SIGNIFICANCE: Neuroblastoma is the most common pediatric cancer, accounting for 15% of cancer deaths, with a 5-yr survival of <40% due to resistant metastases. Neuroblastoma tumors almost universally express the somatostatin receptor 2 (SSTR2) and high expression has been shown clinically using peptides targeting SSTR2 (PMID10706954). FDA approved SSTR2-targeted beta(β-)-emitting 177Lu-labeled Lutathera™ has been shown to be safe and feasible (PMID21680680), but tumor response to SSTR2-targeted β--therapy has been poor. On the other hand, Viewpoint’s next-generation SSTR2-targeted [212Pb]VMT-α-NET alpha(α)-particle therapy (α-PRRT) produced complete responses (CRs) in 70% of mice bearing SSTR2+ tumors. Data show that the significantly improved PK properties of VMT-α-NET compared to competing SSTR2 targeted radiopharmaceuticals leads to significantly improved tumor to normal accumulation and lower risk of toxicities (particularly in dose limiting kidneys). In the revised application, the team introduces an innovative immune-competent genetically engineered metastatic mouse model (GEMM) of neuroblastoma (new Co-Investigator Wang PhD at Nationwide Children’s Hospital) that genetically mimics neuroblastoma in humans and develops spontaneously in mice. Thus, we will identify effective regimens and assess potential toxicities (e.g., kidney) and inflammatory markers in preparation for FDA submissions. The revised project is significant because predicate data demonstrate that Viewpoint’s [212Pb]VMT-α-NET α-PRRT has the potential to provide for complete/durable tumor responses (and be well tolerated) for neuroblastoma patients. The project is further significant because the GEMM rodent model and CMC plan included is aligned with FDA guidance for micro-dosed radiopharmaceutical therapeutics and our communications with the FDA for Fast Track designation. Therefore, there is a critical need to advance Viewpoint’s α-PRRT to clinical trials for neuroblastoma patients for whom other therapies (including SSTR2 β-particle therapy) fall short. PREDICATE MILESTONES: $13M Series A; 70% CRs in mice; 203Pb/212Pb secured; Communications with FDA to secure two INDs and complete a pre-IND meeting with support from the FDA for α-particle therapy for adult trials. FDA communications are ongoing. We will achieve our objectives by completing these Specific Aims. AIM 1. Determine the dosing regimens of [203Pb]VMT-α-NET image-guided [212Pb]VMT-α-NET therapy that maximize complete responses and minimize toxicity in mouse models of metastatic neuroblastoma. AIM 2. Optimize [212Pb]VMT-α-NET production and complete technology transfer for CMC and IND submission to the US FDA to initiate a Phase 1 imaging-guided therapy trial in neuroblastoma patients. IMPACT: With completion of these Aims, we expect to have developed a detailed understanding of the therapeutic regimens that maximize tumor responses (minimizing toxicity) in metastatic models of neuroblastoma in mice that align with...