“Identifying novel drug therapies for desmoid tumors.”

A major focus of my research program is to study the molecular pathology of desmoid tumors (DTs), with a long-term goal of developing improved treatments. DTs are locally invasive soft tissue tumors, which we found are caused by mutations resulting in the stabilization of the protein, ß-catenin. Stabilized ß-catenin binds to TCF transcription factors to regulate the expression of genes in a cell type specific manner. We developed mouse models of DT based on this knowledge and used these to study the role of target genes in the DT phenotype. Our ultimate goal is to develop an improved approach to DT therapy. In this project we will continue our ongoing work funded by the DTRF in which we identified pharmacologic agents that target DT cell viability by screening compound libraries composed of agents which have a high potential to be rapidly translated into patient care. We identified agents that decreased cell viability in DT cultures but not in normal fibroblasts. Over the past two years, we tested several compounds in multiple DT cell lines, tested one in a mouse model of DT, and this work is in press in PLoS One, and found three others that have strong potential to be used as a therapeutic approach to DTs. Two agents target platelet derived growth factor (PDGF) signaling, a pathway we also found can modulate ß-catenin activity. The other targets Notch signaling. We also developed a new mouse model in which we can regulate expression of conditional stabilized ß-catenin alleles, which can be used to rapidly screen signaling pathway interactions in-vivo. We hypothesize that compound screening will identify agents that can be developed into novel therapies to treat DTs, and rapidly be brought to patient care. In this next phase of our ongoing work, we propose to test this hypothesis by answering the following two questions: How does Platelet Derived Growth Factor (PDGF) and Notch signaling modulation target DT cell viability? In the initial phase of our DTRF work, we identified three compounds that decreased cell viability in DT cultures but not normal fibroblasts: suntinib and mastinib, both of which block PDGF signaling; and DAPT, a gamma-secretase inhibitor which blocks canonical notch signalling. In our preliminary data, we found that PDGF signaling regulates ß-catenin activity. Cells in culture will be tested for how they alter DT cell behavior, by studying proliferation rate, apoptosis rate, and ß-catenin protein level. A new mouse model we developed will be used to test the interaction of signaling pathways identified in the compound screen. Can PDGF and Notch pharmacologic blockade be used to treat DTs? Suntinib, Mastinib, and DAPT will be tested using a genetically modified mouse that develops DTs and using xenografted human DT tumors in immunodeficient mice. The mechanistic data generated in aim one will also be verified in-vivo in this aim. The role of these agents in modulating different cell subpopulations in DTs will also be analyzed. In our previous work, we found that DTs contain a small cell population, which excludes Hoechst dye (called side population, or SP, cells). The SP cells have an enhanced ability to form tumors when implanted into immunodeficient mice, and as such act as tumor initiating cells (TICs), also called cancer stem cells. TICs may be resistant to anti-neoplastic drugs, and as such SP cells may be responsible for the resistance to treatments, and for tumor recurrence. We will also test theses compounds for differential effects on SP and non-SP cell populations. This work will identify compounds that can rapidly be developed as a novel DT treatment. Such agents will ultimately be translated to clinical trials, resulting in an improved pharmacologic approach to DT management. In addition, the various agents likely target different aspects of controlling DT viability (e.g. proliferation -vs- apoptosis), and as such, this knowledge could be used to develop a rationale multi-drug approach to DT treatment.