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Preclinical Benefit of Hypoxia-Activated Intra- Arterial Published OnlineFirst July 20, 2016; DOI: 10.1158/1078-0432.CCR-16-0725 Cancer Therapy: Preclinical Clinical Cancer Research Preclinical Benefit of Hypoxia-Activated Intra- arterial Therapy with Evofosfamide in Liver Cancer Rafael Duran1,2, Sahar Mirpour1, Vasily Pekurovsky1, Shanmugasundaram Ganapathy- Kanniappan1, Cory F. Brayton3, Toby C. Cornish4, Boris Gorodetski1, Juvenal Reyes5, Julius Chapiro1,2,Rudiger€ E. Schernthaner1,2, Constantine Frangakis6, MingDe Lin2,7, Jessica D. Sun8, Charles P. Hart8, and Jean-Francois¸ Geschwind2 Abstract Purpose: To evaluate safety and characterize anticancer efficacy Results: cTACE þ Evo showed a similar profile of liver of hepatic hypoxia-activated intra-arterial therapy (HAIAT) with enzymes elevation and pathologic scores compared with cTACE. evofosfamide in a rabbit model. Neither hematologic nor renal toxicity were observed. Animals Experimental Design: VX2-tumor-bearing rabbits were treated with cTACE þ Evo demonstrated smaller tumor volumes, assigned to 4 intra-arterial therapy (IAT) groups (n ¼ 7/group): lower tumor growth rates, and higher necrotic fractions com- (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin– pared with cTACE. cTACE þ Evo resulted in a marked reduction lipiodol emulsion followed by embolization with 100–300 mm in the HF and HC. Correlation was observed between decreases beads (conventional, cTACE); or (iv) cTACE and evofosfamide in HF or HC and tumor necrosis. cTACE þ Evo promoted (cTACE þ Evo). Blood samples were collected pre-IAT and 1, 2, 7, antitumor effects as evidenced by increased expression of and 14 days post-IAT. A semiquantitative scoring system assessed g-H2AX, apoptotic biomarkers, and decreased cell proliferation. hepatocellular damage. Tumor volumes were segmented on Increased HIF1a/VEGF expression and tumor glycolysis sup- multidetector CT (baseline, 7/14 days post-IAT). Pathologic ported HAIAT. tumor necrosis was quantified using manual segmentation on Conclusions: HAIAT achieved a promising step towards the whole-slide images. Hypoxic fraction (HF) and compartment locoregional targeting of tumor hypoxia. The favorable tox- (HC) were determined by pimonidazole staining. Tumor DNA icity profile and enhanced anticancer effects of evofosfamide damage, apoptosis, cell proliferation, endogenous hypoxia, and in combination with cTACE pave the way towards clinical metabolism were quantified (g-H2AX, Annexin V, caspase-3, Ki- trials in patients with liver cancer. Clin Cancer Res; 23(2); 536–48. 67, HIF1a, VEGF, GAPDH, MCT4, and LDH). Ó2016 AACR. Introduction sion and resistance to chemotherapy (1, 2). In addition, tumor hypoxia has been shown to promote the emergence of a more Hypoxia is one of the most common and frequent physio- aggressive and metastatic cancer phenotype (1, 3) which logic alteration of solid tumors, including hepatocellular car- demonstrates increased resistance to apoptosis (4), stimulates cinoma, and has been strongly correlated with disease progres- angiogenesis (1), and favors cancer growth by altering cell metabolism (5). Overall, tumor hypoxia contributes to a poor clinical prognosis (6). As a result, a variety of hypoxia-targeted 1Russell H. Morgan Department of Radiology and Radiological Science, Division therapies have been developed including hypoxia-inducible of Vascular and Interventional Radiology, The Johns Hopkins Hospital, Balti- factor 1 (HIF-1a) targeting, hypoxia-selective gene therapy, more, Maryland. 2Department of Radiology and Biomedical Imaging, Yale genetic engineering of anaerobic bacteria and hypoxia-activated 3 University School of Medicine, New Haven, Connecticut. Department of Molec- prodrugs (HAP; ref. 2). ular and Comparative Pathobiology, The Johns Hopkins University School of Among these different hypoxia-targeted strategies, HAPs are Medicine, Baltimore, Maryland. 4Department of Pathology, Division of Gastro- intestinal and Liver Pathology, The Johns Hopkins University School of Medicine, unique in that they are selectively activated under low oxygen- Baltimore, Maryland. 5Department of Radiation Oncology and Molecular Radi- ation conditions, and remain as nontoxic prodrug during ation Sciences, The Johns Hopkins Hospital, Baltimore, Maryland. 6Department normoxic or aerobic conditions. This distinctive characteristic of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Balti- rendersHAPsaspotentiallyveryeffectiveinthesettingof 7 more, Maryland. U/S Imaging and Interventions (UII), Philips Research North transarterial chemoembolization (TACE). Indeed, the embolic 8 America, Cambridge, Massachusetts. Threshold Pharmaceuticals, South San effect of TACE increases the hypoxic microenvironment of solid Francisco, California. tumors and provides an attractive setting for selective activation Note: Supplementary data for this article are available at Clinical Cancer of bioreductive prodrugs under low tissue oxygen state. More- Research Online (http://clincancerres.aacrjournals.org/). over, TACE allows for the locoregional delivery of high-doses of Corresponding Author: Jean-Francois¸ Geschwind, Yale University School of chemotherapy that have the potential to reach distal tumor Medicine, 330 Cedar Street, TE 2-230, New Haven, CT 06520. Phone: 203-785- regions where hypoxic cells reside in a pharmacologic sanctuary 6938; Fax: 203-785-3024; E-mail: [email protected] (7, 8). Furthermore, the use of HAPs in TACE could help doi: 10.1158/1078-0432.CCR-16-0725 mitigate detrimental effects triggered by the embolization Ó2016 American Association for Cancer Research. with the activation of HIF-1a–dependent pathways, such as 536 Clin Cancer Res; 23(2) January 15, 2017 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst July 20, 2016; DOI: 10.1158/1078-0432.CCR-16-0725 Selective Hepatic Hypoxia-Activated Intra-arterial Therapy – þ n ¼ Translational Relevance with 100 300 mm bland beads (cTACE Evo group; 7). Animals underwent multidetector computed tomography Tumor hypoxia has long been considered as one of the main (MDCT) 24 hours pretreatment and then at 7 and 14 days after challenges of anticancer therapy. As a result, hypoxia-activated the interventional treatment. Comprehensive blood work (com- therapies have been developed and hold promise in achieving plete liver, hematologic, and renal panels) was obtained at base- meaningful results once translated to the clinic. The use of line, 1, 2, 7, and 14 days after treatment. Daily clinical monitoring hypoxia-activated prodrugs in the setting of transarterial che- was performed. Three animals in each group were randomly moembolization (TACE) is particularly appealing as it allows sacrificed 2 days after treatment for histopathologic and immu- locoregional delivery of high doses of chemotherapy that have nohistochemical analysis. The rest of the animals were sacrificed the potential to reach distal tumor regions where hypoxic cells on day 14 after the last imaging assessment. reside in a pharmacologic sanctuary. Moreover, the embolic effect of TACE provides an attractive setting for selective Treatment regimen activation of bioreductive prodrugs. The main finding of this Evofosfamide was formulated in saline at 5 mg/mL and filtered study is that TACE in combination with evofosfamide through a 0.2-mm filter before animal dosing. Evofosfamide was achieved enhanced anticancer efficacy with limited additive prepared by study members who did not participate in the toxicity compared with TACE alone. The observed correlation embolization procedures. A treatment dose of 7.7 mg/kg was between the magnitude of hypoxia and evofosfamide efficacy used on the basis of the FDA guidelines for dose translation based established the in vivo proof-of-concept of selective hypoxia- on body surface area and previous studies (14, 19–21, 25). activated intra-arterial therapy for liver cancer. The results of Doxorubicin powder was reconstituted with saline immediately this study suggest that clinical trials should be considered. before intra-arterial injection, for a final concentration of 10 mg/mL. This dose calculation was based on the most common clinically administered doses of doxorubicin in the setting of cTACE (50 mg, for a 70 kg person; ref. 26). The doxorubicin solution was mixed to obtain a homogenous clear red solution. In subsequent gene overexpression of VEGF (9, 10) and hypoxia- a separate syringe, an equal-to-doxorubicin-solution volume of induced chemoresistance (11). lipiodol was withdrawn. The two solutions were mixed according Evofosfamide (formerly called TH-302), is a 2-nitroimida- to the push-and-pull method using a metallic stopcock. Emulsion zole triggered HAP of the cytotoxin bromo-isophosphoramide (0.6–0.8 mL; total doxorubicin dose: 3–4 mg) was administered mustard (12). Evofosfamide has shown broad-spectrum anti- (cTACE and cTACE þ Evo groups) followed by a volume of up to cancer efficacy in multiple human cell lines and xenograft 0.1–0.2 mL of 100–300 mm beads mixed with an equal volume of models (13–18) and is currently undergoing clinical evaluation nonionic contrast medium (Visipaque 320, GE Healthcare). In (19–21). the cTACE þ Evo group, the emulsion was injected following a The purpose of this study was to evaluate the safety and efficacy sequential protocol. First a small volume of the emulsion (0.1–0.2 of hypoxia-activated intra-arterial therapy (HAIAT) with evofos- mL) was injected and pushed with saline to occlude distal tumor famide
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