Abstract 5271: Hepatic hypoxia-activated intra-arterial therapy: effect of selective targeting of hypoxia in a rabbit liver tumor model

Abstract

Abstract Purpose: Tumor hypoxia is considered a challenge of anticancer therapy. The use of hypoxia-activated prodrugs (HAPs) in the setting of transarterial chemoembolization (TACE) is particularly appealing by allowing the locoregional delivery of high-doses of chemotherapy which has the potential to reach distal hypoxic tumor regions. Moreover, the embolic effect provided by TACE constitutes an attractive setting for the selective activation of HAPs. We aimed to evaluate the safety and characterize the anticancer efficacy of hepatic hypoxia-activated intraarterial therapy (HAIAT) in a rabbit liver tumor model. Experimental Design: Twenty-eight animals bearing VX2-tumors were randomly assigned to 4 intraarterial therapy (IAT) groups: (1) saline (control); (2) TH-302; (3) doxorubicin-Lipiodol emulsion followed by bland embolization with 100-300μm beads (conventional TACE - cTACE); or (4) cTACE in combination with TH-302 (cTACE+TH-302). Blood samples were collected at baseline and 24 hours, 48 hours, 7 days, and 14 days post-IAT to evaluate treatment-related toxicity. A semi-quantitative pathologic scoring system was used to assess hepatocellular damage. Tumor volumes were segmented on multidetector computed tomography (baseline, 7 days, and 14 days post-IAT). Tumor necrosis was quantified in the whole tumor using a slide-by-slide histosegmentation. Hypoxic fraction (HF) and hypoxic compartment (HC) was determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia and metabolism were quantified using color deconvolution analysis (including γ-H2AX, annexin V, caspase-3, Ki-67, HIF1α, VEGF, MCT4 and LDH). Results: cTACE+TH-302 showed similar profile in liver enzyme elevation and pathologic scores compared to cTACE. Neither hematologic nor renal toxicity was observed. Animals treated with cTACE+TH-302 demonstrated smaller tumor volumes, lower tumor growth rate and higher necrotic fraction compared to cTACE. cTACE+TH-302 resulted in a pronounced reduction in the HF and HC. Negative correlation was found between tumor necrosis and the magnitude of HF or HC. cTACE+TH-302 treatment increased the expression of γ-H2A.X, apoptotic biomarkers and decreased the proliferative potential of VX-2 tumor cells. Increased expression level of HIF1α/VEGF and tumor glycolysis biomarkers supports the HAIAT mechanism of action. TH-302 demonstrated a bystander effect with antitumor activity observed beyond hypoxic tumor regions. Conclusion: HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and strong anticancer effects of TH-302 in combination with cTACE support further investigation in clinical trials in patients with liver cancer. Citation Format: Rafael Duran, Sahar Mirpour, Vasily Pekurovsky, Shanmugasundaram Ganapathy-Kanniappan, Cory F. Brayton, Toby C. Cornish, Boris Gorodetski, Julius Chapiro, Rüdiger Schernthaner, Constantine Frangakis, MingDe Lin, Jessica D. Sun, Charles P. Hart, Jean-François H. Geschwind. Hepatic hypoxia-activated intra-arterial therapy: effect of selective targeting of hypoxia in a rabbit liver tumor model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5271. doi:10.1158/1538-7445.AM2015-5271