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Type: Thesis
Title: Targeting Cancer in the Bone with the Hypoxia Activated Pro-Drug Evofosfamide
Author: Liapis, Vasilios
Issue Date: 2017
School/Discipline: Adelaide Medical School
Abstract: Tumour hypoxia is widely recognised as a major cause of treatment failure and poor outcome for a variety of malignancies. Tumour hypoxia also results in resistance to conventional anticancer therapies leading to an increase in malignancy and metastases to other sites, in particular, the bone. Bone metastases occur in more than 75% of patients with breast, prostate and lung cancer. Tumours in the bone are often resistant to anticancer therapy due to the hypoxic nature of the bone micro-environment, resulting in their recurrence and metastasis. Hypoxia also offers treatment opportunities, exemplified by the development of highly active compounds that target hypoxic zones known as Hypoxia Activated Pro-drugs. Evofosfamide is a hypoxia activated pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When Evofosfamide is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin is released resulting in cancer cell death. The cytotoxic activity of evofosfamide against osteosarcoma cells was assessed in vitro and its anticancer efficacy as a single agent and in combination with doxorubicin was evaluated in an orthotopic mouse model of human osteosarcoma (OS). In vitro, evofosfamide was cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. Evofosfamide reduced tumor burden in bone and cooperated with doxorubicin to protect the bone from osteosarcoma induced bone destruction, while also reducing lung metastases. In addition, under hypoxic conditions in vitro, evofosfamide cooperated with Pro Apoptotic Receptor Agonists (PARAs) dulanermin and drozitumab, resulting in a dose-dependent increase in cytotoxicity to osteosarcoma cells selectively under hypoxic conditions. In contrast primary normal human osteoblasts under the same hypoxic conditions were resistant. In vivo, evofosfamide cooperated with drozitumab, reducing tumor burden in the orthotopic mouse model of human osteosarcoma and protected the bone from osteosarcoma-induced bone destruction while also reducing the growth of pulmonary metastases. In order to assess the anticancer efficacy of evofosfamide against breast cancer, a panel of human breast cancer cell lines were treated with evofosfamide and shown to be highly cytotoxic under hypoxia. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad or into the tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. In vivo evofosfamide demonstrated tumor suppressive activity as a single agent and cooperated with paclitaxel to reduce mammary tumor growth. Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. Treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and with an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. In conclusion the preclinical data presented in this thesis demonstrate that evofosfamide may be an attractive therapeutic agent when used alone and in combination with chemotherapy or PARAs for the treatment of osteosarcoma and breast cancer.
Advisor: Evdokiou, Andreas
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2017
Keywords: Cancer
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