I have broad interests in human cancer genetics, and have been Program Leader for the DFHCC Cancer Genetics program for the past 8 years. I am an Associate Member of the Broad Institute, and have been active in multiple NCI TCGA (The Cancer Genome Atlas) projects, including adenocarcinoma and squamous cell carcinoma of the lung, bladder cancer, kidney chromophobe cancer, mesothelioma, and pathway analyses. I have run or co-directed DNA analysis and diagnostic laboratories for many years.
A major research interest is the tumor suppressor gene syndrome Tuberous Sclerosis (TSC), its causative genes, TSC1 and TSC2, and regulation both in normal and cancer cells of mTOR. We identified the TSC1 gene in 1997, have made mouse models of both Tsc1 and Tsc2, and have generated cell line models that are used widely. We pursue studies on the human molecular genetics of TSC, develop mouse models using null and conditional alleles of Tsc1 and Tsc2, explore biochemical and signaling pathways and therapeutic approaches. There is a particular interest in mosaicism in TSC, and the pathogenesis of all of the tumors that occur in this disease, including lymphangioleiomyomatosis (LAM), angiomyolipomas, subependymal giant cell astrocytomas, and renal carcinoma.
It has become apparent that a variety of cancers (partially due to our analyses) have mutations in TSC1 or TSC2 at rates of 1 – 10%. Moreover, in some cases TSC1/TSC2-mutant cancers are highly sensitive to treatment with rapalogs, with durable CRs lasting several years. We are studying these patients to elucidate the genetic and other determinants of response to rapalogs, and investigating synergistic treatment approaches. I am the PI of a Novartis-sponsored Investigator-initiated trial to treat all cancers with mutations in either TSC1 or TSC2 with everolimus. A variety of correlative genetic studies will be done as part of that trial.