Chemosensitization of Glioblastoma by Propentofylline

丙茶碱对胶质母细胞瘤的化疗增敏作用

• 批准号: 10480470
• 负责人: Nhan L Tran
• 金额: $ 40万
• 依托单位: OLEOLIVE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480470
• 关键词: Adjuvant Therapy; Alzheimer' s Disease; Animals; Arizona; Biotechnology; Brain; Cells; Central Nervous System Neoplasms; Chemicals; Chemosensitization; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DNA Damage; Data; Diagnosis; Disease; Down-Regulation; Excision; Exhibits; Glioblastoma; Glioma; Goals; Human; Image; Immunocompetent; In Vitro; Infiltration; Lead; Legal patent; Malignant neoplasm of central nervous system; Malignant neoplasm of pancreas; Methods; Microglia; Modeling; Molecular; Molecular Analysis; Molecular Target; Monitor; Mus; Newly Diagnosed; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phosphodiesterase Inhibitors; Play; Primary Neoplasm; Privatization; Proteins; Radiation; Radiation therapy; Recurrence; Reporting; Research; Research Personnel; Resistance; Role; Route; Safety; Small Business Technology Transfer Research; Survival Rate; Techniques; Testing; Therapeutic; Time; Tumor Necrosis Factor Receptor; Xenograft procedure; animal data; cell motility; cellular targeting; chemotherapy; clinical predictors; clinical prognosis; clinically relevant; cost; design; drug development; drug repurposing; experience; human disease; improved; in vivo; innovation; invention; knock-down; member; molecular subtypes; mouse model; neoplastic cell; new therapeutic target; novel therapeutics; patient derived xenograft model; pre-clinical; predict responsiveness; prognostic; propentofylline; standard of care; temozolomide; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor xenograft

SUMMARY Glioblastoma (GBM) is the most common primary tumor of the CNS with limited treatment options and a poor clinical prognosis. Standard of care treatment, including surgical resection, radiation therapy and concurrent temozolomide (TMZ) treatment followed by adjuvant TMZ, produces a median survival in newly diagnosed GBM of ~15 months. Tumor recurrence happens due to therapy resistant tumor cells; therefore, therapeutic strategies that improve tumor cell sensitivity to chemotherapy are needed to improve patient outcomes. TROY (TNFRSF19), a member of the TNF receptor superfamily, has recently been discovered to impact GBM progression. Briefly, TROY expression increases with increasing glial tumor grade and inversely correlates with patient survival. Increased expression of TROY stimulates GBM cell migration/invasion in vitro and in vivo and increases resistance to TMZ or radiation in vitro, while knockdown of TROY expression inhibits cell invasion, increases sensitivity to TMZ, and prolongs survival in a murine patient-derived xenograft (PDX) model. These and additional studies indicate that TROY represents a potential novel therapeutic target for GBM. Propentofylline (PPF), a drug that has been studied in numerous clinical trials for several non-GBM indications, downregulates TROY, inhibits GBM invasion and increases sensitivity in vitro and in vivo to TMZ and radiotherapy. PPF exhibits a well-characterized pharmacological profile, including good brain distribution and favorable safety metrics. Repurposing PPF could be faster to clinical trials, less risky and less costly than the traditional drug development pathway for new chemical entities. The primary goal of this proposal is to test the ability of PPF to sensitize GBM to TMZ. Secondary goals include assessing: the necessity of TROY for PPF activity, the mechanisms of action for PPF-induced TROY downregulation, and the impact of PPF treatment and TROY expression on tumor-promoting microglia. The following aims have been designed to answer these questions. Specific Aim 1: Test the ability of PPF to sensitize TMZ resistant GBM tumors to therapeutic treatment in intracranial PDX models and a syngeneic model. The ability of PPF to sensitize GBM cells to TMZ will be evaluated in five TMZ resistant PDX mouse models and one immunocompetent syngeneic model. IVIS-monitoring of tumor growth, duration of survival as well as histopathological and molecular analysis of tumor and tumor microenvironment will be evaluated. Specific Aim 2: Characterize the cellular and molecular targets of PPF to predict clinical responsiveness. Live-cell automated imaging and molecular techniques will be used to help define the cellular and molecular targets of PPF. We will test the ability of PPF to sensitize a diverse panel of 20 human GBM PDX lines, representing varied molecular and prognostic subtypes, to TMZ treatment ex vivo and assess the effects of PPF on microglia in vitro.

总结 胶质母细胞瘤（GBM）是最常见的中枢神经系统原发性肿瘤，治疗选择有限， 临床预后标准治疗，包括手术切除、放射治疗和同时 替莫唑胺（TMZ）治疗后辅助TMZ，产生新诊断GBM的中位生存期 约15个月。肿瘤复发是由于治疗抵抗性肿瘤细胞;因此，治疗策略 需要提高肿瘤细胞对化疗敏感性来改善患者的结果。 TROY（TNFRSF 19）是TNF受体超家族的成员，最近被发现影响GBM 进展简而言之，TROY表达随着神经胶质肿瘤分级的增加而增加，并且与肿瘤的生长呈负相关。 患者生存率。TROY表达的增加在体外和体内刺激GBM细胞迁移/侵袭， 增加体外对TMZ或辐射的抗性，而TROY表达的敲低抑制细胞侵袭， 增加对TMZ的敏感性，并在鼠患者来源的异种移植物（PDX）模型中增加存活率。这些 另外的研究表明，TROY代表了GBM的潜在的新的治疗靶点。 丙戊茶碱（PPF），一种已在许多非GBM临床试验中研究的药物 适应症，下调TROY，抑制GBM侵袭并增加体外和体内对TMZ的敏感性 和放射治疗。PPF具有良好的药理学特征，包括良好的脑分布 和有利的安全指标。重新利用PPF可以更快地进行临床试验，风险更小，成本更低， 传统的药物开发新化学实体的途径。 本提案的主要目的是测试PPF使GBM对TMZ敏感的能力。次要目标 包括评估：TROY对PPF活性的必要性，PPF诱导的TROY的作用机制， 下调，以及PPF治疗和TROY表达对促肿瘤小胶质细胞的影响。 以下目标旨在回答这些问题。具体目标1：测试PPF的能力 在颅内PDX模型中使TMZ耐药GBM肿瘤对治疗性治疗敏感， 同源模型将在5个TMZ耐药PDX中评价PPF使GBM细胞对TMZ敏感的能力。 小鼠模型和一种免疫活性同基因模型。IVIS-监测肿瘤生长，持续时间 存活以及肿瘤和肿瘤微环境组织病理学和分子分析将 评估。具体目标2：表征PPF的细胞和分子靶点，以预测临床 响应能力。活细胞自动成像和分子技术将用于帮助确定细胞 和PPF的分子靶点。我们将测试PPF致敏20个人GBM PDX的能力。 线，代表不同的分子和预后亚型，以TMZ治疗离体和评估的影响 PPF对小胶质细胞的作用。