Our lab is interested in Renal Cell Carcinoma (RCC). We focus both on molecular mechanisms of RCC development as well as on research translation.
RCC affects about 35,000 individuals in the US every year. The most frequent histological type is Clear Cell RCC and it results typically from inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL). pVHL normally functions in an oxygen sensing pathway. pVHL targets the Hypoxia-inducible factor (HIF) for degradation when oxygen abounds. HIF is a transcription factor and it inappropriately accumulates in cells deficient for pVHL leading to increased gene expression and, in some settings, tumor formation. It is very intriguing that pVHL, a protein that normally functions in oxygen sensing, when mutated, predisposes to tumor development.
Based on some similarities between two highly divergent inherited tumor-prone syndromes, von Hippel-Lindau (resulting from germline mutations in VHL) and Tuberous Sclerosis Complex (resulting from germline mutations in either TSC1 or TSC2), we hypothesized that TSC1/TSC2 might also regulate HIF. The TSC1 and TSC2 proteins form a protein complex that inhibits the mTOR complex TORC1. TORC1 is a heterotrimeric complex with protein kinase activity that regulates the translation of a subset of mRNAs. We have now demonstrated that TSC1/TSC2, through TORC1, also regulates HIF. Understanding the mechanism of HIF regulation and the role of HIF in tumor development in Tuberous Sclerosis Complex patients are areas of intense research in the lab.
We have further discovered that TSC1/TSC2, like pVHL, functions in a pathway regulated by oxygen. In response to hypoxia, TORC1 is inhibited, and this process requires TSC1/TSC2. While the mechanism whereby hypoxia regulates TORC1 remains to be elucidated, we have identified a critical component of this signaling pathway, the REDD1 protein. Using both loss-of-function as well as gain-of-function studies, we have determined that REDD1 is both necessary and sufficient for TORC1 inhibition by hypoxia and that it functions upstream of TSC1/TSC2. How REDD1 acts is being explored in the lab using innovative biochemical and genetic approaches.
Like pVHL, the TSC1/TSC2 complex functions to regulate HIF and is in an oxygen sensing pathway. Thus, similarities between two quite different diseases have led us to profound insights into the function and regulation of the TSC1/TSC2 complex and to the discovery of a second tumor suppressor that functions in an oxygen sensing pathway.
These observations have paved the way for the use of TORC1 inhibitors in RCC. It is therefore quite exciting that TORC1 inhibition with Temsirolimus was recently shown in a phase III clinical trial to prolong survival of patients with advanced high risk clear cell RCC.
Finally, the lab is embarking upon an ambitious project in RCC translational medicine. The objectives of this project are threefold. First, the discovery of new pathways leading to RCC development using a variety of genomic and bioinformatic tools. Second, the evaluation of these pathways as potential targets for new therapies. Third, the development of in vitro systems with therapeutic predictive value.
The identification and careful analysis of biochemical pathways involved in RCC development should continue to lead to improvements in the treatment of patients with this disease.
RESEARCH INTERESTS
Mechanisms of tumor development
Hypoxia signaling
Tuberous Sclerosis Complex
Renal Cell Carcinoma
Targeted therapies
RECENT PUBLICATIONS
Brugarolas, J, "Renal-Cell Carcinoma - Molecular Pathways and Therapies" NEJM, 356:185-187, January 2007
Brugarolas, J., K. Lei, R.L. Hurley, B.D. Manning, J.H. Reiling, E. Hafen, L.A. Witters, L.W. Ellisen, and W.G. Kaelin, Jr., "Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex" Genes Dev, 18:2893-904, 2004
Brugarolas, J. and W.G. Kaelin, Jr., "Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes" Cancer Cell, 6:7-10, 2004
Majumder, P.K., P.G. Febbo, R. Bikoff, R. Berger, Q. Xue, L.M. McMahon,J. Manola, J. Brugarolas, T.J. McDonnell, T.R. Golub, M. Loda, H.A. Lane, and W.R. Sellers, "mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways" Nat Med, 10:594-601, 2004
Brugarolas, J.B., F. Vazquez, A. Reddy, W.R. Sellers, and W.G. Kaelin, Jr., "TSC2 regulates VEGF through mTOR-dependent and -independent pathways" Cancer Cell, 4:147-58, 2003
SIGNIFICANT PUBLICATIONS
Brugarolas, J., B.F. Haynes, and J.R. Nevins, "Towards a genomic-based diagnosis" Lancet, 357:249-50, 2001
Brugarolas, J., K. Moberg, S.D. Boyd, Y. Taya, T. Jacks, and J.A. Lees, "Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation" Proc Natl Acad Sci U S A, 96:1002-7, 1999
Brugarolas, J., R.T. Bronson, and T. Jacks, "p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells" J Cell Biol, 141:503-14, 1998
Brugarolas, J. and T. Jacks, "Double indemnity: p53, BRCA and cancer" Nat Med, 3:721-2, 1997
Brugarolas, J., C. Chandrasekaran, J.I. Gordon, D. Beach, T. Jacks, and G.J. Hannon, "Radiation-induced cell cycle arrest compromised by p21 deficiency" Nature, 377:552-7, 1995
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