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 eliminate every tumor cell, but instead to stabilize or shrink the tumor. 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 two years, we screened drugs in the laboratory on cell lines from desmoid tumor patients to see which agents specifically target tumor cell viability and tested a first cohort of drugs in mice that develop desmoid tumors, identifying several agents already in use or close to being in use for patient care that could be repurposed for use in desmoid tumor treatment.
Over the remaining course of the proposal we plan to:
- Complete the testing of drugs identified in the screen in a mouse model that is engineered to develop desmoids.
- The agents identified will then be rescreening for drug combinations with synergistic effects.
- A pilot multi-drug regimen will be tested in mice.
In the past two years 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 then tested these agents using a collection of desmoid tumor cell cultures of different genetic etiologies, and based on this, as well as how available the selected agents are for clinical use today, prioritized 18 for testing in mice that develop desmoid tumors. We completed testing of nine agents, and found that five: Dasatinib (an oral Bcr-Abl tyrosine kinase inhibitor); A multi-target PI3K inhibitor; an FAK inhibitor; Letrozole; and a gamma secretase inhibitor. An additional nine drugs are currently being tested in the mice.
In the next year, we will undertake a rescreening of the five drugs that were effective in mice, by undertaking a sensitization test, in which we first treat the cells with the positively identified agents, and then rescreening them using the libraries. Agents that have a synergistic or additive effect will show lower cell viability than either agent alone. This approach will rapidly identify a multi-drug combination. We will then test the drug combinations in mice. Depending on the number of agents identified, we will either test all combinations, or if the number if too large, we will prioritize which to test based on a pharmacokinetic and then undertake analysis prioritizing agents that can be used in patients at the present time.
This data will identify new treatment regiments, which can rapidly be brought to patient care. 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.
LAY VERSION OF ABSTRACT- Collaboration for a Cure: Identifying new therapeutic targets for desmoid tumors
