In developed countries, cancer is diagnosed in nearly 50% of the population, and cancer accounts for approximately 25% of all deaths. While there has been a shift in cancer therapy from drugs that for the most part induce DNA damage, disrupt microtubule function, or affect nucleotide synthesis (chemotherapy), to drugs that act on pathways specifically deregulated in cancer cells (molecularly targeted therapies), new approaches for cancer treatment are desperately needed.
One of the most challenging cancer types is kidney cancer. Up until 2005 a single drug had been approved by the U.S. Food and Drug Administration for this disease. In addition, kidney cancer is predicted to affect over 50,000 individuals in the U.S. in 2008.
The most frequent histological type of kidney cancer, accounting for 75% of malignant kidney tumors, is renal cell carcinoma (RCC) of the clear cell type. Clear cell RCC results typically from the inactivation of the gene von Hippel-Lindau (VHL), which regulates the transcription factor hypoxia-inducible factor (HIF). When VHL is inactivated, HIF becomes inappropriately active and triggers a program of gene expression that leads to the growth of the tumor and the development of blood vessels (angiogenesis). The importance of HIF in RCC is well established, and HIF inactivation in VHL-deficient renal carcinoma cells markedly reduces their tumorigenic potential. Furthermore, drugs that inhibit pathways activated by HIF have been shown to delay the growth of kidney cancer in humans.
Similarities between two highly divergent familiar cancer syndromes, von Hippel-Lindau (resulting from germline mutations in the VHL gene) and Tuberous Sclerosis Complex (resulting from germline mutations in either the TSC1 or TSC2 genes) led me to hypothesize the existence of a functional link between the VHL protein (pVHL) and the TSC1/TSC2 complex formed by the TSC1 and TSC2 proteins. We have discovered that like pVHL, the TSC1/TSC2 complex regulates HIF, and that inactivation of the TSC1/TSC2 complex, like inactivation of pVHL, leads to increased HIF activity. The mechanism whereby TSC1/TSC2 inactivation leads to increased HIF activity involves mammalian target of rapamycin (mTOR; referring to mTOR complex 1), an atypical serine/threonine kinase that is inappropriately activated in TSC1/TSC2-deficient cells. Importantly, inhibition of mTOR in TSC1/TSC2-deficient cells normalizes HIF activity.
Our findings that inactivation of the TSC1/TSC2 complex results in mTOR-dependent HIF upregulation have contributed to establishing a rationale for targeting the mTOR pathway in RCC. The importance of these observations was recently highlighted by the results of a phase III clinical trial showing that an mTOR inhibitor, temsirolimus, improved the survival of patients with metastatic RCC.
We have further discovered that the TSC1/TSC2 complex, like pVHL, functions in a pathway regulated by oxygen. In response to hypoxia, mTOR is inhibited, and this process requires the TSC1/TSC2 complex. While the mechanism whereby hypoxia regulates mTOR remains to be elucidated, we have identified a critical component of this signaling pathway, a protein of heretofore unknown function, regulated by development and DNA damage 1 (REDD1). REDD1 is a conserved 25 kDa protein with no recognizable structural or functional domains. Using both loss-of-function as well as gain-of-function studies, we have determined that REDD1 is both necessary and sufficient for mTOR inhibition by hypoxia. However, how REDD1 acts is not known, and this is an area of active investigation. To understand the mechanism of REDD1 action, both biochemical and genetic approaches have been undertaken. In addition, the function of REDD1 is also being studied in a genetically engineered mouse model.
Finally, the lab has embarked upon an ambitious project in research translation. The objectives of this project are threefold. First, the discovery of new pathways that contribute to RCC development through the analysis of patient tumor samples using a variety of genomic and bioinformatics tools. Second, the generation of a mouse model that recapitulates the behavior of RCC in humans and that can be used in preclinical studies. Finally, the development and testing of new therapeutic strategies that harness the knowledge acquired from molecular genetic studies of patient tumor samples.
The biochemical and genetic analysis of patient tumor samples coupled with laboratory studies in tractable experimental systems represents a powerful approach in which to deepen our understanding of cancer and provides a strong foundation for the development of new therapies.
RESEARCH INTERESTS
Mechanisms of tumor development
Hypoxia signaling
Tuberous Sclerosis Complex
Renal Cell Carcinoma
Molecularly targeted cancer 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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