Grant: Operating Grant

Glioblastoma (GBM) is an incurable cancer that often effects otherwise healthy young people. Despite aggressive treatment, outcomes for patients with glioblastoma remain dismal. Patients inevitably succumb to their disease in just over one year. One hallmark of GBM is its highly vascular nature. Tumour growth depends on angiogenesis, or new blood vessel formation. There has thus been interest in employing therapies that block angiogenesis in GBM. The initial experience with the angiogenesis inhibitor, bevacizumab (Avastin), appeared to justify this interest: it improved survival in patients with progressive GBM from 3.3 to 8.1 months. This excitement was tempered, however, by findings that Avastin's effects are non-sustained. Two recent trials found that addition of Avastin to conventional therapy for patients with newly diagnosed GBM did not improve survival, suggesting an alternative mechanism for angiogenesis unaffected by Avastin. It has been speculated that an analogous alternative mechanism for angiogenesis is responsible for progression of breast and colon cancer through Avastin therapy. In our previous work, we identified a molecule involved in normal blood vessel maturation, which has been coopted in GBM to allow cancer cells to become blood vessel cells. This process, known as vascular mimicry, has been described in melanoma, but only recently found to occur in GBM. In a GBM mouse model, inhibition of this molecular, which we named LIVE, inhibited new blood vessel growth and resulted in tumour regression and prolonged survival. Our findings suggest that LIVE modulates alternative angiogenesis in GBM. In this project, we will determine if LIVE-mediated vascular mimicry is a mechanism of Avastin resistance, and if so, if LIVE inhibition enhances survival in GBM. If successful, these studies could open a new venue for treatment of patients with GBM, and in other cancers in which vascular mimicry plays a role in therapeutic resistance.