Discovering mechanisms of neuroblastoma tumorigenesis to improve patient outcomes

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY After stunning improvements in patient outcomes for most childhood cancers in the latter half of the last century, cure rates have since plateaued, and treatment related morbidity continues to mount. Children with metastatic solid malignancies continue to have a less than 50% chance of survival despite being treated with highly intensive cytotoxic therapies. Neuroblastoma, a diverse malignancy typically affecting very young children that arises from the developing sympathetic nervous system, is responsible for a disproportionate amount of morbidity and mortality attributable to childhood cancer and is the main focus of this R35. Our primary motivation in this competitive renewal application is to improve patient outcomes, and we also deem neuroblastoma an outstanding model of cancer in general, such that discoveries of basic mechanisms of tumorigenesis are broadly applicable to other human malignancies. Over the next seven years, we will continue to seek to substantively improve cure rates for patients through a multidisciplinary and collaborative research program. Our broad goal is to discover the fundamental mechanisms that subvert normal neuronal development and orchestrate neuroblastoma tumorigenesis, and then to translate this knowledge into patient-specific therapies that will be more effective and less toxic. We thus propose to expand on our comprehensive approach to discover and develop novel therapeutic strategies for patients with high-risk neuroblastoma and other childhood cancers. We will build on progress in the current R35 and address genomic vulnerabilities with precision therapies with a focus on novel immunotherapies. Having developed methods to identify exquisitely tumor specific immunotherapeutic targets, we will create synthetic immunotherapies including antibodies, antibody drug conjugates, bi-specific T cell engagers, and chimeric antigen receptor (CAR) T cells. With several of the therapies created in the current R35 having entered clinical trials recently and throughout the next seven years, we have a unique opportunity to have robust correlative biology to guide our evolving armamentarium of therapeutics. We will enhance the efficacy and persistence of CAR T cells with through both T cell intrinsic (enhancing metabolic fitness) and extrinsic (vaccination to provide an antigenic stimulus) methods. While the current R35 focused almost exclusively on neuroblastoma, we have recently extended our immunotherapy target discovery efforts to other childhood cancers with a high unmet need, and this will be expanded moving forward through both new discovery efforts and the rigorous definition of biomarkers for immunotherapeutic selection across childhood cancers. We think that our research program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, epigenetic adaptation, and immune evasion. This R35 is and will remain steadfastly translational. The significance of the proposed program is the discovery of fundamental mechanisms of tumorigenesis that will lead to new therapies with markedly improved probability of cure coupled with reduced morbidity for children, adolescents, and young adults with neuroblastoma and other childhood cancers.