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
Web Page: The Garraway Lab Page
Our laboratory is pursuing combined genomic and functional approaches to the characterization of human solid tumors, with an emphasis on melanoma. A major thrust of our work in recent years has been to perform comprehensive genomic characterization of a large collection of patient-derived melanoma “short-term” cultures and cell lines, and to apply both computation al and experimental approaches to identify the critical target genes and pathways enacted by these alterations. This approach has proved successful in several instances, including the identification of MITF as a “lineage survival” oncogene. Ongoing work involves the application of second generation sequencing approaches to identify several novel chromosomal rearrangements, as well as systematic pooled RNAi screening to propel a systematic functional interrogation of the melanoma genome.
With this detailed genomic information in hand, a parallel effort in the lab involves mechanistic studies of hallmark tumor pathways that are perturbed by the most prevalent genomic alterations in human solid tumors. Prominent examples include the MAP kinase pathway, which is activated by oncogene mutations involving BRAF or NRAS in the vast majority of melanomas; and the PI3 kinase pathway, which is activated by mutation in many human cancers. Ongoing studies have identified mechanisms by which MAP kinase-dependent melanomas may become resistant to the targeted inhibitors in clinical development, as well as novel effector genes activated downstream of MAP kinase in melanoma. Work from our lab has also nominated a novel oncogenic effector mechanism within the PI3 kinase pathway. In particular, many cancer cells that contain activating PIK3CA gene mutations (encodes a catalytic subunit of PI3 kinase) may elaborate an AKT-independent signaling mechanism that engages PDK1 and SGK3, whereas PTEN-null cancers almost invariably show a strong dependence on AKT signaling. These observations underscore the importance of linking specific tumor genetic alterations to key “druggable” cellular mechanisms, one of the overarching goals of our research.
Finally, our group has applied or adapted several genomic technologies to create avenues by which critical tumor genetic alterations might be identified rapidly in the clinical or translational setting. Altogether, these integrative genomic and experimental approaches applied to melanoma and other tumor types offer considerable promise to aid investigators and patients alike along the path to rational cancer therapeutics.
- Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005;436(7047):117-22.
- Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, Macconnaill LE, Lee JC, Nicoletti R, Hatton C, Goyette M, Girard L, Majmudar K, Ziaugra L, Wong KK, Gabriel S, Beroukhim R, Peyton M, Barretina J, Dutt A, Emery C, Greulich H, Shah K, Sasaki H, Gazdar A, Minna J, Armstrong SA, Mellinghoff IK, Hodi FS, Dranoff G, Mischel PS, Cloughesy TF, Nelson SF, Liau LM, Mertz K, Rubin MA, Moch H, Loda M, Catalona W, Fletcher J, Signoretti S, Kaye F, Anderson KC, Demetri GD, Dummer R, Wagner S, Herlyn M, Sellers WR, Meyerson M, Garraway LA. High-throughput oncogene mutation profiling in human cancer. Nature Genetics. 2007;39(3):347-351.
- Lin WM, Baker AC, Beroukhim R, Winckler W, Feng W, Marmion JM, Laine E, Greulich H, Tseng H, Gates C, Hodi FS, Dranoff G, Sellers WR, Thomas RK, Meyerson M, Golub TR, Dummer R, Herlyn M, Getz G, Garraway LA. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Research. 2008; 68(3):664-73.
- Vasudevan, K.M., Barbie, D.A., Davies, M.A., Rabinovsky, R., Hennessy, B.T., Tseng, H., Pochanard, P., Kim, S.Y., Dunn, I.F., Schinzel, A.C., McNear, C.J., Sandy, P., Hoersch, S., Sheng, Q., Gupta, P.B., Boehm, J.S., Reiling, J.H., Silver, S., Lu, Y., Stemke-Hale, K., Dutta, B., Joy, C., Sahin, A.A., Gonzalez-Angulo, A.M., Lluch, A., Rameh, L.E., Jacks, T., Root, D.E., Lander, E.S., Mills, G.B., Hahn, W.C., Sellers, W.R., Garraway, L.A. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009 Jul 7;16(1):21-32.
BBS webpage updated 12/02/2009