DF/HCC Program Affiliation

Prostate Cancer
Cutaneous Oncology and Melanoma

Research Abstract

Targeting cancer based on genetics requires knowledge of critical dependencies underlying the recurrent genomic alterations characteristic of human tumors. Elucidating such information on a large scale also requires experimental model systems that mirror the genetic changes manifest in vivo. Malignant melanoma offers a robust avenue in this regard-- this highly lethal malignancy remains unresponsive to most therapies when metastatic; however, cells from patients with advanced disease grow readily in vitro. Our group has completed a comprehensive genomic analysis (including chromosomal copy number/loss-of-heterozygosity data, gene expression profiles, and oncogene mutation detection) of ~100 melanoma short-term cultures and cell lines. A novel analytic approach to identify statistically significant alterations on a genome scale (presumably enriched for 'driver' events) indicates that cultured melanoma cells appear to encompass the full genomic diversity operant in primary melanoma tumors. Integration of gene expression and chromosomal copy number data allows a systematic means to credential candidate effector genes linked to recurrent genomic alterations. Moreover, integration of pharmacologic data identifies new candidate genetic/molecular modifiers of the NRAS/BRAF/MEK dependency operant in most melanomas. A major ongoing effort of our laboratory is to apply systematic functional approaches such as RNAi and small molecule studies to elaborate critical effector mechanisms enacted by recurrent melanoma genomic/molecular alterations. An additional focus of the lab involves the functional dissection of signaling pathways that result from PTEN/PI3 kinase pathway deregulation, which commonly occurs in prostate cancer and many other malignancies. Together, these genomic and functional approaches promise to identify essential and possibly ‘druggable’ tumorigenesis mechanisms linked to recurrent genomic alterations in many different tumor types.

Publications

• Li C, Beroukhim R, Weir BA, Winckler W, Garraway LA, Sellers WR, Meyerson M.Major copy proportion analysis of tumor samples using SNP arrays.BMC Bioinformatics 2008;9:204.
  18426588
• Demichelis F, Greulich H, Macoska JA, Beroukhim R, Sellers WR, Garraway L, Rubin MA.SNP panel identification assay (SPIA): a genetic-based assay for the identification of cell lines.Nucleic Acids Res 2008 Apr;36(7):2446-56.
  18304946
• 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
  18245465
• Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, Vivanco I, Lee JC, Huang JH, Alexander S, Du J, Kau T, Thomas RK, Shah K, Soto H, Perner S, Prensner J, Debiasi RM, Demichelis F, Hatton C, Rubin MA, Garraway LA, Nelson SF, Liau L, Mische
  18077431
• Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M
  17982442
• Hill AD, Chang BS, Hill RS, Garraway LA, Bodell A, Sellers WR, Walsh CA.A 2-Mb critical region implicated in the microcephaly associated with terminal 1q deletion syndrome.Am J Med Genet A 2007 Jun 29.
  17603806
• Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, Mulvey LA, Shen RR, Ambrogio L, Hirozane-Kishikawa T, Hill DE, Vidal M, Meyerson M, Grenier JK, Hinkle G, Root DE, Rober
  17574021
• Ji H, Wang Z, Perera SA, Li D, Liang MC, Zaghlul S, McNamara K, Chen L, Albert M, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Thomas RK, Garraway LA, Jänne PA, Johnson BE, Chin L, Wong KK.Mutations in BRAF and KRAS converge on activation of the
  17510423
• Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, MacConaill L, 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,
  17293865
• Chin L, Garraway LA, Fisher DE.Malignant melanoma: genetics and therapeutics in the genomic era.Genes Dev 2006 Aug 15;20(16):2149-82.
  16912270
• Garraway LA, Weir BA, Zhao X, Widlund H, Beroukhim R, Berger A, Rimm D, Rubin MA, Fisher DE, Meyerson ML, Sellers WR."Lineage Addiction" in Human Cancer: Lessons from Integrated Genomics.Cold Spring Harb Symp Quant Biol 2005;70:25-34.
  16869735
• Garraway LA, Sellers WR.Lineage dependency and lineage-survival oncogenes in human cancer.Nat Rev Cancer 2006 Aug;6(8):593-602.
  16862190
• Thomas RK, Nickerson E, Simons JF, Janne PA, Tengs T, Yuza Y, Garraway LA, LaFramboise T, Lee JC, Shah K, O'Neill K, Sasaki H, Lindeman N, Wong KK, Borras AM, Gutmann EJ, Dragnev KH, DeBiasi R, Chen TH, Glatt KA, Greulich H, Desany B, Lubeski CK, Brockman
  16799556
• Berger R, Lin DI, Nieto M, Sicinska E, Garraway LA, Adams H, Signoretti S, Hahn WC, Loda M.Androgen-dependent regulation of Her-2/neu in prostate cancer cells.Cancer Res 2006 Jun 1;66(11):5723-8.
  16740710
• Beroukhim R, Lin M, Park Y, Hao K, Zhao X, Garraway LA, Fox EA, Hochberg EP, Mellinghoff IK, Hofer MD, Descazeaud A, Rubin MA, Meyerson M, Wong WH, Sellers WR, Li C.Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide S
  16699594
• Garraway LA, Sellers WR.From integrated genomics to tumor lineage dependency.Cancer Res 2006 Mar 1;66(5):2506-8.
  16510564
• Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N.BRAF mutation predicts sensitivity to MEK inhibition.Nature 2006 Jan 19;439(7074):358-62.
  16273091
• 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 onc
  16001072
• Späth GF, Garraway LA, Turco SJ, Beverley SM.The role(s) of lipophosphoglycan (LPG) in the establishment of Leishmania major infections in mammalian hosts.Proc Natl Acad Sci U S A 2003 Aug 5;100(16):9536-41.
  12869694
• Garraway LA, Lin D, Signoretti S, Waltregny D, Dilks J, Bhattacharya N, Loda M.Intermediate basal cells of the prostate: in vitro and in vivo characterization.Prostate 2003 May 15;55(3):206-18.
  12692787
• Garraway LA, Chabner B.MDR1 inhibition: less resistance or less relevance?.Eur J Cancer 2002 Dec;38(18):2337-40.
  12460776
• Garraway LA, Tosi LR, Wang Y, Moore JB, Dobson DE, Beverley SM.Insertional mutagenesis by a modified in vitro Ty1 transposition system.Gene 1997 Oct 1;198(1-2):27-35.
  9370261
• Pimenta PF, Saraiva EM, Rowton E, Modi GB, Garraway LA, Beverley SM, Turco SJ, Sacks DL.Evidence that the vectorial competence of phlebotomine sand flies for different species of Leishmania is controlled by structural polymorphisms in the surface lipophos
  8090785
• Ryan KA, Garraway LA, Descoteaux A, Turco SJ, Beverley SM.Isolation of virulence genes directing surface glycosyl-phosphatidylinositol synthesis by functional complementation of Leishmania.Proc Natl Acad Sci U S A 1993 Sep 15;90(18):8609-13.
  8378337
• Gerard NP, Garraway LA, Eddy RL, Shows TB, Iijima H, Paquet JL, Gerard C.Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones.Biochemistry 1991 Nov 5;30(44):10640-6.
  1657150