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

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