Study of mTOR Signaling Inhibitors as Potential Treatment for TSC

Background: Tuberous sclerosis complex (TSC) affects about 1 in 6,000 live births and is characterized by benign tumors 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 protein complex that normally regulates the activity of a key regulatory molecule called mTORC1. Thus, cells with diminished TSC function exhibit abnormally high mTORC1 activity, resulting in abnormal cellular growth and differentiation.

Rationale: Early clinical trial results have shown that the mTORC1 inhibitor rapamycin (sirolimus) or its derivative RAD-001 (everolimus) can reduce tumor volume and seizure frequency. These observations raise great hope that effective treatments for TSC may soon emerge through regulating mTORC1. Unfortunately, the results also showed that rapamycin therapy is associated with clinically important side effects and that cessation of therapy led to tumor regrowth in most patients. New drugs suitable for long-term treatment are needed.

Innovation: We have discovered six new inhibitors of mTORC1 signaling. The drugs are already approved for use in other human disease indications. The drugs belong to three different classes that are structurally different from each other and from rapamycin and, unlike rapamycin, they are reversible inhibitors of mTORC1 signaling. Importantly, the drugs can inhibit mTORC1 even in the absence of TSC function. Furthermore, in their current applications they are often taken for months and some even for years. These observations raised the possibility that drugs already approved for human use might have therapeutic potential for TSC and motivated us to enter into TSC research.

Objective of Proposed Work: We will first determine the preferred dose and schedule at which the drugs reduce or normalize mTORC1 signaling in TSC-defective cells grown in tissue culture. We will then evaluate their efficacy in reducing abnormal phenotypes associated with TSC in tissue culture cells. The best performing drugs will then be tested to determine whether they can inhibit mTORC1 signaling and abnormal cell proliferation in animals, using TSC-defective cells of human and mouse origin grown as tumors in mice. A successful outcome will be the selection of one or more drugs that could be rapidly taken to the stage of clinical testing.

Impact: A successful outcome will open up new avenues for the development of treatments that could be appropriate for child and adult TSC patients. 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.