Tuberous Sclerosis Complex (TSC) is an inherited disorder that manifests with seizures, mental retardation, and benign tumors in multiple organs including the brain, kidney, heart, and skin. There are approximately 40,000 patients with TSC in the United States alone, and 900,000 world-wide. TSC is caused by mutations in two genes: TSC1 and TSC2. Another disease caused by TSC1 and TSC2 mutations is the rare disorder, lymphangioleiomyomatosis (LAM), which manifests primarily in the lungs and affects exclusively women. Loss of TSC1 or TSC2 function causes uncontrolled cell growth through the activation of mTOR, a protein that is sensitive to the antibiotic rapamycin. Clinical trials are underway to determine whether rapamycin can be a potential drug for the treatment of TSC and LAM. However, rapamycin is not effectively killing tumor cells, and targeting multiple proteins in the TSC/mTOR pathway may provide additional treatment options.
Recently, we have found Plk1 as a new interacting partner of TSC1. Plk1 is a protein regulating several aspects of cell division, including cytokinesis, the final stage of cell division that physically separates the two daughter cells. Plk1 is increased in various forms of cancer, and inhibition of Plk1 leads to cell death. In preliminary results, we have found that mTOR is activated by Plk1, that cells without TSC1 have abnormal cytokinesis, and that Plk1 expression is increased in cells without TSC1 or TSC2 and in samples from LAM patients. Finally, a newly developed Plk1 inhibitor decreases the survival of cells lacking TSC1 or TSC2.
The objectives of this proposal are to define the pathway leading to mTOR activation by Plk1, investigate the consequences of TSC1 or TSC2 loss in cell division, more specifically, cytokinesis, and determine whether targeting Plk1 by specific inhibitors causes death in cells without TSC1 or TSC2.
The success of this project will lead to a new preclinical model for TSC treatment, the use of Plk1 inhibitors in TSC mice. Currently, there are three Plk1 inhibitors in Phase I and II clinical trials for treating cancer. We anticipate that the discovery of additional "drugable" targets in the TSC/mTOR pathway (such as Plk1) will benefit patients with TSC and LAM, and other patient groups who have increased activation of mTOR.