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

直接激活 PP2A 作为 3 组髓母细胞瘤治疗的新方法

基本信息

批准号：
10382481
负责人：
Michael Ohlmeyer
金额：
$ 40.65万
依托单位：
ATUX ISKAY GROUP LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382481
关键词：
Adverse effects Animal Model Area Back Binding Sites Biological Availability Blood - brain barrier anatomy Brain Cancer Cell Growth Cancer Model Cell Proliferation Characteristics Chemicals Chemotherapy and/or radiation Child Childhood Childhood Extracranial Solid Tumor Childhood Medulloblastomas Clinical Combined Modality Therapy Data Development Disease Dose Endocrine Evaluation Funding Glioblastoma Growth Holoenzymes Human Immunotherapy In Vitro Infant Laboratories Lead Legal patent Long-Term Effects MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Medical Modeling Molecular Motor Mutagenesis Neoplasm Metastasis Neuroblastoma Neuropsychology Oncogenic Operative Surgical Procedures Oral Pathology Patients Pediatric Oncology Penetration Pharmaceutical Chemistry Phase Photoaffinity Labels Population Primary Brain Neoplasms Primitive Neuroectodermal Tumor Probability Prognosis Program Development Property Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Publications Publishing Research Research Project Grants SHH gene STAT3 gene Safety Sensory Series Small Business Innovation Research Grant Structure Subgroup Sulfonamides Synthesis Chemistry Therapeutic Toxic effect Toxicology Tumor Suppressor Proteins antitumor effect base blood-brain barrier penetration cancer cell cell type course development experience improved in vivo in vivo Model in vivo evaluation innovation interest lead candidate medulloblastoma member metabolic profile molecular targeted therapies mouse model novel novel strategies novel therapeutic intervention novel therapeutics patient derived xenograft model patient population preclinical study prototype scale up small molecule tumor tumor growth water solubility

项目摘要

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.

项目摘要髓母细胞瘤是小儿种群中最常见的原发性脑肿瘤。一旦被认为是奇异病理学，髓母细胞瘤现在分为四个分子亚组：第3组肿瘤帐户大约25-30％的髓母细胞瘤的预后最差。尽管当前的多模式手术，化学疗法和放射线治疗，婴儿和3组肿瘤儿童的治疗5年总体生存率分别为45％和58％。此外，生存的孩子经常遭受长期的困扰运动，感觉，内分泌和神经心理学后遗症。这些孩子是一个需要新颖疗法的患者人群，单独应用或与标准方法结合使用有效治疗其疾病，并提供较少的毒性疗法，长期影响较少。这个阶段1 SBIR 提案的目的是证明使用肿瘤的新型小分子激活剂的可行性抑制剂PP2A作为3组髓母细胞瘤的新型治疗剂。已知原型化合物是中枢神经系统渗透物，并在胶质母细胞瘤的颅内动物模型中表现出功效。 PP2A激活是第3组髓母细胞瘤中的新型治疗策略和该肿瘤抑制的激活癌细胞生长和增殖的多个驱动因素，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的铅候选者的扩大合成改善了理化特性和生物利用度。铅化合物应具有足够的体内第3组的髓母细胞瘤模型的活动具有合理的可能性，基于同量缩放人类，有效的临床剂量具有可接受的安全性。根据我们在胶质母细胞瘤的经验以及我们预期的其他癌症模型的剂量或低于10mg/kg，每天两次是合适的，并且可以实现。第二个目标是识别具有专利保护的新颖，专有的备份可预见。因此，第1阶段项目的具体目的是：目标1A。候选人的扩大合成从三环磺酰胺PP2A激活量序列中用于第3组髓母细胞瘤模型中的评估。这候选人将改善口服生物利用度，代谢概况，水溶性和体内功效髓母细胞瘤模型与已发表的原型。目标1B。替代，备用化合物的合成具有与原型和文件专利相当的体外剖面。 AIM2。2A体外和2B在体内评估人类3组髓母细胞瘤患者衍生的异种移植模型中的候选化合物。目标是 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演示型号。我们每天两次以<10mg/kg的态度靶向体内功效，作为推进候选人的可行标准第2阶段SBIR项目。第3组髓母细胞瘤和其他儿科癌症的新治疗选择是迫切需要。该阶段1项目中提出的研究是证明可行性的第一步使用小分子PP2A激活剂作为患者人群的新型治疗剂大量未满足的医疗需求。