Dr. Ian Lorimer; Senior Scientist/Associate Professor, Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Project Title: “Targeting Glioblastoma tumour initiating cells via inhibition of fatty acid synthase”
Glioblastoma is a very aggressive form of adult brain tumour. In spite of treatment with surgery, radiation and chemotherapy, patients typically do not live much longer than one year. Within Glioblastoma tumours, some of the cancer cells have properties of more mature cells in the brain, while a subset of cells more closely resemble neural stem cells.
These gllioblastoma stem-like cells appear to be the cell type that is resistant to radiation and chemotherapy treatments. A recent paper has shown that normal neural stem cells in the brain have to synthesize their own fats in order to proliferate. This is markedly different from most other cell types, which can readily obtain fats from the circulation.
We wish to test the hypothesis that glioblastoma stem-like cells also have this requirement, and that they can be eradicated with drugs that target enzymes involved in the synthesis of fats inside these cells. We will test this strategy using glioblastoma stem-like cells that have been isolated from patients and implanted in the brain of mice.
Progress Report 2015
This proposal was based on literature showing that neural stem cells were uniquely dependent on endogenous fatty acid synthesis for their proliferation. As glioblastoma tumour initiating cells have neural stem cell-like properties, we hypothesized that they might also exhibit this dependency. This was supported by cell culture studies with a fatty acid synthase inhibitor drug, which was cytotoxic to glioblastoma tumour initiating cells isolated from multiple patients. We tested a fatty acid synthase inhibitor drug, C75, for activity against glioblastoma in mice. We first determined a maximum tolerated dose for this drug in immunocompromised mice. Mice treated with this drug exhibited a very rapid weight loss with this drug due to fluid loss, which was unexpected. Working with the maximum tolerated dose we did not find efficacy for this drug when we tested it in immunocompromised mice that had had human glioblastoma tumour initiating cells implanted intracerebrally. This is likely due to an inability to achieve sufficiently high drug levels in the brain due to the systemic toxicities seen with the drug. We are carrying out further work to validate fatty acid synthase as a drug target in glioblastoma to provide a strong basis for the development of new drugs with greater activity in the central nervous system.