Grant: Operating Grant

Macrophages are normal cells in our immune system that are sometimes recruited by cancers, because of their ability to help tumor cells invade, spread and to obtain a blood supply. The main signaling protein used by cancers to recruit macrophages is called CSF1. As a creative new approach to treat cancer, researchers and drug companies around the world are busy developing drugs that block CSF1, some of which are now entering clinical trials. Our previous work helped to identify some specific tumor types that are especially dependent on CSF1 production. One, called tenosynovial giant cell tumor, is to date the only tumor type known to have activating mutations in the CSF1 gene itself. Another, called leiomyosarcoma, directly produces CSF1 in some cases, and these patients have particularly aggressive disease and a high death rate. However, testing new CSF1 inhibitors has been hampered by a lack of experimental systems where macrophage recruitment can be measured. We recently developed a new technique (implanting tumor under the kidney capsule of mice) that allows us to do this, and found that CSF1 inhibitor drugs indeed do block macrophage recruitment. In this grant application, we propose to use this model to understand how CSF1 promotes cancer progression, and to test a new generation of especially good candidate drugs for their effect on these diseases, to guide future clinical trials. We also plan to develop a new transgenic mouse model of tenosynovial giant cell tumor that would greatly accelerate future research.