Abstract LB-244: BAY 87-2243, an inhibitor of HIF-1α - induced gene activation, showed promising anti-tumor efficacy in combination with anti-angiogenic therapy and irradiation in preclinical tumor models

Abstract

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 >100 genes involved in cellular energy metabolism, neoangiogenesis, anti-apoptotic and pro-proliferative mechanisms promoting invasion and metastasis. Recently, we showed that BAY 87-2243, a small molecule inhibitor of hypoxia-induced HIF-1 activation that specifically suppressed hypoxia-induced HIF-1α stabilization is able to achieve very promising results in combination with standard treatments in several preclinical tumor xenograft models. Here, we present outstanding preclinical anti-tumor efficacy of BAY 87-2243 in combination with anti-angiogenic therapy and irradiation in xenografts of various histological type. BAY 87-2243 was dosed continuously in combination with the tyrosine kinase inhibitors regorafenib as well as sorafenib and the anti-VEGF antibody, bevacizumab. The combinations produced long-term tumor growth control or tumor stasis of either cell line derived or patient-derived subcutaneous colorectal carcinoma xenografts (HCT116, HT29, LoVo). In a fully established lung carcinoma model (A549) the combination treatment of BAY 87-2243 with regorafenib resulted in slight regression of tumor growth that was maintained for up to 18 days. In a prostate carcinoma model (PC-3) a combination of BAY 87-2243 and regorafenib resulted in an additive improvement of the tumor growth inhibition as compared to either agents alone. A first combination treatment of BAY 87-2243 and a single subcurative irradiation dose (8 Gy) in a radioresistant, severely hypoxic head and neck squamous cell carcinoma xenograft (UT-SCC-5) led to tumor regression, which did not occur in the respective single-agent/radiation treatment. These promising preclinical results suggest that inhibition of HIF-1 by BAY 87-2243 in particular in combination with anti-angiogenic therapy and irradiation 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 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 LB-244. doi:1538-7445.AM2012-LB-244