Abstract 1014: Novel selective HIF1 alpha inhibitor: Well tolerated with excellent efficacy in renal cell cancer xenograft studies

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. 1014
• Main Authors: Dubey, Ramin, Grishagin, Ivan, Nagavarapu, Usha, Balan, Chenera, Gupta, Shalabh, Olenyuk, Bogdan Z.
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-1014

Abstract Traditional anticancer therapies are limited in their efficacy because they often lead to drug-resistant tumors and display toxicity to normal cells. Control of angiogenesis represents one of the key goals in cancer therapy, as exemplified by targeting the VEGF pathway with bevacizumab.Chronic hypoxia, a hallmark of many solid tumors is responsible for the elevated levels of VEGF and other pro-proliferative factors. The cellular response to hypoxia is primarily mediated by a family of transcription factors, among which hypoxia-inducible factor 1 (HIF1) plays a major role. Under normoxia, the oxygen-sensitive α subunit of HIF1 is rapidly and constitutively degraded but is stabilized and accumulates under hypoxia. Upon nuclear translocation, HIF1 controls the expression of over 100 genes involved in angiogenesis, and pro-proliferative mechanisms that promote tumor growth. The specific hypothesis behind the proposed research is that angiogenesis could be effectively controlled by down-regulation of hypoxia-inducible gene expression via a disruption of key transcription factor-coactivator interactions with designed molecules. The team at BioCycive and its collaborators at USC are currently developing such compounds that block hypoxia-inducible transcription of key genes. We have designed and synthesized a novel dimeric epidithiodiketopiperazine, ETP2, which targets pleiotropic coactivator p300 disrupts HIF1α-p300 complex in vitro and effectively down-regulates hypoxia-inducible signaling and gene expression. ETP 2 effectively inhibits HIF1-induced activation of VEGFA, LOX, Glut1, and c-Met genes in a panel of breast and lung cancer cell lines. We have shown excellent antitumor efficacy of both (±)-ETP 2 and meso-ETP 2 in a fully established breast carcinoma model by intravital microscopy. A significant decrease in the vascularization of these tumors upon treatment with ETP 2 was also noticed, which is consistent with the proposed mechanism of inhibition of vascularization via down-regulation of hypoxia-inducible signaling.Our efficacy studies with renal carcinoma cells lines resulted in similar findings, where we successfully reached the primary endpoint of efficacy (reduction in tumor volume of >50%) and secondary endpoint of survival. Nude mice engrafted with 786-O (renal cell carcinoma) were treated with ETPs at 1 mg/kg given IV every three days for 45 days. All tumors were imaged at the end of the study and harvested for histopathology studies. MTD studies clearly indicated that ETP 2 was non-toxic within the range of injected doses, with an average MTD of 21.1 mg/kg. Our preliminary PK studies show that the ETP 2 is a lipophilic molecule, with a plasma half-life of 3.5-5 days. Our results suggest that inhibition of HIF1 transcriptional activity by designed dimeric ETPs could offer an innovative approach to cancer therapy with the potential to overcome hypoxia-induced tumor growth and resistance. Citation Format: Ramin Dubey, Ivan Grishagin, Usha Nagavarapu, Chenera Balan, Shalabh Gupta, Bogdan Z. Olenyuk. Novel selective HIF1 alpha inhibitor: Well tolerated with excellent efficacy in renal cell cancer xenograft studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1014. doi:10.1158/1538-7445.AM2014-1014