Abstract 3720: Combination treatment with hypoxia-activated prodrug TH-302 and the mTOR inhibitor everolimus results in enhanced antitumor efficacy in preclinical models

Abstract

Abstract TH-302, a 2-nitroimidazole triggered hypoxia-activated prodrug, releases bromo-isophosphoramide mustard (Br-IPM), which induces DNA crosslinking in hypoxic cells. It shows broad antitumor activity in a number of preclinical models, both as a single agent and in combination with conventional chemotherapeutics. The intracellular kinase mTOR plays a key role in multiple pathways which are important in cancer progression. Everolimus directly targets mTOR and results in reduced tumor cell proliferation, decreased tumor angiogenesis, and an inhibiton of tumor cell metabolism. Here we investigated whether TH-302 in combination with everolimus could improve the efficacy profile versus the agents as monotherapies. Two renal cell carcinoma (RCC) ectopic xenograft models and a neuroblastoma ectopic xenograft model were established by subcutaneous implantation of Caki-1, 786-O, or SK-N-BE(2) cells into the flanks of nude mice. When tumor size was approximately 150mm3, animals were treated with everolimus (5mg/kg, QDx19, oral), TH-302 (50mg/kg, QDx5/wk x 3wks, ip), or both everolimus and TH-302. In the Caki-1 model, 87% Tumor Growth Inhibition (TGI) was observed in the combination group versus 52% TGI from everolimus monotherapy or 16% TGI from TH-302 monotherapy. A pharmacodynamic immunohistochemistry study showed that after 7 days of treatment with everolimus, cell proliferation (by Ki67), microvessel density (by CD31) and phosphorylation of the S6 ribosomal protein (by p-S6) was significantly decreased. In the 786-O model, everolimus alone showed 49% TGI, while TH-302 alone did not demonstrate statistically significant efficacy. However, when TH-302 was combined with everolimus, a TGI of 85% was reached. In the ectopic SK-N-BE(2) neuroblastoma model, TH-302 or everolimus alone demonstrated 45% and 40% TGI, respectively, while the combination therapy yielded 65% TGI. Importantly, body weight loss was very minor (<5%) in all groups tested, indicating no significant added toxicity in the combination groups. In summary, there is additive antitumor activity when TH-302 is combined with everolimus. The efficacy profile of TH-302 in combination with the mTOR inhibitor temsirolimus also shows an additive effect in the combination therapy setting. These studies provide a translational rationale for combining TH-302 with mTOR inhibitors to increase the treatment benefit. 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 3720. doi:1538-7445.AM2012-3720