Grant: Master's Award: Canada Graduate Scholarships

Tuberous sclerosis complex (TSC) is a genetic disease that occurs in about 1 in 6000 live births and is characterized by benign tumours in multiple organs and neurological manifestations, including epilepsy, mental retardation, and autism, that can be devastating. TSC results from loss of function of the TSC proteins that normally regulate the activity of a key regulatory protein complex called mTORC1. Cells with diminished TSC function have abnormally high mTORC1 activity, causing them to grow out of control. Currently, there is no cure for TSC. Very recent clinical trials have shown that the mTORC1 inhibitory drug rapamycin can reduce tumor volume and seizure frequency. These observations raise great hope that effective treatments for TSC may soon emerge. Unfortunately, rapamycin is also immunosuppressive and rapamycin therapy was associated with clinically detrimental side effects that require dose reduction or cessation of therapy leading to tumor re-growth in many patients. Recently, Dr. Roberge's laboratory has discovered three new inhibitors of mTORC1 signaling. They are drugs already approved for use in other human disease indications. They are structurally different from each other and from rapamycin and, unlike rapamycin, they are reversible inhibitors of mTORC1 signaling. The objective of my proposal is to determine how these drugs inhibit mTORC1 and whether these drugs can be used to attenuate abnormalities in TSC-defective cells in vitro. A successful outcome will open up new avenues for the development of TSC treatments. Finding new uses for drugs that are already approved for use in humans is a proven way to considerably reduce the cost and time associated with preclinical and clinical drug development. This factor is particularly relevant to diseases such as TSC which do not involve the large numbers of patients that attract strong interest from the pharmaceutical industry.