Cs Wong

Abstract 1373: Preclinical activity of axitinib and its associated change of serum biomarkers in nasopharyngeal carcinoma (NPC)

Background: We have previously demonstrated promising activity of sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) against vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor (PDGFR), c-kit and RET, in preclinical models of NPC (Invest New Drugs 2011:1123-31). However, the significant host related toxicity encountered in a phase 2 clinical trial of NPC patients has limited its clinical efficacy (Ann Oncol 2011:1280-7). Axitinib is a highly selective TKI of VEGF receptor 1, 2 and 3. Selectively targeting a single growth factor receptor pathway provides the potential to rationally adjust dosages and combine drugs directed at specific parts of the pathway to minimize toxicity and achieve the optimum therapeutic benefit. Methods: In vitro cytotoxicity of axitinib was evaluated by MTT assay in five NPC cell lines (C666-1, CNE-2, HK1-LMP1, HNE-1, HONE-1-EBV). In vivo activity was tested in two representative NPC xenograft models (CNE-2 and HK1-LMP1). We also studied treatment induced changes in tumor histology, microvessel density (MVD) and murine serum biomarkers. Results: All NPC cell lines tested except C666-1 were sensitive to axitinib with IC50 of 0.8-7 µM and maximum growth inhibition of 45-87%. In vivo, axitinib demonstrated significant tumor growth inhibition (fractional tumor volume reduction of 32-63% for axitinib treated mice versus 0-10% for vehicle control), reduced MVD and induced extensive tumor necrosis with no significant host toxicity in mice. There were significant increases in serum murine-derived VEGF and SDF-1α and decrease of sVEGFR-2 in axitinib treated tumor bearing mice as compared to vehicle treated controls. Conclusion: Axitinib demonstrated potent in vitro and in vivo activity in NPC preclinical models. Host derived serum proteins may serve as potential biomarkers of drug activity. A phase 2 clinical trial of axitinib in NPC is on-going (NCT01249547) to validate these findings in patients. Acknowledgement: supported by a direct grant (2041496) from CUHK. Axitinib was provided by Pfizer Inc. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1373. doi:1538-7445.AM2012-1373

Abstract 1006: TP53-induced glycolysis and apoptosis regulator (TIGAR) induces NADPH production and growth in nasopharyngeal carcinoma cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL TIGAR (TP53-induced glycolysis and apoptosis regulator) is a novel dual regulator of glycolysis and apoptosis regulated by p53. TIGAR was first found to protect normal cells from oxidative stress by inducing cellular production of NADPH, a powerful reducing agent in the cell, via the pentose phosphate shunt. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer prevalent in Southeast Asia. Our previous studies demonstrated that overexpression of TIGAR rescued NPC cells from growth inhibition induced by c-Met kinase inhibitors and an RNA anti-metabolite (ECyd), suggesting an anti-apoptotic function of TIGAR in NPC. Here, we demonstrated by Western blotting and immunohistochemistry that TIGAR was expressed in primary tumor biopsies of NPC. Moreover, NPC cell lines from various differentiation status also expressed TIGAR. Using an Epstein-Barr virus-associated NPC cell line, HONE-1-LMP1 cells, we showed that specific knockdown of TIGAR by siRNA inhibited cell proliferation (∼45%) at 48 hrs. Moreover, TIGAR overexpression markedly increased NPC cell proliferation (>300%), which was accompanied by significant induction of cellular NADPH production (>200%). This indicates that TIGAR-induced generation of NADPH, which is an important building block for major cellular metabolites for proliferation (including DNA, RNA and fatty acids, etc), may be involved in NPC carcinogenesis. Furthermore, TIGAR overexpression induced the expression of a pro-survival protein, Mcl-1 in NPC cells, which supports an anti-apoptotic function of TIGAR in NPC. Our results implicate that TIGAR may confer survival benefits to NPC cells via metabolic alteration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1006. doi:10.1158/1538-7445.AM2011-1006