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.
This is a pilot study examining the role of Rapamycin in the treatment of children and young adults with DT deemed likely to recur following resection. Rapamycin directly targets and inhibits mTOR, a growth promoting pathway that may be critical in the development and growth of DT. The mTOR cell proliferation/survival pathway was shown to be activated and essential for tumorigenesis when the APC gene is mutated (affecting the Beta catenin signaling pathway). It is an oral drug being evaluated as an anti-neoplastic agent in a variety of cancer types.
Skapek et al plan to determine how effectively rapamycin blocks mTOR activation in desmoid tumors and whether mTOR inhibition blocks desmoid tumor blood vessel growth. Skapek et al plan to determine how effectively rapamycin blocks mTOR activation in desmoid tumors . If Rapamycin is found to be active, they intend to extend this pilot study to a national collaborative study run through the Children’s Oncology Group (COG).
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.
DTRF-funded investigators at Stanford have developed a novel technique to analyze RNA from paraffin embedded tissue. This is important as many more paraffin embedded samples are available for study than frozen. Currently this technology is being used to study “usual” coding mRNA in desmoids in the Stanford lab. In this study they will be including the study of a new class of “non-coding RNA” and to examine the role of these molecules in the clinical behavior of desmoids. Conventional standard microarray expression profiling has been limited in that it only measures known genes that contain probes on the array platform. The new method being used allows for identification of novel transcripts. The new class of RNA (large intergenic non-coding RNA (lincRNA)) is thought to be a major regulator of gene expression. In the past year it has been shown that over one thousand evolutionarily conserved lincRNA’s are expressed in mammalian cells and that expression of these lincRNA’s correlates significantly with genes important in carcinogenesis. The long term goal is that the characterization of lincRNA’s in DT will lead to new diagnostic markers and treatment strategies for DT.