Levi A. Garraway

Department of Biological Chemistry and Molecular Pharmacology
Dana-Farber Cancer Institute/Brigham and Women's Hospital
Broad Institute of Harvard and MIT
Dana Building, Room 1542
44 Binney St.
Boston, MA 02115
Tel: 617-632-6689
Fax: 617-632-3460
Email: levi_garraway@dfci.harvard.edu

Our laboratory is pursuing combined genomic and functional approaches to the characterization of human solid tumors, with an emphasis on melanoma.  Our initial studies toward this end utilized the NCI60 cancer cell line collection and its associated data sets as an integrative model system.  These efforts led to the discovery that the MITF transcription factor is an amplified melanoma oncogene that may anchor a novel lineage dependency required for the survival of a melanoma subset.  A second integrated approach that queried NCI60 genetic and pharmacologic data revealed that the BRAF(V600E) oncogenic mutation confers an exquisite sensitivity to MEK kinase inhibitors in melanoma and other cancer cell lines.  These studies suggest that combined analyses of large-scale data sets within testable model systems may elucidate pertinent tumor dependencies. 

Our current research focus builds upon these observations through a comprehensive genomic characterization of patient-derived, short-term melanoma cultures.  Such cultures have typically undergone only a few passages outside of the patient and therefore constitute a renewable and experimentally accessible source of genomic material.  We have performed a comprehensive genomic characterization (including SNP array-based genetic maps, gene expression data, and oncogene mutation data) of a large melanoma short-term culture collection, and have applied computational algorithms to identify candidate melanoma subtypes characterized by specific genomic alterations.  Currently, we are integrating matched gene expression and pharmacologic data to pinpoint candidate target genes and refine knowledge of effector pathways.  We are also interrogating these mechanisms functionally through systematic RNAi, ectopic expression, and other established molecular/cell biology approaches.  Additional projects involve functional characterization of the selective tumor dependencies associated with cancer cells that harbor different mutations in the MAP kinase and PI3 kinase signaling pathways.  Together, these studies should provide a robust framework for large-scale functional genomic studies in melanoma and other tumors.

References:

• Garraway, L.A., Widlund, H. R.,  Rubin, M.A.,  Getz, G.A., Berger, A.J., Ramaswamy, S., Beroukhim, R., Milner, D.A., Granter, S.R., Du, J., Lee, C., Wagner, S.N.,  Li, C., Golub, T.R., Rimm, D.L., Meyerson, M., Fisher, D.E., & Sellers, W.R.  Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.  Nature. 436: 117-122, 2005.  News and Views: Nature. 436:33-35, 2005.
• Solit, D.B., Garraway, L.A., Pratilas, C.A. Sawai, A., Getz, G., Basso, A., Ye, Q., Lobo, J.M., She, Y., Osman, I., Golub, T.R., Sebolt-Leopold, J., Sellers, W.R., Rosen, N.  BRAF mutation predicts sensitivity to MEK inhibition.  Nature. 439:358-62, 2006.
• Garraway, L.A. and Sellers, W.R.  Lineage dependency and ‘lineage survival’ oncogenes in human cancer.  Nature Reviews Cancer, 2006. 593-602.
• Thomas, R.K., Baker, A.C., Debiasi, R.M., Winckler, W., Laframboise, T., Lin, W.M., Wang, M., Feng, W., Zander, T., Macconnaill, L.E., Lee, J.C., Nicoletti, R., Hatton, C., Goyette, M., Girard, L., Majmudar, K., Ziaugra, L., Wong. K.-K., Gabriel, S., Beroukhim, R., Peyton, M., Barretina, J., Dutt, A., Emery, C., Greulich, H., Shah, K., Sasaki, H., Gazdar, A., Minna, J., Armstrong, S.A., Mellinghoff, I.K., Hodi, F.S., Dranoff, G., Mischel, P.S., Cloughesy, T.F., Nelson, S.F., Liau, L.M., Mertz, K., Rubin, M.A., Moch, H., Loda, M., Catalona, W., Fletcher, J., Signoretti, S., Kaye, F., Anderson, K.C., Demetri, G.D., Dummer, R., Wagner, S., Herlyn, M., Sellers, W.R., Meyerson, M., & Garraway, L.A. High-throughput oncogene mutation profiling in human cancer. Nature Genetics. 2007;39(3):347-351.