Preclinical benefit of hypoxia-Activated intraarterial therapy with evofosfamide in liver cancer

Rafael Duran, Sahar Mirpour, Vasily Pekurovsky, Shanmugasundaram Ganapathy-Kanniappan, Cory F. Brayton, Toby C. Cornish, Boris Gorodetski, Juvenal Reyes, Julius Chapiro, Rudiger E. Schernthaner, Constantine Frangakis, Ming De Lin, Jessica D. Sun, Charles P. Hart, Jean Fraņcois Geschwind

Research output: Contribution to journalArticle

Abstract

Purpose: To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-Activated intra-Arterial therapy (HAIAT) with evofosfamide in a rabbit model. Experimental Design: VX2-Tumor-bearing rabbits were assigned to 4 intra-Arterial therapy (IAT) groups (n 7/group): (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin- lipiodol emulsion followed by embolization with 100-300 mm beads (conventional, cTACE); or (iv) cTACE and evofosfamide (cTACE Evo). Blood samples were collected pre-IAT and 1, 2, 7, and 14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole-slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia, and metabolism were quantified (g-H2AX, Annexin V, caspase-3, Ki- 67, HIF1a, VEGF, GAPDH, MCT4, and LDH). Results: cTACE Evo showed a similar profile of liver enzymes elevation and pathologic scores compared with cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE Evo demonstrated smaller tumor volumes, lower tumor growth rates, and higher necrotic fractions compared with cTACE. cTACE Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE Evo promoted antitumor effects as evidenced by increased expression of g-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1a/VEGF expression and tumor glycolysis supported HAIAT. Conclusions: HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer.

Original languageEnglish (US)
Pages (from-to)536-548
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number2
DOIs
StatePublished - Jan 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Duran, R., Mirpour, S., Pekurovsky, V., Ganapathy-Kanniappan, S., Brayton, C. F., Cornish, T. C., Gorodetski, B., Reyes, J., Chapiro, J., Schernthaner, R. E., Frangakis, C., Lin, M. D., Sun, J. D., Hart, C. P., & Geschwind, J. F. (2017). Preclinical benefit of hypoxia-Activated intraarterial therapy with evofosfamide in liver cancer. Clinical Cancer Research, 23(2), 536-548. https://doi.org/10.1158/1078-0432.CCR-16-0725