DTF is a devastating cancer of the soft tissue and more effective treatments are needed. We found that JUN expression is increased in DTF patients by sequencing studies and protein expression measurements and that JUN-inducible mice developed desmoid-type fibromatosis when aged prior to JUN induction. These results suggest that desmoid-type fibromatosis has a pathological mechanism that relies on JUN induction and some other yet unidentified molecular event, e.g., possibly b-catenin activation. Novel treatment strategies could potentially be developed once the pathological mechanism is better understood. The JUN-inducible mice represent a novel mouse model for desmoid-type fibromatosis that, after complete characterization, could be used for preclinical evaluation of novel treatments.
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 JUN is upregulated and expressed in DTF tumors in patients. In addition, our preliminary data suggest that a very low level of 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 JUN induction to induce DTF lesions. Additionally, the small molecule PF- 03084014 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 JUN-inducible mice with regards to prevention of desmoid tumor formation. In addition, we will study effects of JUN and NOTCH pathway inhibition in primary cell lines of human Desmoids, in contrary to our initial proposal we will modify our approach and study the molecular interactions of JUN with the WNT and NOTCH pathways with next generation mass spectrometry and pull-down and immunoprecipitation assays. Our inducible DTF mouse model subsequently could serve as a novel preclinical platform to evaluate additional inhibitors to ultimately find better treatments.