Desmoid tumors (DT) are locally invasive lesions that are difficult to treat using conventional therapies. While there is some success with chemotherapy in people who have recurrence of their tumors after surgery and/or radiation, much of the time the results from chemotherapy are temporary, and regrowth of tumor is seen. One approach to treatment is to develop a combination of medications that target different aspects of tumor growth, but have few side effects. Since desmoids are locally invasive but do not metastasize to other locations in the body, it is not necessary to wipe out every tumor cell, but just to get the tumor to shrink. We assembled a consortium of researchers from different backgrounds, and with complementary skills, whose ultimate goal is to develop a treatment to therapeutically target tumor cells in desmoid patients without causing serious side effects.
To achieve this goal, over the past year, we screened drugs in the laboratory on cell lines from desmoid tumor patients to see which agents specifically target tumor cell viability, and are in the process of testing the drugs in cell lines. Over the remaining course of the proposal we plan to: (1) Complete the testing of drugs identified in the screen using cell lines from a variety of desmoid tumors to determine the mechanism by which they inhibit cell viability. (2) Test drugs that are effective in cell lines in a mouse model that is engineered to develop desmoids. (3) The agents identified in the screen will then be analyzed for the ability to use them in combination, and these combinations will be tested in both desmoid cell cultures and in genetically modified mice.
In the past year we screened eight cell lines using the Maybridge HitFinderTM Collection; DIVERSetTM Collection (Chembridge); LOPAC (Sigma); BIOMOL collection; Prestwick collection (Prestwick Chemical); Seminatural compounds (AnalytiCon Discovery); and the NIH Clinical Collection (BioFocusDPI). This screening identified 45 compounds that inhibited cell proliferation in desmoid tumors by greater than 50% while not affecting normal fibroblast proliferation, and that also are either in use in patients or that have the potential to be rapidly developed for patient care.
We are currently testing these drugs using a large collection of desmoid tumor cell cultures of different genetic etiologies, and based on this, will test them in mice that develop desmoid tumors. Drugs that inhibit desmoid tumor growth in both cells and mice will then be studied using pharmacokinetic analysis, to identify drugs that work in an additive fashion when used in combination, but will still have an acceptable safety profile. We will then test the drugs already approved for use in patients in a multi drug regimen as informed by pharmacokinetic data. Then these combinations will be tested in multiple human desmoid tumor cultures and in genetically modified mouse models.
New candidate drugs will also be analyzed to identify their underlying biologic mechanism, to identify novel pathways that are activated by beta-catenin in desmoid tumors. These data will be used to prioritize new research into the biology of how beta-catenin causes desmoid tumors. This approach should rapidly identify a multi-drug combination that can then safely be tested for efficacy in patients. In addition, it will identify new pathways activated by beta-catenin and new agents not yet in use for patient care that target desmoid tumors, both of which can be developed in future work which might ultimately identify even more effective therapeutic approaches.
