Susanne Greschat

Abstract 4509: BAY 87-2243 targets hypoxia-induced activation and stabilization of HIF-1α: A novel approach to overcome resistance mechanisms in cancer therapy

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The development of resistance against radio- or chemotherapy is one of the main causes for relapse after treatment and ultimately cancer progression. Local hypoxia within tumors is associated with radio- and chemoresistance as well as aggressive tumor growth and invasion (Vaupel et al., 2004). The transcription factor HIF-1α (hypoxia-inducible factor) is stabilized under low oxygen tension and heterodimerizes with HIF-1s to regulate the expression of a plethora of genes involved in cellular energy metabolism, neoangiogenesis, anti-apoptotic and pro-proliferative mechanisms promoting tumor progression and metastasis (Calzada et al. 2007). Because hypoxia-induced upregulation of HIF-1α appears to be of pivotal importance in tumor resistance mechanisms during cancer treatment, we screened for inhibitors of hypoxia-induced HIF-1 activation. A HCT116 cell line containing 4X-hypoxia response element-luciferase reporter was used in high-throughput screening of small molecule inhibitors under hypoxic condition (1% O2). Lead optimization resulted in the identification of BAY 87-2243, a highly selective and potent inhibitor of hypoxia-induced HIF-1α stabilization and activation. In vitro characterization showed that BAY 87-2243 specifically suppressed HIF-1 regulated target genes as assayed by qPCR. Analyses addressing the mode of action revealed that BAY 87-2243 acts upstream of VHL and PHD because the compound did not suppress HIF-1α protein stabilization and HIF target gene expression either in the presence of a PHD inhibitor in H460 cells or in VHL-null RCC4 cells. In preclinical animal models, BAY 87-2243 dosed orally was well tolerated at therapeutic doses up to 15 mg/kg and showed moderate to high anti-tumor growth inhibitory activity as monotherapy in various subcutaneous and orthotopic xenograft models. Analysis of tumor samples demonstrated a decrease of nuclear HIF-1α protein level by immunohistochemistry as well as a specific suppression of HIF-1 target genes. These data indicate that specific inhibition of hypoxia-induced HIF-1 activation is achievable with small molecule inhibitors and is a novel approach to cancer therapy. Vaupel P, Mayer A, Hockel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335-354 M. J. Calzada, L. del Peso, Hypoxia inducible factors and cancer. Clin. Transl. Oncol. 2007, 9(5), 278-289: 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 4509. doi:10.1158/1538-7445.AM2011-4509

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

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL 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 >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