The Kwiatkowski Lab is focused on a tumor suppressor gene syndrome, tuberous sclerosis complex (TSC), and cancers that commonly have activation of the mTOR signaling pathway.   We have an interest in all of the tumors that occur in TSC, especially angiomyolipoma and lymphangioleiomyomatosis (LAM).

The Kwiatkowski Lab is best known for the identification of the TSC1 gene, and a long series of pioneering genetic studies in TSC, including most recently the use of massively parallel sequencing and computational methods to identify mosaic mutations in TSC1/TSC2 in most TSC individuals in whom previous efforts had been unsuccessful at mutation identification.

In addition, we were the first group to generate and explore mouse models of TSC, with a particular focus on brain models of TSC.  Preclinical studies in these mouse models demonstrated activation of mTORC1, and major clinical and survival benefit of treatment with a class of drugs known as rapalogs (including rapamycin and everolimus). This preclinical work enabled translation to patients, and rapalogs have subsequently been shown to provide major benefit to TSC individuals with a variety of types of tumors, including angiomyolipoma and LAM, and have also shown success in several different types of cancer in which TSC1, TSC2, or MTOR mutations occurred.

We use a variety of approaches in our work, with a primary focus on genetics and computational analyses, but also cell culture studies, mouse models, and pathology.  The fundamental mission is to 1) improve our understanding of mechanisms of disease development in TSC and related conditions, with the premise that such understanding will lead to therapeutic discovery; 2) extend this understanding to the common cancers (kidney, bladder) in which Tsc1/TSC2/MTOR mutations are frequently seen.  Our work has led to two ongoing clinical studies led by Dr. Kwiatkowski: 1) COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC; and 2) A Phase II trial of everolimus for cancer patients with inactivating mutations in TSC1 or TSC2 or activating MTOR mutations.