DFMO Synergy with Chemo-immunotherapy to Eradicate MYC-Driven Neuroblastoma
Scientists are learning a great deal about how our immune system can find and kill cancer cells and, importantly, how cancer cells have learned to evade this attack. Groundbreaking new treatments that successfully use the immune system to kill certain childhood cancers, like leukemia, have had a hard time killing many common childhood solid tumors. This is because solid tumors create their own environment that acts as a barrier to the body's immune cells. An assortment of tumor-secreted chemicals can cloak the tumor cells to prevent them from being recognized and prevent immune cells from entering the tumor, creating a tumor-supporting microenvironment (TME). We are developing a drug called DFMO to treat high-risk neuroblastoma. DFMO causes stress in neuroblastoma cells by preventing them from making the many proteins needed for the cancer to grow and the many chemicals used to create the tumor-permissive TME. We are currently studying DFMO in a Phase 1 trial in combination with chemotherapy for children with relapsed neuroblastoma.
Because of new evidence of an effect of DFMO on the immune-TME and that dinutuximab (an anti-neuroblastoma antibody) has recently shown to be effective when combined with chemotherapy, we propose pre-clinical studies of DFMO with chemotherapy and dinutuximab immunotherapy in complementary mouse models. Our work will define the dose required for anti-tumor activity and the tumor features most correlated with benefit from therapy. We will also provide the pre-clinical rationale for a Phase 2 study in children with relapsed or refractory disease.