Posted August 27, 2013
Aristotelis Astrinidis, Ph.D., Drexel University, Philadelphia, Pennsylvania
Tuberous sclerosis complex (TSC) is an inherited disorder resulting from loss of function of the TSC1 or TSC2 protein, which leads to uncontrolled cell growth through the hyperactivation of the mTOR signaling pathway. In addition to the development of non-malignant tumors throughout the body, individuals with TSC often display neurological symptoms including developmental delay, autism, and seizures. Currently, treatment options for individuals with TSC are very limited. Even though the protein mTOR is sensitive to treatment with the antibiotic rapamycin, this drug has not been effective at killing TSC tumor cells. Dr. Aristotelis Astrinidis, formerly of Drexel University (currently at the University of Ioannina School of Medicine in Ioannina, Greece), believes that targeting multiple proteins in the TSC/mTOR pathway may yield novel treatment avenues for this disease. He has demonstrated that the protein polo-like kinase 1 (PLK1), which regulates several aspects of cell division, interacts with the TSC1 protein and that depletion of TSC1 increased the level of PLK1 in cells. Dr. Astrinidis hypothesized that the interaction of PLK1-TSC1 regulates cytokinesis and cell survival. He received an Idea Development Award in fiscal year 2008, while at Drexel University, to investigate this hypothesis and determine the effect of PLK1 inhibition on cells lacking TSC1 and TSC2 (TSC1/TSC2-null cells).
Dr. Astrinidis demonstrated that the increased levels of PLK1 in TSC1/TSC2-null cells was due to increased protein stability, and that PLK1 protein levels are reduced following treatment with rapamycin. Additionally, he provided evidence that PLK1 acts upstream of TSC1/TSC2 to positively regulate mTOR signaling in a TSC1-PLK1 interaction dependent manner. Treatment of TSC1/TSC2-null cells with the PLK1 inhibitor BI-2536 decreased cell viability and clonogenic survival through induction of apoptosis. Combination treatment of rapamycin and BI-2536 further decreased viability and increased apoptosis of TSC1/TSC2-null cells. Dr. Astrinidis also found that BI-2536 disrupts autophagy, the process of the breakdown and recycling of damaged or unnecessary cellular components. These results were confirmed by gene expression profiling studies showing that key autophagy and survival genes were differentially expressed in TSC2-null cells following PLK1 inhibition. The combination of increased apoptosis and disrupted autophagy following PLK1 inhibition leads to enhanced cell death of TSC1/TSC2-null cells, suggesting that this may be an effective treatment against TSC tumors. BI-2536 has already been investigated in clinical trials for several different cancers and has been found to be safe and effective in a subset of leukemia patients, making it an attractive candidate for further testing in TSC.