“A rational search for novel anti-drug therapies.” Year 3 of 3

Desmoid tumors (DTs) are a locally aggressive tumor type that can cause remarkable morbidity and even mortality in afflicted patients. While desmoid clinical phenotype has been well characterized, the underlying tumor molecular biology is poorly understood. In studies conducted within the premise of our previously funded DTRF seed grant we were able to establish a large desmoid tissue and cell strain repository and have confirmed that β-catenin mutations are highly prevalent in sporadic desmoid tumors. Furthermore, we showed that a specific mutation, 45F possibly significantly correlates with dismal outcome for patients with primary lesions. This initial observation merits further confirmation and in the recent grant period, through an international collaboration, we have been able to assemble a large cohort (>160) of clinically annotated primary DT samples; all were sequenced for β-catenin. Interim results are promising, confirming our initial observation. We have also evaluated the effects of agents commonly used for the treatment of DT such as tamoxifen, celecoxib, and Gleevec on the growth of a large panel of desmoids primary cultures. Sensitive and resistant cell strains were identified; therapeutic response was independent of β-catenin mutation status or type or the expression level of the presumed drug targets. Finally, we have identified a potential DT gene expression signature enriched for genes regulated by TCF/LEF highlighting the role of β-catenin deregulation in these tumors. Midkine is one of the DT overexpressed targets; our studies further identified a correlation between midkine expression level and primary DT recurrence potential and a role for this protein in DT cell migration and invasion. In the current, third year of the project, we aim to: 1. Finalize our studies evaluating the role of β-catenin mutations as DT molecular prognosticators. 2. Identify molecular signatures corresponding with sensitivity/resistance to commonly utilized anti-DT systemic agents. 3. Determine the role of the notch pathway in DT and its utility as a node of DT therapeutic vulnerability. 4. Unravel additional gene mutations operative in DT through whole exome sequencing of human samples (including matched specimens). We hope that these studies will result in meaningful observations that will enhance the management of patients burdened by this devastating disease.