Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer

Durán, Rafael; Mirpour, Sahar; Pekurovsky, Vasily; Ganapathy-Kanniappan, Shanmugasundaram; Brayton, Cory; Cornish, Toby C.; Gorodetski, Boris; Reyes, Juvenal; Chapiro, Julius; Schernthaner, Rüdiger; Frangakis, Constantine; Lin, Ming De; Sun, Jessica; Hart, Charles P.; Geschwind, Jean François H.

doi:10.1158/1078-0432.ccr-16-0725

Cited by 29 publications

(26 citation statements)

References 52 publications

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“…In this study, we observed an increase in hypoxia upon evofosfamide treatment in both CT-1 and CT-2 experiments. Though this finding is in agreement with a previous finding where evofosfamide enhanced hypoxia in liver cancer xenografts after 14 days of treatment, other studies have reported reduction in tumor hypoxia in renal cell carcinoma and leukemia in response to evofosfamide treatment [33] , [34] , [35] . These contradictory findings indicate the possibility that the effect of evofosfamide on the extent of tumor hypoxia may depend upon factors such as tumor type and dose and duration of the therapy.…”

Section: Discussionsupporting

confidence: 93%

Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models

Kumar¹,

Sun

Zhang

et al. 2018

Translational Oncology

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Antiangiogenic therapy has shown promising results in preclinical and clinical trials. However, tumor cells acquire resistance to this therapy by gaining ability to survive and proliferate under hypoxia induced by antiangiogenic therapy. Combining antiangiogenic therapy with hypoxia-activated prodrugs can overcome this limitation. Here, we have tested the combination of antiangiogenic drug sunitinib in combination with hypoxia-activated prodrug evofosfamide in neuroblastoma. In vitro, neuroblastoma cell line SK-N-BE(2) was 40-folds sensitive to evofosfamide under hypoxia compared to normoxia. In IV metastatic model, evofosfamide significantly increased mice survival compared to the vehicle (P=.02). In SK-N-BE(2) subcutaneous xenograft model, we tested two different treatment regimens using 30 mg/kg sunitinib and 50 mg/kg evofosfamide. Here, sunitinib therapy when started along with evofosfamide treatment showed higher efficacy compared to single agents in subcutaneous SK-N-BE(2) xenograft model, whereas sunitinib when started 7 days after evofosfamide treatment did not have any advantage compared to treatment with either single agent. Immunofluorescence of tumor sections revealed higher number of apoptotic cells and hypoxic areas compared to either single agent when both treatments were started together. Treatment with 80 mg/kg sunitinib with 50 mg/kg evofosfamide was significantly superior to single agents in both xenograft and metastatic models. This study confirms the preclinical efficacy of sunitinib and evofosfamide in murine models of aggressive neuroblastoma. Sunitinib enhances the efficacy of evofosfamide by increasing hypoxic areas, and evofosfamide targets hypoxic tumor cells. Consequently, each drug enhances the activity of the other.

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Section: Discussionsupporting

confidence: 93%

Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models

Kumar¹,

Sun

Zhang

et al. 2018

Translational Oncology

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“…of three independent experiments. activity (Sun et al, 2012) and augments the efficacy of approved therapies, including radiation (Peeters et al, 2015;Lohse et al, 2016;Jamieson et al, 2018;Takakusagi et al, 2018), immune checkpoint blockade (Jamieson et al, 2018;Jayaprakash et al, 2018), bortezomib (Hu et al, 2013), mTOR (mammalian target of rapamycin) inhibitors (Sun et al, 2015), transarterial chemoembolisation (Duran et al, 2017), and various cytotoxic agents (Liu et al, 2012;Zhang et al, 2016;Haynes et al, 2018). Clinically, evofosfamide is well tolerated (Weiss et al, 2011) and was active in combination with gemcitabine for advanced pancreatic cancer (Borad et al, 2015) and doxorubicin for soft-tissue sarcoma (Chawla et al, 2014) in phase 2 randomized and single-arm studies, respectively.…”

Section: Introductionmentioning

confidence: 98%

Functional CRISPR and shRNA Screens Identify Involvement of Mitochondrial Electron Transport in the Activation of Evofosfamide

Hunter

Devaux

Meng

et al. 2019

Molecular Pharmacology

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Evofosfamide (TH-302) is a hypoxia-activated DNA-crosslinking prodrug currently in clinical development for cancer therapy. Oxygen-sensitive activation of evofosfamide depends on oneelectron reduction, yet the reductases that catalyze this process in tumors are unknown. We used RNA sequencing, wholegenome CRISPR knockout, and reductase-focused short hairpin RNA screens to interrogate modifiers of evofosfamide activation in cancer cell lines. Involvement of mitochondrial electron transport in the activation of evofosfamide and the related nitroaromatic compounds EF5 and FSL-61 was investigated using 143B r 0 (r zero) cells devoid of mitochondrial DNA and biochemical assays in UT-SCC-74B cells. The potency of evofosfamide in 30 genetically diverse cancer cell lines correlated with the expression of genes involved in mitochondrial electron transfer. A whole-genome CRISPR screen in KBM-7 cells identified the DNA damage-response factors SLX4IP, C10orf90 (FATS), and SLFN11, in addition to the key regulator of mitochondrial function, YME1L1, and several complex I constituents as modifiers of evofosfamide sensitivity. A reductasefocused shRNA screen in UT-SCC-74B cells similarly identified mitochondrial respiratory chain factors. Surprisingly, 143B r 0 cells showed enhanced evofosfamide activation and sensitivity but had global transcriptional changes, including increased expression of nonmitochondrial flavoreductases. In UT-SCC-74B cells, evofosfamide oxidized cytochromes a, b, and c and inhibited respiration at complexes I, II, and IV without quenching reactive oxygen species production. Our results suggest that the mitochondrial electron transport chain contributes to evofosfamide activation and that predicting evofosfamide sensitivity in patients by measuring the expression of canonical bioreductive enzymes such as cytochrome P450 oxidoreductase is likely to be futile.

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“…Evofosfamide is a clinical-stage hypoxia-activated prodrug designed to target the DNA-crosslinking nitrogen mustard bromo-iso-phosphoramide (Br-IPM) to regions of hypoxia (37), leading to DNA damage, γH2AX phosphorylation, cell cycle arrest, and cleavage of caspase-3 and -6 (38)(39)(40). Despite narrowly missing its primary phase 3 overall survival (OS) endpoint with gemcitabine for advanced pancreatic adenocarcinoma (41), evofosfamide shows abundant evidence of preclinical (40,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) and clinical activity (52,53). However, evofosfamide has not been comprehensively investigated for HNSCC.…”

Section: Introductionmentioning

confidence: 99%

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

Jamieson¹,

Tsai²,

Kondratyev³

et al. 2018

JCI Insight

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Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.

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Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer

Cited by 29 publications

References 52 publications

Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models

Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models

Functional CRISPR and shRNA Screens Identify Involvement of Mitochondrial Electron Transport in the Activation of Evofosfamide

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

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