Desmoid-type fibromatosis (DTF) is not well understood. It is a rare, devastating, low-grade, soft-tissue malignancy characterized by severely fibrotic tumors occurring preferentially deep visceral or axial/truncal, currently treated with surgical resection and/or radiation and/or chemotherapy. Despite initial good response, DTF has a high propensity to relapse locally, and repetitive surgical excisions can severely debilitate patients, causing comorbidities with poor quality of life and mortality. One of the most important drawbacks in DTF research is the lack of a detailed understanding of the molecular pathomechanism beyond b-catenin activation. We have demonstrated by sequencing and immunohistochemistry studies that the AP1 transcription factor cJUN is upregulated and expressed in DTF tumors in patients. In addition, our preliminary data suggest that very low level of c-Jun induction in vivo leads to DTF in mice aged between 3–7 months. In the current proposal, we propose to first better characterize this mouse model, with particular attention to the role of b-catenin/wnt and Notch pathways. Since tumors only occur in aged mice, we hypothesize that mutations in other pathways cooperate in a 2-hit model with c-Jun induction to induce DTF lesions. Additionally, the small molecule PF03084014 showed promising effects in a Phase I clinical trial for DTF, suggesting a role for a g-secretase inhibitor-dependent pathway. We therefore propose to evaluate efficacy of PF-03084014 in c-Jun-inducible mice. In addition, we will study effects of c-JUN and NOTCH pathway inhibition in primary cell lines of human Desmoids as well as patient samples from the clinical trial pre- and post treatment with gene expression studies. Our inducible DTF mouse model subsequently could serve as novel pre-clinical platform to evaluate additional inhibitors to ultimately find better treatments.
LAY VERSION OF ABSTRACT- “c-Jun-inducible mice, to study the pathomechanism of desmoid-type fibromatosis in vivo with particular attention to the role of b-catenin/wnt and Notch pathways.”