efficacy of an anti-HSP-90 drug, AUY922 in treating NPC in cell culture in vitro and xenograft model in vivo in nude mice. Experimental Design: WST assay was used to determine the growth inhibitory dose of AUY922 in 3 NPC cell lines (C666, HONE1 &amp; CNE2) and 2 cisplatin resistant NPC cell lines (HONE1-EBV-Cisp-Res &amp; HK1-LMP1-Cisp-Res). Subcutaneous NPC xenografts was treated by AUY922 i.p. to examine tumor growth inhibition. DNA flow cytometric analysis (DNA-FCM) and Yo-Pro staining were carried out to analyze the effect of AUY922 in cell cycle progression and apoptosis. RT-PCR and Western blotting were performed to examine the effects of AUY922 in regulating Epstein-Barr virus (EBV) gene transcripts and kinase pathway phosphorylation respectively. Results: AUY922 (at GI-50 of 22 nM for C666) could effectively induce tumor growth inhibition in all the 3 NPC cell lines with 300-900 and 180-2700 folds of higher sensitivity than cisplatin or 5-FU. NPC xenograft regression was accomplished by AUY922 treatment at 35-65 mg/kg alone with additive effect when combined with cisplatin. Importantly, AUY922 was also growth inhibitory in the 2 cisplatin resistant NPC cell lines in vitro or in vivo hinting its potential use in the clinical setting in patients refractory to cisplatin. By DNA-FCM, AUY922 could induce prominent G2 cell cycle phase arrest and sub-G1 apoptotic peak at 60 nM (with low level of early apoptosis by YoPro staining). &amp;gt;95% NPC patients in Hong Kong are EBV positive. AUY922 can dramatically induce the expression of 2 EBV transcripts - BZLF1 (for viral lytic cycle) and LMP2A (associated with cytotoxic T cell lysis) indicating its potential in facilitating tumor lysis through these processes. Western blot delineated substantial regulation of phosphorylation in AKT, mTOR, GSK-3-beta, NF-KappaB, IKK-alpha/beta and IKB-alpha pathways but not in CREB, p38 and PARP pathways. Conclusion: The findings of this preclinical study clearly showed the good potential of this HSP90 inhibitor drug, AUY922 in NPC treatment. Ethics approval is pending to initial clinical trials of AUY922 in patients with metastatic/locally recurrent NPC in Hong Kong. Citation Format: Timothy T.C. Yip, Roger K.C. Ngan, Wai-Tong Ng, Lewis T.C. Chan, William C.S. Tai, Wai-Wai Cheng, Victor W.S. Ma, Kwok-Wai Lo, Ya-Ping Li, Michael B.H. Yang, Eric C.H. Wong, Brigette B.Y. Ma, Nai-Ki Mak, George S.W. Tsao, Maria Li-Lung. Preclinical study of HSP-90 inhibitor drug, AUY922 showed good efficacy in treatment of nasopharyngeal cancer. [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 1734. doi:10.1158/1538-7445.AM2015-1734