Healthy ?phagocytosis? ? a process by which foreign cells such as tumor cells and apoptotic debris are engulfed and removed by inflammatory monocytes and macrophages ? is a defense against cancer, including breast cancer. However, phagocytosis against cancer can become inhibited by ?don?t eat me? signaling caused by overexpression of CD47 on the surface of solid tumor cells. Remarkably, anti-CD47 antibodies can restore phagocytosis of tumor cells, causing tumors to shrink or stabilize. Unfortunately, these antibodies may also sometimes have severe side effects, especially anemia and reticulocytosis. This project addresses the challenge of restoring phagocytosis against solid tumors via the CD47 pathway without the side effects of anti-CD47 antibodies. We will do this by testing nanoparticles we developed to selectively deliver small molecule inhibitors of the enzyme SHP1 intracellularly into inflammatory monocytes and macrophages within breast tumors. SHP1 is part of the CD47 signaling pathway within macrophages and an excellent target for restoring phagocytosis without side effects. Strong evidence indicates our nanoparticles can act as a kind of Trojan horse to deliver small molecule drugs selectively into inflammatory monocytes and macrophages that infiltrate solid tumors. We will reveal the mechanisms of: A) selective nanoparticle uptake; and B) in vivo nanoparticle delivery of SHP1 inhibitors in 2 murine breast cancer models.
Aim 1 will identify the nanoparticle uptake receptor and elucidate the mechanisms of nanoparticle uptake and persistence in tumors.
Aim 2 will test nanoparticles for selectively releasing SHP1 inhibitors inside inflammatory macrophages, then restoring phagocytosis and shrinking tumors in vivo without causing anemia and reticulocytosis. Impact: This project will advance understanding of the CD47 pathway in cancer, develop an intracellular therapeutic approach to inhibit CD47-related signaling, help remove a major barrier to progress in oncology ? the lack of selective drug delivery into inflammatory monocytes and macrophages, and advance design principles for translational therapies based on in vivo immune cell selectivity.
New treatments for solid tumors can induce immune cells to ?eat? cancer cells, but not without toxic side effects. To avoid these side effects, we have developed nanoparticles for delivering drugs very selectively into inflammatory immune cells that infiltrate solid tumors. Our studies will reveal the mechanisms by which these selective nanoparticles can deliver drugs into tumors like a ?Trojan Horse,? so that inflammatory immune cells are unleashed to eat solid tumors without unwanted toxicity.
