56P - Inhibition of HIF-2α-dependent transcription with small molecule inhibitors may provide therapeutic benefit beyond renal cell carcinoma

Background

Inhibition of HIF-2α has had a substantial impact on the treatment paradigm for cancer patients with germline mutations in VHL. Preclinically, selective HIF-2α inhibitors demonstrate dramatic anti-tumor effects in xenograft models in which HIF-2α is a molecularly defined tumorigenic driver. However, therapeutic application of HIF-2α inhibitors beyond VHL-mutated clear cell renal cell carcinoma remains to be seen. In contrast to HIF-1α, HIF-2α has a more selective expression profile accompanying tailored regulons that may guide indications of interest.

Methods

The potential therapeutic benefit of HIF-2α inhibition in various oncology indications was investigated using bioinformatic, in vitro, and in vivo approaches. In mice, the role of HIF-2α in hepatocellular carcinoma (HCC) was investigated using an autochthonous high-fat diet carcinogen-induced tumor model.

Results

Consistent with the mechanism of action, inhibition of HIF-2α in various cell lines did not attenuate cell growth in 2D culture. However, significant alterations in the hypoxic gene signatures were detected, with substantial variation in HIF-2α-dependence. HIF-2α-specific gene signatures derived using pharmacological inhibition or genetic deletion applied to available datasets predicted poorer survival in multiple cancer indications, including renal (as validation) and liver. In an HCC mouse model, mice with deletion of HIF-2α in hepatocytes had significantly reduced number and size of liver nodules. These effects were apparent upon deletion of HIF-2α from birth or after tumors were established. Finally, mice treated with a HIF-2α inhibitor after tumor formation also had significantly decreased tumor burden.

Conclusions

HIF-2α plays a distinct and differential role in the transcriptional response to hypoxia in different tissue types and cell lines. In vivo data suggest that HIF-2α may contribute to the formation and progression of HCC, supporting clinical investigation of HIF-2α inhibition beyond ccRCC. AB521 is a potent and selective inhibitor that has been evaluated in healthy volunteers and is progressing through a phase Ib clinical trial in cancer patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Arcus Biosciences, Inc.

Funding

Arcus Biosciences, Inc.

Disclosure

K.S. Gauthier, D. Piovesan, S. Cho,K.V. Lawson, K. Liao, P. Foster, T. Cheng, M. Walters: Financial Interests, Institutional, Stocks/Shares: Arcus Biosciences; Financial Interests, Institutional, Full or part-time Employment: Arcus Biosciences. Y. Shah: Financial Interests, Institutional, Funding: Arcus Biosciences. All other authors have declared no conflicts of interest.