Investigating HIF1-alpha Signaling to Identify Predictive Markers and Therapeutic Targets in Desmoid-Type Fibromatosis

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Desmoid-type fibromatosis is a mesenchymal tumor that does not progress to high-grade disease or metastasize. Surgery was the standard treatment for desmoids, but in patients with extensive disease, surgery can lead to complications as morbid as the tumors themselves, and ~30% of patients have local recurrence. For these and other reasons, active observation is prescribed to an increasingly large subset of patients with asymptomatic disease. Desmoid outcomes, however, are highly variable; under observation half of desmoids do not progress over two years and a subset will regress spontaneously, while other desmoids grow relentlessly. Locally aggressive tumors can cause severe symptoms: pain and contracture from desmoids in the extremities and intestinal fistulization and death from abdominal desmoids. Once present, symptoms can be difficult to reverse. Therefore, there is need for tools to predict outcome prior to recommending active observation. Nearly all desmoids contain CTNNB1 mutations that constitutively activate the gene product, β- catenin, but extensive genetic analyses have failed to identify any additional genetic alterations that may underlie variations in patient prognosis. This proposal builds upon preliminary results suggesting that β-catenin promotes desmoid oncogenesis through non-canonical downstream targets, including hypoxia-inducible factor α (HIF1α). Both HIF1α protein levels and desmoid cell proliferation are also increased by activated PDGFRβ, which may explain the fact that sorafenib, an inhibitor of PDGFRβ among other receptor tyrosine kinases, has activity in desmoids. Based on these and other preliminary data, we hypothesize that HIF1α mediates mitogenic signals from PDGFRβ in a manner dependent on activated β-catenin. We propose to investigate the role of this and other pathways in desmoid biology and to use the insight gained to identify and test potential biomarkers of desmoid tumor growth. In Aim 1, we seek to determine the roles of HIF1α and β-catenin in mediating PDGFRβ signaling and proliferation in desmoid cells. In Aim 2, we perform highly focused screens to identify additional genes and druggable pathways that are necessary for desmoid cell proliferation. We will then test whether they act upstream of a PDGFRβ/β-catenin/HIF1α axis or act independently of this axis. Finally, in Aim 3, we propose to use biopsy specimens, collected as part of a phase II trial, to examine whether desmoid progression during active observation can be predicted by markers from the PDGFRβ/β- catenin/HIF1α pathway or other pathways defined in Aims 1 and 2. We expect the proposed studies to identify biomarkers that will help clinicians to identify optimal therapeutic pathways for individual desmoid patients. In addition, by elucidating the molecular basis of oncogenesis in desmoids, this work may identify novel therapeutic targets for the disease. Because aberrant β-catenin activity can be observed in a wide range of neoplasms, our results may provide insight that affects our approach to other cancers as well.