Our laboratory is pursuing combined genomic and functional approaches to the characterization of human solid tumors, with an emphasis on melanoma and prostate cancer. 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 massively parallel sequencing approaches to identify novel chromosomal rearrangements in melanoma and prostate cancer, global studies of resistance to targeted anticancer agents, and systematic genetic and functional studies of human cancer cell lines.
A major 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. Together, 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. 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