Desmoid Tumors are locally invasive soft tissue tumors, which are found to be caused by mutations resulting in the stabilization of the protein, ß-catenin. Stabilized ß-catenin binds to TCF transcription factors to regulate the expression of genes in a cell type specific manner. Mouse models were developed based on this knowledge and used to study the role of target genes in the DT phenotype. The ultimate goal is to develop an improved approach to Desmoid Tumor therapy. Dr. Alman is continuing the work begun last year to screen compounds to identify pharmacologic agents that target Desmoid Tumor cell viability. He screened libraries composed of agents already in use for patient care to identify compounds that decreased cell viability in Desmoid Tumor cultures but not normal fibroblasts. In the past year, three compound libraries were screened, and three potential classes of compounds were identified that have the potential to be used as a therapeutic approach to Desmoid Tumors. Three of the compounds identified are drugs already approved for use by the FDA, and as such this work has the potential to be rapidly brought to patient care.
Dr. Lev proposes a three-pronged research design based on her findings stemming from the previously funded DTRF seed grant that will address these knowledge deficits. Her studies will focus on improving the understanding of the role of ß-catenin, a protein which is highly deregulated in desmoids, on tumor progression and recurrence. Studies will use cell strains and also siRNA screens to identify potential anti-desmoid therapeutic targets.
Aim 1: To validate the prognostic impact of the specific beta-catenin 45F mutation in predicting the outcome of patients with primary desmoids.
Aim 2: To identify the molecular deregulations contributing to sensitivity or resistance to the commonly used anti-desmoid therapies mainly tamoxifen, NSAIDs (sulindac), and Gleevec.
Aim 3: To identify potential novel anti-desmoid therapeutic targets using a rational siRNA screen.