“A rational search for novel anti-drug therapies.” Year 1 of 4

The goal is to investigate the molecular driving forces behind the development and progression of desmoid tumors. Lev et al are trying to identify potential targets that modify beta-catenin transcriptional activity using an siRNA screen. Identifying genes and their cognate proteins whose alteration would inhibit beta-catenin activity might provide future targets for novel molecular therapies relevant to DT patients. Aim 1: To validate previous findings of the prognostic power of beta-catenin 45F mutation in predicting the outcome of patients with primary desmoids. Aim 2: To identify the molecular deregulations contributing to the sensitivity or resistance to the commonly used anti-desmoid therapies, mainly Tamoxifen, NSAIDS and Gleevec. Aim 3: To identify potential novel anti-desmoid therapeutic targets using a rational siRNA screen. Potentially these targets harbor the capacity to modify the transcriptional effect of beta-catenin. Note: Dr. Lev has previously identified significant associations between the presence of 45F mutations and an increased rate of desmoid recurrence as well as shorter time intervals to recurrence. Analysis of a large primary desmoid subset showed that desmoids having a 45 F mutation had an estimated five year recurrence -free survival rate of only 47% and a median time to recurrence of 3.16 years. In sharp contrast, the estimated five year recurrence free survival rate for all other desmoid primary tumors was 83%; median time to recurrence not yet being reached.