ArticleAmerican journal of cancer research2015
Combination treatment with hypoxia-activated prodrug evofosfamide (TH-302) and mTOR inhibitors results in enhanced antitumor efficacy in preclinical renal cell carcinoma models.
Article in American journal of cancer research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy.Frontiers in oncology · 2021Pooled it
- Tumor Microenvironment Responsive TPZ-Loaded Core-Shell Polymeric Nanoparticles for Selective Cancer Bioreductive Therapy.Advanced pharmaceutical bulletin · 2025Article
- Hypoxia-activated prodrug and antiangiogenic therapies cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration.JCI insight · 2024Article
- Spelling Out CICs: A Multi-Organ Examination of the Contributions of Cancer Initiating Cells' Role in Tumor Progression.Stem cell reviews and reports · 2022Review
- Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506.Molecular cancer therapeutics · 2021Article
- The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy.Frontiers in pharmacology · 2021Review
- In vitro hypoxia responsiveness of [EJNMMI radiopharmacy and chemistry · 2020Article
- Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology · 2019Article
- Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine.Gut · 2019Review
- Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials.Clinical and translational radiation oncology · 2019Article
- Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models.Translational oncology · 2018Article
- Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer.Cell reports · 2018Article
- Radiotherapy Synergizes with the Hypoxia-Activated Prodrug Evofosfamide: In Vitro and In Vivo Studies.Antioxidants & redox signaling · 2018Article
- Proteoglycan-targeting applied to hypoxia-activated prodrug therapy in chondrosarcoma: first proof-of-concept.Oncotarget · 2017Article
- Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Review
- Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors.Advanced healthcare materials · 2016Article
- Emerging targets for radioprotection and radiosensitization in radiotherapy.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumors often consist of hypoxic regions which are resistant to chemo- and radiotherapy. Evofosfamide (also known as TH-302), a 2-nitroimidazole triggered hypoxia-activated prodrug, preferentially releases the DNA cross-linker bromo-isophosphoramide mustard in hypoxic cells. The intracellular kinase mTOR plays a key role in multiple pathways which are important in cancer progression. Here we investigated the enhanced efficacy profile and possible mechanisms of evofosfamide in combination with mTOR inhibitor (mTORi) everolimus or temsirolimus in renal cell carcinoma (RCC) xenograft models. The antitumor activities of the mTORi everolimus or temsirolimus alone, evofosfamide alone, or the combination were investigated in the 786-O and Caki-1 RCC cells in vitro and in vivo xenograft models. Two schedules were tested in which evofosfamide was started on the same day as the mTORi or 1 week after. Combination mechanisms were investigated by measuring a panel of pharmacodynamic biomarkers by immunohistochemistry. Antitumor efficacy in both RCC xenograft models was enhanced by the combination of evofosfamide and mTORi. Evofosfamide reduced the increased hypoxia induced by mTORi. Combination treatment induced increased DNA damage, decreased cell proliferation, and decreased survivin. Addition of mTORi did not change evofosfamide-mediated cytotoxicity in 786-O or Caki-1 cells in vitro which might suggest cell non-autonomous effects, specifically increased tumor hypoxia, are important for the in vivo combination activity. Taken together, evofosfamide potentiates the antitumor efficacy of mTOR inhibitors and inhibits the increased tumor hypoxia caused by mTOR inhibition. These studies provide a translational rationale for combining evofosfamide with mTOR inhibitors in clinical studies.
Indexed as
Identifiers
26328245PMC4548326W1226804075What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.