Abstract 485: Hypoxia inducible factor (HIF) inhibitor 64B has superior anti-tumor effects compared to two different tyrosine kinase inhibitors when tested in mouse models of uveal melanoma

Abstract

Abstract Uveal melanomas (UMs) arise from melanocytes along the uveal tract and are distinct from cutaneous melanomas, with different molecular events in their pathogenesis. While primary treatment generally results in good local control, UMs spread systemically in approximately 50% of patients, most commonly to the liver. Patients who develop metastases are more likely to express the hypoxia-induced transcription factor HIF-1α and the HIF-regulated genes CXCR4 and c-Met when compared to patients who do not develop metastatic disease1, suggesting that blocking HIF function might be clinically beneficial for the management of UM, a tumor type that fails to respond to treatments that are effective for treating cutaneous melanoma. 64B is a small molecule therapeutic that inhibits the function of hypoxia inducible factors (HIFs) by disrupting the recruitment of the transcription co-factor paralogs, p300/CBP, while leaving intact p300/CBP’s ability to function with multiple other transcription factors. As a consequence, 64B is well tolerated and blocks transcription of multiple genes that help tumor cells survive and spread, including genes involved in angiogenesis, multidrug resistance, invasion and metastases. Using several different UM tumor cell lines implanted in the uveal tract of mice, we previously showed that 64B given systemically inhibits primary tumor growth and metastases1. We now compare the anti-cancer efficacy of 64B to two different tyrosine kinase inhibitors (TKIs) that are in clinical testing for UM, sunitinib and selumetinib. Sunitinib is a TKI that suppresses the function of the growth factor receptors c-kit and VEGFR, proteins that are highly expressed in UM. Selumetinib is a highly selective MEK1/2 inhibitor, targeting the MEK pathway that is activated in UM due to the GNAQ/11 activation that occurs in about 85% of UMs. Human UM cells (92.1; GNAQ Q209P mutant) were implanted in the flank of nude mice, and systemic treatment (i.p.) with 64B was started once the s.c tumor reached 100 mm3. 64B was far superior to either sunitinib or selumetinib at causing a regression in tumor size and in reducing the number and size of liver metastases. The metastases that were observed in 64B-treated animals were very small and did not show evidence of tumor vascularization, unlike the control tumors which were much larger and were vascularized. The tumor-bearing animals receiving 64B were behaviorally normal and were healthier than control mice or mice receiving either sunitinib or selumetinib, some of which died in the non-64B groups. The efficacy of 64B at causing tumor regression and reducing metastases combined with its safety profile support advancing 64B to clinical testing for metastatic UM. 1 Dong L et al, Clin Cancer Res. 2019;25(7):2206-18. Citation Format: Hua Yang, Hans E. Grossniklaus, Erwin G. Van Meir, Margaret K. Offermann. Hypoxia inducible factor (HIF) inhibitor 64B has superior anti-tumor effects compared to two different tyrosine kinase inhibitors when tested in mouse models of uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 485.