Direct Activation of PP2A as a Novel Approach to Group-3 Medulloblastoma Therapy

项目摘要 髓母细胞瘤是儿童最常见的原发脑肿瘤。曾经被认为是 单一的病理，髓母细胞瘤现在被分为四个分子亚群：组3肿瘤占 对于大约25%-30%的髓母细胞瘤，预后最差。尽管目前是多式联运 结合手术、化疗和放射治疗，婴儿和儿童第3组肿瘤有5年 总存活率分别为45%和58%。此外，幸存下来的儿童往往患有长期的 运动、感觉、内分泌和神经心理后遗症。无可争议的是，这些孩子是 需要新疗法的患者群体，单独应用或与标准方法结合应用，以 有效地治疗他们的疾病，提供毒性较小、长期影响较小的治疗方法。此阶段1 SBIR 提案的目的是论证使用新型肿瘤小分子激活剂的可行性。 抑制PP2A作为治疗第3组髓母细胞瘤的新疗法。已知原型化合物是 中枢神经系统具有穿透性，在脑内胶质母细胞瘤动物模型中显示出疗效。PP2A激活是一种 第3组髓母细胞瘤的新治疗策略及该抑癌基因的激活 癌细胞生长和增殖的多种驱动因素包括PERK、PAKT、MYC和STAT3。钥匙 里程碑是在原型三环磺酰胺化学类型中放大合成的主要候选化合物 改善了物理化学性质和生物利用度。先导化合物在体内应该有足够的 根据异速生长比例，第3组髓母细胞瘤模型中的活动具有合理的概率 人体，临床剂量有效，安全性可接受。根据我们在胶质母细胞瘤方面的经验 和其他癌症模型，我们预计剂量在10毫克/公斤或更低，每天两次是合适的， 是可以实现的。第二个目标是识别受专利保护的新颖、专有的备份 可预见的。因此，第一阶段项目的具体目标是：目标1A。候选者的放大合成 来自三环磺酰胺PP2A激活剂系列，用于第3组髓母细胞瘤模型的评估。这 候选人将在口服生物利用度、代谢谱、水溶性和体内疗效方面有所改善 髓母细胞瘤模型与已发表的原型。目标1B。替代、后备化合物的合成 具有可与体外图谱相媲美的原型和专利(S)。目的2.2A体外和2B体内评价 人类第3组髓母细胞瘤患者来源的异种移植模型中的候选化合物。我们的目标是 第3组肿瘤中髓母细胞瘤生长和转移的活性与关键驱动因素的关系 模特们。我们的体内药效目标是每天两次，10毫克/公斤，作为一个可行的标准 第二阶段SBIR项目。第三组髓母细胞瘤和其他儿童癌症的新治疗选择是 急需之物。本一期工程中提出的研究是论证可行性的第一步 使用小分子PP2A激活剂作为新的治疗药物用于有 巨大的未得到满足的医疗需求。

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, are urgently needed. The research proposed in this Phase 1 project is the first step to demonstrate the feasibility of using small molecule PP2A activators as novel therapeutics for a patient population where there is a significant unmet medical need.