Abstract 2823: TAK-441, a novel investigational small molecule hedgehog pathway inhibitor for use in cancer therapy

Abstract

Abstract Dysregulation of hedgehog (Hh) signal, which is caused by Hh-ligand overexpression or patched1 (Ptch1) mutation, has been found to play an important role in tumorigenesis. TAK-441 is a potent and selective smoothened (Smo) antagonist that blocks Hh signaling. In the Gli-responsive promoter-luciferase (Gli-luc) reporter assay in NIH3T3/Gli-luc cells, TAK-441 inhibited Gli transcriptional activity with an IC50 of 4.4 nM. TAK-441 also inhibited expression of human Gli1 messenger mRNA with an IC50 of 1.9 nM in MRC5 human embryonic fibroblasts. In addition, TAK-441 inhibited binding of cyclopamine, a plant-derived well-known Smo inhibitor, to human Smo on 293T cells overexpressing human Smo with an IC50 of 8.6 nM. These data suggest that TAK-441 inhibits the Hh signaling pathway through its binding to Smo. Oral administration of TAK-441 (0.5, 1, 5, 25 mg/kg QD) in mice bearing a Ptch1 (+/-), p53(−/-) medulloblastoma allograft resulted in dose-dependent antitumor activity with concomitant reduction of Gli1 mRNA expression in the tumors. Complete remissions were observed in the 25 mg/kg QD dose cohort after two consecutive weeks of treatment. Significant (p≤0.025 by one-tailed Williams test) antitumor activity was also detected in sonic hedgehog expressing human primary pancreatic and ovarian cancer xenografts when dosed at 10 and 25 mg/kg QD for two weeks, and in a colon cancer xenograft when dosed at 6.25 and 25 mg/kg BID for three weeks. In these models, the expression of tumor-associated mouse stromal Gli1 mRNA was markedly decreased following TAK-441 treatment, suggesting that Hh signaling in these tumors was driven in a paracrine mode of action. The combination of TAK-441 and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), demonstrated significantly better antitumor activity than either agent alone in human primary pancreatic cancer xenograft models (p≤0.05 by Students’ t-test). In addition, delayed tumor re-growth was observed in the TAK-441/rapamycin combination treatment group compared with the rapamycin single-agent treatment group after terminating treatment. As a result of these preclinical studies, TAK-441 has recently entered Phase I clinical studies in cancer patients. 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 2823. doi:10.1158/1538-7445.AM2011-2823