Anticancer efficacy of the hypoxia-activated prodrug evofosfamide is enhanced in combination with proapoptotic receptor agonists against osteosarcoma
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Updated: Feb 24, 2026
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Vasilios Liapis1, Aneta Zysk1, Mark DeNichilo2
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Woodville, South Australia, Australia.
Abstract:
Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia also leads to treatment opportunities as demonstrated by the development of compounds that target regions of hypoxia within tumors. Evofosfamide is a hypoxia-activated prodrug that is created by linking the hypoxia-seeking 2-nitroimidazole moiety to the cytotoxic bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions of tumors, the DNA cross-linking toxin, Br-IPM, is released leading to cell death. This study assessed the anticancer efficacy of evofosfamide in combination with the Proapoptotic Receptor Agonists (PARAs) dulanermin and drozitumab against human osteosarcoma in vitro and in an intratibial murine model of osteosarcoma. Under hypoxic conditions in vitro, evofosfamide cooperated with dulanermin and drozitumab, resulting in the potentiation of cytotoxicity to osteosarcoma cells. In contrast, under the same conditions, primary human osteoblasts were resistant to treatment. Animals transplanted with osteosarcoma cells directly into their tibiae developed mixed osteosclerotic/osteolytic bone lesions and consequently developed lung metastases 3 weeks post cancer cell transplantation. Tumor burden in the bone was reduced by evofosfamide treatment alone and in combination with drozitumab and prevented osteosarcoma-induced bone destruction while also reducing the growth of pulmonary metastases. These results suggest that evofosfamide may be an attractive therapeutic agent, with strong anticancer activity alone or in combination with either drozitumab or dulanermin against osteosarcoma.
Insights
Evofosfamide, a hypoxia-activated prodrug, effectively targets osteosarcoma cells, especially when combined with dulanermin or drozitumab. This combination therapy reduced tumor burden and prevented metastasis in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Tumor hypoxia is a significant challenge in cancer treatment, often leading to therapeutic failure.
- Hypoxia also presents therapeutic opportunities through the development of hypoxia-targeted agents.
- Evofosfamide is a hypoxia-activated prodrug designed to release a cytotoxic agent in hypoxic tumor regions.
Purpose of the Study:
- To evaluate the anticancer efficacy of evofosfamide, alone and in combination with Proapoptotic Receptor Agonists (PARAs) dulanermin and drozitumab.
- To assess the efficacy against human osteosarcoma in vitro under hypoxic conditions and in an in vivo murine model.
- To determine the drug's effect on primary human osteoblasts to assess selectivity.
Main Methods:
- In vitro studies exposed human osteosarcoma cells and primary osteoblasts to hypoxic conditions with evofosfamide, dulanermin, and drozitumab.
- An in vivo study utilized an intratibial murine model of osteosarcoma, assessing tumor burden, bone destruction, and lung metastases.
- Evofosfamide's mechanism involves releasing bromo-isophosphoramide mustard (Br-IPM) in hypoxic tumor areas.
Main Results:
- Evofosfamide demonstrated synergistic cytotoxicity with dulanermin and drozitumab against osteosarcoma cells under hypoxia in vitro.
- Primary human osteoblasts showed resistance to the treatment, indicating potential selectivity.
- In vivo, evofosfamide alone and in combination reduced bone tumor burden, prevented bone destruction, and decreased lung metastasis growth.
Conclusions:
- Evofosfamide exhibits potent anticancer activity against osteosarcoma, particularly in combination with PARAs dulanermin or drozitumab.
- The drug shows promise as a therapeutic agent targeting hypoxic osteosarcoma.
- The combination therapy warrants further investigation for clinical application in osteosarcoma treatment.
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