“Identifying novel drug therapies for desmoid tumors.” Year 1 of 3

One way to identify new drug therapies is to screen known drugs on cell cultures from tumors to see which drugs will kill the tumor cells. In the past Alman et al had tested 1,000 drugs on desmoid tumor cells and identified one such agent. Unfortunately, this agent is not readily available for use in North America. In this 2010 DTRF-funded study Dr. Alman plans to undertake a comprehensive screen of agents to identify drugs that specifically target cell viability in DTs. Building on previous work, Dr. Alman will focus on drugs that inhibit DT cell growth presumably by blocking Beta catenin signaling in mesenchymal cells. The agents identified will be tested for their ability to alter DT cell proliferation, Beta catenin protein level and differential effects on stem cells. Such drugs will be tested using DT cell cultures from patients and also transgenic mice that develop DTs. Identified agents can then be investigated in clinical trials. The exciting part is that the agents found to have clinical benefit will already have been FDA-approved for use in patients and can therefore be rapidly brought to patient care.

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.

This is the third year of a three-year study. A small portion of stem cells in a given tissue give rise to all of the cells that make up that tissue. These cells help regenerate and maintain the tissue over its lifespan. These stem cells have been identified in a variety of tumor types and are called tumor initiating cells (TIC). These investigators will be testing the hypothesis that desmoid tumors contain a subpopulation of TIC and that desmoid tumors are derived from mesenchymal stem cells (MSC) that have a mutation leading to elevated levels of beta catenin, a protein thought to be instrumental in the development of familial adenomatous polyposis along with a mutation in the APC gene. In familial cases, desmoid tumors are associated with an APC mutation. Preliminary data suggest that desmoid tumors may be derived from MSC’s in which beta catenin signaling is misregulated. Dr. Alman and his team currently have 22 desmoid tumor cell lines with which to work. They will be (1) attempting to identify cell lines of TICs in desmoid tumors using established surface markers, and (2) using mice to determine if the tumors arise from misregulated MSC’s. Their goal is to ultimately develop a novel strategy of targeting desmoid tumor initiating cells.

This is the third year of a three-year study. These investigators will be studying three molecular factors believed to be important in desmoid tumors: beta catenin, TCF-3 (a transcription factor) and ER-beta (an estrogen receptor). They are using a three-pronged approach. Aim 1 is the establishment of multiple desmoid tumor cell lines. Aim 2 is the examination of the role of beta catenin, TCF-3 and ERbeta interactions in desmoid proliferation using the cell lines developed in Aim 1. Aim 3 is the identification of desmoid tumor related molecular markers using oligoarrays and tissue microarrays.

This is a three year grant studying the role of hydroxyurea in the treatment of primary and recurrent Desmoid Tumors in adults and children. Hydroxyurea is a generally well tolerated anti-neoplastic agent used in the treatment of myeloproliferative disease, CML and small group of carcinomas. This study builds on the favorable efficacy:toxicity experience in an earlier study in children in which preliminary results showed partial response or stable disease in 79% of patients. This is a non-randomized trial.