Description
Multiple myeloma (MM) is an incurable malignancy of plasma cells that accounts for 14,000 deaths annually in the USA. Recently we have shown that it is characterized by frequent (70%) chromosome translocations involving the immunoglobulin (Ig) genes and identified three recurrent loci that are commonly involved: 11q13, 4p16, and 16q23. The translocations result in the juxtaposition of powerful Ig enhancers adjacent to oncogenes at these loci (cyclin D1, FGFR3+MMSET, and c-maf, respectively), causing their ectopic and deregulated expression in plasma cells. Subsequent tumor progression occurs with deletion of chromosome 13, mutations of N or K ras, and secondary translocations of c-myc. The central hypothesis of this project is that genes selected by mutations are critical for the pathogenesis of MM and represent attractive targets for drug development. We propose to identify other genes selected by genetic mutation in MM, using a combination of gene expression analysis, comparative genomic hybridization, candidate gene analysis, and cloning of chromosome translocations. We have characterized a panel of cell lines established from patients that represents the spectrum of translocations, and established transfected cell lines, and transgenic mice to model these oncogenic events. We propose to use both in vitro and in vivo models systems to validate these genes as appropriate targets for drug development. Finally we propose to use these reagents to develop assays to screen for drugs that inhibit the function of these targets. The genetic evidence suggests that the IgH translocations are the primary event that leads to oncogenic transformation, making them a particularly attractive target. In particular it should be possible to identify a selective tyrosine kinase inhibitor of FGFR3. We will screen tyrosine kinase inhibitors entering clinical trials, and libraries of tyrosine kinase inhibitors for selective inhibition of FGFR3 auto-phosphorylation, as well as signals downstream of FGFR3, STAT3 and MAPK phosphorylation. We will test inhibitors of cyclin dependent kinases (flavopiridol) for selective toxicity against MM cells, where the immortalizing event is dysregulation of cyclin D1 or D3 by chromosome translocation. We will determine whether lovostatin has selective cytotoxicity against MM cells with activating mutations of ras or FGFR3. These studies will provide the framework for developing targeted therapies of MM, based upon the genetic abnormalities present in each patient. As with STI-571 in CML, we expect that targeting the transforming event (FGFR3, cyclin D1 or D3) may provide very effective therapy, and that targeting events related to progression may delay or prevent disease progression.

1. To identify other genes selected by genetic mutation in MM, using a combination of gene expression analysis, comparative genomic hybridization, candidate gene analysis, and cloning of chromosome translocations.
2. To use both in vitro and in vivo model systems to validate these genes as appropriate targets for drug development.
3. Based on the preclinical data, to carry out a clinical study targeting FGFR3 in year 1. Subsequently we will evaluate additional agents that specifically target the pathways identified by genetic mutations in pilot clinical trials.
   

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