Tuberous sclerosis complex (TSC) is a rare genetic disease that causes benign tumors to grow in many different organs of the body. Although TSC tumors are not metastatic, these tumors can still cause problems, some critical, when the growth is located in vital organs such as the brain, kidney, and lung. Currently, there is no cure for TSC and treatment is largely devoted to surgical removal of tumors. Sometimes drugs such as rapamycin or related drugs are used to keep tumors from growing. Unfortunately, rapamycin only stops the tumor growth, does not make the tumors go away, and tumors enlarge further as soon as rapamycin is discontinued. In addition, long-term treatment can lead to side effects, such as diabetes and resistance. In other words, TSC is an incurable lifelong disease, and the current treatments available only stop disease progression. They are not a cure. It is imperative to develop a new therapeutic approach that can only eliminate tumor rather just block growth but also do so without major side effects.

What are the objectives of our research?

The main objective is to understand why TSC tumor cells are not destroyed by rapamycin, and to discover why cells can become resistant to the blocking effects of rapamycin after long-term treatment. To accomplish this, we plan to identify the biochemical and molecular pathways within the rapamycin-treated cells that are responsible for the development of resistance. Our ultimate goal is to use this new understanding to discover a treatment that will completely kill the cells in the tumors and thereby achieve a cure.

What type of patients will receive benefit from our research?

The immediate benefit would be for current patients facing lifelong treatment with rapamycin. However, the availability of a safe and curative drug would greatly expand the number of TSC patients who would benefit, eventually, from an understanding of the biology of cells treated with rapamycin. In addition, our research may uncover pathways that play a role in the growth of other kinds of tumors that are not caused by TSC but are sensitive to rapamycin.

What are potential risks?

This is a preclinical study. It will not pose a risk to patients.

What are the likely contributions of this proposed research project to advancing the field of TSC research and/or patient care?

Our proposal addresses the basic inadequacy of current rapamycin therapy and, therefore, has the potential for a marked and fundamental long-term impact on treatment of patients with TSC. Importantly, by identifying the pathways used by rapamycin and the ones that are activated when rapamycin stops working, new therapies distinct from rapamycin may be discovered that are more effective than this drug and that are, unlike rapamycin, curative.

In summary, these preclinical studies described in our proposal provide the possibility of a major long-term breakthrough in treatment of TSC.