Friday, May 9, 2025
5/9/2025
Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance - OVERALL SUMMARY/ABSTRACT This is a revised competitive renewal application for a Program focused on high-risk neuroblastoma (NB), a diverse and enigmatic malignancy arising from the developing sympathetic nervous system that remains lethal in 50% of patients despite intensive multi-modal therapy. The primary goal of this multi-institutional and multi- disciplinary Program is to achieve improved outcomes for patients with high-risk NB by 1) discovering basic mechanisms of de novo and acquired resistance to modern therapies; 2) uncovering targetable vulnerabilities driving resistance; and 3) translating these insights into evidence-based clinical trials. The Program has been productive, with important basic, translational, and clinical research achievements over the past 5.5 years. The basic structure of the Program remains the same, with four Projects focusing on interrelated fundamental problems in the broad fields of epigenomics, tumor microenvironment, and immuno-oncology. The central hypothesis is that high-risk NBs evolve to evade therapeutic interventions but that these resistance mechanisms can be targeted therapeutically. The motivation for the proposed research is the urgent need to improve survival of patients with high-risk NB, and to decrease treatment-related morbidities. The four proposed Projects will each address the three Specific Aims of the overall Program: 1) discover mechanisms of NB therapy resistance; 2) discover tumor-intrinsic and -extrinsic therapeutic vulnerabilities imparted by therapy resistance; and 3) develop readily translatable therapeutic strategies to exploit de novo and acquired resistance mechanisms and molecular vulnerabilities. The Projects will each be supported by two Cores: A) Administrative core; B) Translational, statistical, and clinical trials core. Unique to the Program is the New Approaches to NB Therapy (NANT) consortium integrated into Core B now in its 22nd year. A major goal of the NANT is to prioritize new therapies from our Projects for Phase 1 and 2 clinical trials in the high-risk NB relapse population, with the goal of moving these to Phase 3 testing in newly diagnosed patients. The Program is responsible for the two targeted investigational agents currently being tested in an ongoing Children’s Oncology Group Phase 3 trial. The NANT also provides a unique resource of therapy resistant tumors and other biospecimens for Project investigators. Importantly, all Projects have clear milestones to deliver one or more clinical trial to the NANT, with Project specific studies designed to provide the portfolio of nonclinical data required for efficient translation to the refractory NB patient population. This highly integrated Program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis and therapy resistance, but is steadfastly translational, as the investigative team is constituted of physicians who care for children with this disease. The significance of the proposed Program is the continued discovery of fundamental mechanisms of cancer therapy resistance leading to substantively improved probability of cure coupled with reduced therapy-related morbidity for children, adolescents and adults afflicted with high-risk NB.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).