Abstract 4503: BAY 87-2243, an inhibitor of HIF-1α activation and stabilization, showed promising anti-tumor efficacy either as monotherapy or in combination with anti-VEGF and chemotherapy agents in preclinical tumor models
Authors: Berhoerster Kerstin , Ellinghaus Peter , Haerter Michael , Greschat Susanne , Wengner Antje , Scholz Arne , Haegebarth Andrea , Hess-Stumpp Holger 
Published: June 2012

Abstract
Hypoxia is a hallmark of solid tumors and is associated with local invasion, metastatic spread and resistance to radio- as well as chemotherapy (Vaupel et al., 2004). Furthermore, hypoxia constitutes an independent negative prognostic factor in a diverse range of malignant tumors (Harris, 2002; Vaupel et al., 2004). The cellular adaptation to hypoxia is mediated by a heterodimeric transcription factor hypoxia inducible factor-1 (HIF1). HIF-1α, one subunit of HIF, is constitutively degraded under normoxic conditions, but is stabilized and activated in hypoxic regions of tumors. Nuclear activated HIF-1 controls the expression of &gt;100 genes involved in cellular energy metabolism, neoangiogenesis, anti-apoptotic and pro-proliferative mechanisms promoting invasion and metastasis. It was our hypothesis that small-molecule inhibitor that prevent stabilization and activation of HIF-1 may act as valuable novel cancer therapeutics.
Recently, we identified BAY 87-2243 as a small molecule inhibitor of hypoxia-induced HIF-1 activation that specifically suppressed hypoxia-induced HIF-1α stabilization and expression of HIF target genes. Here we present preclinical anti-tumor efficacy of BAY 87-2243 in several xenografts, both as single agent and in combination with standards treatments.
BAY 87-2243 dosed orally as single agent demonstrated moderate to high tumor growth inhibition in several subcutaneous tumor models of various histological type such as prostate carcinoma, lung carcinoma, neuroblastoma, colorectal and mammary carcinomas. BAY 87-2243 dosed continuously in combination with the anti-angiogenic agent bevacizumab produced long-term tumor growth control or tumor stasis of either small or large established subcutaneous and orthotopic lung carcinoma xenografts (NSCLC H460 model). In an orthotopic pancreatic carcinoma model (DAN-G) a combination of BAY 87-2243 and gemcitabine resulted in a synergistic improvement of the median survival as compared to either agents alone (p=0.0004). In general, BAY 87-2243 was well tolerated in mice without any significant body weight loss. These promising preclinical results suggest that inhibition of HIF-1 by BAY 87-2243 is an innovative approach to cancer therapy with the potential to overcome hypoxia/HIF-induced tumor resistance mechanisms.
Harris AL (2002) Hypoxia-a key regulatory factor in tumor growth. Nat Rev Cancer 2: 38-47
Vaupel P, Mayer A, Hockel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335-354
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 4503. doi:10.1158/1538-7445.AM2011-4503