Project Summary Medulloblastoma is the most common primary brain tumor in the pediatric population. Once considered a singular pathology, medulloblastoma is now classified into four molecular subgroups: group 3 tumors account for approximately 25-30% of medulloblastomas and have the worst prognosis. Despite current multimodal therapy with surgery, chemotherapy and radiation, infants and children with group 3 tumors have a 5-year overall survival of 45 and 58%, respectively. Furthermore, children who survive often suffer from long-term motor, sensory, endocrine, and neuropsychological sequelae. It is undisputable that these children are a patient population that requires novel therapies, applied alone or in combination with standard approaches, to effectively treat their disease and provide less toxic therapies with fewer long-term effects. This Phase 1 SBIR proposal has the objective of demonstrating the feasibility of using novel small molecule activators of the tumor suppressor PP2A as novel therapeutics for group 3 medulloblastoma. Prototype compounds are known to be CNS penetrant and have shown efficacy in intracranial animal models of glioblastoma. PP2A activation is a novel therapeutic strategy in group 3 medulloblastoma and activation of this tumor suppressor restrains multiple drivers of cancer cell growth and proliferation including pERK, pAKT, MYC and STAT3. Key milestones are scale-up synthesis of a lead candidate in the prototype tricyclic sulfonamide chemical type with improved physicochemical properties and bioavailability. The lead compound should have sufficient in vivo activity in group 3 medulloblastoma models to have reasonable probability, based on allometric scaling to human, of an efficacious clinical dose with acceptable safety profile. Based on our experience in glioblastoma and other cancer models we anticipate doses at, or lower than, 10mg/kg, twice daily to be appropriate and achievable. A second objective is identification of novel, proprietary, back-ups with patent protection foreseeable. Thus the specific aims for the Phase 1 project are: Aim 1A. Scale-up synthesis of candidate from tricyclic sulfonamide PP2A activator series for evaluation in group 3 medulloblastoma models. This candidate will have improved oral bioavailability, metabolic profile, water solubility and in vivo efficacy in medulloblastoma models versus published prototype. Aim 1B. Synthesis of alternate, back-up compounds with in vitro profile comparable to prototypes and file patent(s). Aim 2. 2A In vitro and 2B in vivo evaluation of candidate compounds in human group 3 medulloblastoma patient-derived xenograft models. The objective is demonstration of activity versus key drivers of medulloblastoma growth and metastasis in group 3 tumor models. We target in vivo efficacy at <10mg/kg twice daily as a feasible criterion for advancing a candidate in a Phase 2 SBIR project. New treatment options for group 3 medulloblastoma, and other pediatric cancers, a...