Medulloblastoma is the most common primary brain tumor in the pediatric population. Once considered asingular 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-yearoverall survival of 45 and 58%, respectively. Furthermore, children who survive often suffer from long-termmotor, sensory, endocrine, and neuropsychological sequelae. It is undisputable that these children are apatient population that requires novel therapies, applied alone or in combination with standard approaches, toeffectively treat their disease and provide less toxic therapies with fewer long-term effects. This Phase 1 SBIRproposal has the objective of demonstrating the feasibility of using novel small molecule activators of the tumorsuppressor PP2A as novel therapeutics for group 3 medulloblastoma. Prototype compounds are known to beCNS penetrant and have shown efficacy in intracranial animal models of glioblastoma. PP2A activation is anovel therapeutic strategy in group 3 medulloblastoma and activation of this tumor suppressor restrainsmultiple drivers of cancer cell growth and proliferation including pERK, pAKT, MYC and STAT3. Keymilestones are scale-up synthesis of a lead candidate in the prototype tricyclic sulfonamide chemical type withimproved physicochemical properties and bioavailability. The lead compound should have sufficient in vivoactivity in group 3 medulloblastoma models to have reasonable probability, based on allometric scaling tohuman, of an efficacious clinical dose with acceptable safety profile. Based on our experience in glioblastomaand other cancer models we anticipate doses at, or lower than, 10mg/kg, twice daily to be appropriate andachievable. A second objective is identification of novel, proprietary, back-ups with patent protectionforeseeable. Thus the specific aims for the Phase 1 project are: Aim 1A. Scale-up synthesis of candidatefrom tricyclic sulfonamide PP2A activator series for evaluation in group 3 medulloblastoma models. Thiscandidate will have improved oral bioavailability, metabolic profile, water solubility and in vivo efficacy inmedulloblastoma models versus published prototype. Aim 1B. Synthesis of alternate, back-up compoundswith in vitro profile comparable to prototypes and file patent(s). Aim 2. 2A In vitro and 2B in vivo evaluation ofcandidate compounds in human group 3 medulloblastoma patient-derived xenograft models. The objective isdemonstration of activity versus key drivers of medulloblastoma growth and metastasis in group 3 tumormodels. We target in vivo efficacy at <10mg/kg twice daily as a feasible criterion for advancing a candidate ina Phase 2 SBIR project. New treatment options for group 3 medulloblastoma, and other pediatric cancers, areurgently needed. The research proposed in this Phase 1 project is the first step to demonstrate the feasibilityof using small molecule PP2A activators as novel therapeutics for a patient population where there is asignificant unmet medical need.
Public Health Relevance Statement: Project Narrative Medulloblastoma is the most common primary brain tumor in the pediatric population and novel therapies, applied alone or in combination with standard approaches, to effectively treat this disease and provide less toxic therapies with fewer long-term effects are urgently needed. Small molecule activators of PP2A restrain multiple drivers of group 3 medulloblastoma growth, proliferation and metastasis. Development of the class of compounds in this Phase 1 SBIR research project is the first step in bringing a new treatment option to this pediatric cancer patient population.
Project Terms: <0-11 years old> | | | | 