Abstract 5583: Response biomarkers for the hypoxia-targeted drug TH-302: imaging, plasma, and tissue.

Biomarkers that assess the therapeutic response to anticancer treatments may aid in tailoring therapeutic regimens to individuals. Ideally, the relative contributory effect of each agent in a muti-agent regimen can be discerned. Hypoxia is a prevalent feature of solid tumors, associated with treatment failure, poor prognosis, and increased metastasis. TH-302, a hypoxia-activated prodrug of the DNA cross-linker bromo isophosphoramide mustard, has demonstrated broad efficacy in preclinical models and is exhibiting promising activity in multiple ongoing clinical trials, both as a monotherapy and in combination therapy regimens. Three fundamental biomarker platforms were assessed in this preclinical study: positron emission tomography (PET) imaging employing the tracer [ 18 F]-HX4; immunohistochemistry of isolated tumor tissue employing antibodies directed against the exogenous hypoxia biomarker pimonidazole (PIMO) and the endogenous hypoxia biomarker carbonic anhydrase IX (CA-IX); and ELISA-based quantification of circulating plasma CA-IX. Both HX4 and PIMO utilize the same 2-nitroimidazole hypoxia-sensitive trigger for their activity and specificity as TH-302 utilizes. CA-IX is up-regulated by two distinct hypoxia sensing pathways: hypoxia-inducible factor 1; and the unfolded protein response. The human H460 non-small cell lung cancer human tumor ectopic xenograft model was employed for these studies. When the tumor size was 300-600 mm 3 , a single dose of TH-302 (150 mg/kg, ip) or vehicle was administered. This TH-302 treatment regimen yields a tumor growth inhibition of 58%, TGD 1000 of 10 d, and maximum body weight loss of 2%. [ 18 F]-HX4 uptake was assessed by PET/CT imaging and the tumor to muscle ratio (T/M) was determined. Animals were scanned pre- and post-treatment and the T/M ratio was significantly reduced 72 hours after TH-302 treatment (from 3.3 ± 0.3 to 2.1 ± 0.2, p 0.05). Blood was collected from the animals pre- and post- treatment via retro-orbital vein. Plasma CA-IX changed from baseline 165 ± 13 to 104 ± 9.3 pg/ml 72 hours after TH-302 dosing, a 37% reduction (p Citation Format: Jessica D. Sun, Qian Liu, Dharmendra Ahluwalia, Yan Wang, Anna-Katrin Szardenings, Luis F. Gomez, Hartmuth Kolb, Karen A. Pierce, Sheryl Brown-Shimer, Walter A. Carney, Charles P. Hart. Response biomarkers for the hypoxia-targeted drug TH-302: imaging, plasma, and tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5583. doi:10.1158/1538-7445.AM2013-5583