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The Desmoid Tumor Research Foundation

“ROR2, a potential novel therapeutic target in desmoid tumors.” Year 2 of 2

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This is a grant for a three-year project studying Receptor tyrosine (RTK’s) which are proteins that are expressed on the surface of cells and are known to play an important role in cellular differentiation and tumor growth. ROR2 is a RTK which is expressed at high levels in a significant subset of desmoid tumors. It is a receptor for the Wnt family of proteins, proteins that are known to play a role in a pathway in the development of desmoid tumors. They will generate a novel monoclonal antibody against the extracellular part of ROR2 and study its effect on desmoid tumor cell growth in vitro.

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This is the second year of a three-year study. A small portion of stem cells in a given tissue give rise to all of the cells that make up that tissue. These cells help regenerate and maintain the tissue over its lifespan. These stem cells have been identified in a variety of tumor types and are called tumor initiating cells (TIC). These investigators will be testing the hypothesis that desmoid tumors contain a subpopulation of TIC and that desmoid tumors are derived from mesenchymal stem cells (MSC) that have a mutation leading to elevated levels of beta catenin, a protein thought to be instrumental in the development of familial adenomatous polyposis along with a mutation in the APC gene. In familial cases, desmoid tumors are associated with an APC mutation. Preliminary data suggest that desmoid tumors may be derived from MSC’s in which beta catenin signaling is misregulated. Dr. Alman and his team currently have 22 desmoid tumor cell lines with which to work. They will be (1) attempting to identify cell lines of TICs in desmoid tumors using established surface markers, and (2) using mice to determine if the tumors arise from misregulated MSC’s. Their goal is to ultimately develop a novel strategy of targeting desmoid tumor initiating cells.

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This is the second year of a three-year study. These investigators will be studying three molecular factors believed to be important in desmoid tumors: beta catenin, TCF-3 (a transcription factor) and ER-beta (an estrogen receptor). They are using a three-pronged approach. Aim 1 is the establishment of multiple desmoid tumor cell lines. Aim 2 is the examination of the role of beta catenin, TCF-3 and ERbeta interactions in desmoid proliferation using the cell lines developed in Aim 1. Aim 3 is the identification of desmoid tumor related molecular markers using oligoarrays and tissue microarrays.

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Conclusions: 1. MMP1 (matrix metallopeptidase) expression predominant in highly invasive FAP-related DT while MMP3 more representative of less invasive sporadic DT. (two manuscripts in progress) 2.FAP desmoids are more likely resistant to chemo than sporadic DT. Dr. David Joyner will continue to contribute to the DTRF collaborative effort that was initiated during the May 2008 Symposium.

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This is a new grant for a three-year project studying Receptor tyrosine (RTK’s) which are proteins that are expressed on the surface of cells and are known to play an important role in cellular differentiation and tumor growth. ROR2 is a RTK which is expressed at high levels in a significant subset of desmoid tumors. It is a receptor for the Wnt family of proteins, proteins that are known to play a role in a pathway in the development of desmoid tumors. They will generate a novel monoclonal antibody against the extracellular part of ROR2 and study its effect on desmoid tumor cell growth in vitro.

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Desmoid tumors can grow rapidly and be highly invasive or they can remain static for many years. These investigators are studying whether the proteins EGF (epidermal growth factor) and TGF-alpha (transforming growth factor) influence the invasive nature of desmoids and if either factor determines desmoid drug sensitivity. They hypothesize that these factors exert an influence on relevant genes. They have a three-pronged approach (1) measuring the mRNA and protein levels of relevant genes using polymerase chain reaction and tissue staining, (2) testing cell cultures for the influence of EGF and TGF-alpha on cell invasiveness and doxorubicin toxicity and (3) performing microarrays on lab-altered desmoid cell cultures in order to identify genes responsive to growth factor modulation. They anticipate that this may provide a list of potential therapeutic targets for use against desmoid tumors.