Targeting Mechanisms of Acquired Temozolomide Resistance in Glioblastoma

胶质母细胞瘤获得性替莫唑胺耐药的靶向机制

• 批准号: 10057396
• 负责人: Clark Chin-Chung Chen
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057396
• 关键词: 5' -exoribonuclease; Address; Adult; Brain Neoplasms; Caring; Cell Line; Cells; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Collaborations; DNA Damage; DNA Repair; DNA Repair Gene; Data; Disease; Engineering; Excision; Genes; Genetic; Genetically Engineered Mouse; Glioblastoma; Immunocompetent; Industry; Laboratories; Malignant neoplasm of brain; Mediating; Methyltransferase; MicroRNAs; Modeling; Molecular; Operative Surgical Procedures; Patients; Phosphotransferases; Physiology; Process; Progression-Free Survivals; Publications; Radiation; Research Personnel; Resistance; Retroviridae; Ribonucleases; Role; Specimen; Testing; Therapeutic; Transgenes; Untranslated RNA; Up-Regulation; Vertebral column; Virus; Work; chemotherapy; clinical practice; experimental study; fighting; gene therapy; homologous recombination; human disease; in vivo; innovation; inorganic phosphate; insight; novel; nucleotidyltransferase; overexpression; patient derived xenograft model; patient response; patient subsets; preclinical evaluation; promoter; resistance mechanism; response; standard of care; subcutaneous; targeted treatment; temozolomide; therapeutic gene; therapy development; therapy resistant; tumor

Project Summary BACKGROUND: Glioblastoma is the most common form of primary adult brain cancer and remains a deadly disease. The standard of care for glioblastoma involves surgical resection followed by radiation and temozolomide chemotherapy (TMZ). While Progression Free Survival (PFS) studies have revealed that nearly 80% of treated patients are responsive to TMZ at 6 months, only approximately 10% of these patients remain responsive by 24 months. We investigated whether altered microRNA (miRNA) expression during TMZ treatment contributes to acquired TMZ resistance. To this end, we profiled miRNAs in matched pre- and post- TMZ treated glioblastoma cell lines and clinical specimens. We identified one miRNA, miR-181d, which is down-regulated in response to TMZ treatment in both of these settings and profoundly influenced cellular TMZ sensitivity. miR-181d normally suppresses the expression of multiple DNA repair genes critical for TMZ resistance, including Methyl-Guanine Methyl-Transferase (MGMT) and homologous recombination (HR) genes. TMZ-induced miR-181d degradation up-regulates both processes and contributes to TMZ resistance. This proposal will characterize miRNA degradation as an acquired resistance mechanism and develop a therapy that targets this resistance. AIM 1 proposes experiments to characterize a) the molecular mechanisms by which the DNA damage response triggers miRNA degradation and b) the relevance of this process to acquired TMZ resistance. AIM 2 proposes experiments to a) characterize the genetic context in which miR- 181d degradation contributes to acquired TMZ resistance and b) determine the miR-181d regulated processes that contribute to this resistance. AIM 3 is built on the premise that over-expression of miR-181d beyond cellular capacity for degradation will suppress acquired TMZ resistance; to that end, we propose a miRNA based gene therapeutic approach to address the issue of acquired TMZ resistance. INNOVATION: The proposed study to characterize TMZ-induced miRNA degradation as a novel mechanism of acquired TMZ resistance is an innovative and heretofore unexplored approach. Moreover, this proposal develops an original framework that miRNA degradation simultaneously up-regulates multiple DNA repair processes that, in turn, contribute to TMZ resistance. Finally, we propose an innovative therapeutic strategy for addressing this form of resistance. LONG-TERM OBJECTIVE: We seek to meaningfully impact the care of glioblastoma patients through the application of principles developed in the fields of DNA repair, microRNAs, and retroviral gene therapy.

项目摘要 背景：胶质母细胞瘤是最常见的原发性成人脑癌， 疾病胶质母细胞瘤的标准护理包括手术切除，然后进行放射治疗， 替莫唑胺化疗（TMZ）。虽然无进展生存期（PFS）研究显示， 在6个月时，80%的治疗患者对TMZ有反应，只有大约10%的患者仍然存在 24个月后回复。我们研究了TMZ过程中microRNA（miRNA）表达的改变是否 治疗有助于获得TMZ抗性。为此，我们分析了匹配的术前和术后的miRNAs。 TMZ处理的胶质母细胞瘤细胞系和临床标本。我们鉴定了一种miRNA，miR-181 d， 在这两种情况下对TMZ治疗的反应下调，并深刻影响细胞TMZ 灵敏度miR-181 d通常抑制TMZ关键的多个DNA修复基因的表达 耐药性，包括甲基鸟嘌呤甲基转移酶（MGMT）和同源重组（HR） 基因. TMZ诱导的miR-181 d降解上调了这两个过程，并有助于TMZ耐药性。 该提案将描述miRNA降解作为获得性耐药机制的特征，并开发一种新的方法。 针对这种抵抗力的治疗。AIM 1提出了实验来表征a）分子机制 DNA损伤反应通过其触发miRNA降解，和B）该过程与 获得性TMZ耐药AIM 2提出了以下实验：a）表征miR-12表达的遗传背景， 181 d降解有助于获得性TMZ抗性和B）确定miR-181 d调节的过程 这些都是导致这种抵抗的原因。AIM 3是建立在miR-181 d过表达超过 细胞的降解能力将抑制获得性TMZ抗性;为此，我们提出了一种miRNA， 基于基因的治疗方法来解决获得性TMZ耐药的问题。创新：The 提出的研究将TMZ诱导的miRNA降解表征为获得性TMZ的新机制 抵抗是一种创新的、迄今尚未探索的方法。此外，该提案还开发了一个原始的 miRNA降解同时上调多个DNA修复过程的框架，反过来， 有助于TMZ抗性。最后，我们提出了一种创新的治疗策略，以解决这种形式的 阻力长期目标：我们寻求有意义地影响胶质母细胞瘤患者的护理 通过应用在DNA修复、微小RNA和逆转录病毒基因领域中发展的原理， 疗法

项目成果

Survival Association and Cell Cycle Effects of B7H3 in Neuroblastoma.

• DOI: 10.3340/jkns.2019.0255
• 发表时间: 2020-11
• 期刊: Journal of Korean Neurosurgical Society
• 影响因子: 1.6
• 作者: Zhang H;Zhang J;Li C;Xu H;Dong R;Chen CC;Hua W
• 通讯作者: Hua W

IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry.

胶质母细胞瘤中的 IDH 突变和 MGMT 启动子甲基化：前瞻性登记结果。

• DOI: 10.18632/oncotarget.5683
• 发表时间: 2015-12-01
• 期刊: Oncotarget
• 作者: Yang P;Zhang W;Wang Y;Peng X;Chen B;Qiu X;Li G;Li S;Wu C;Yao K;Li W;Yan W;Li J;You Y;Chen CC;Jiang T
• 通讯作者: Jiang T

miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma.

• DOI: 10.18632/oncotarget.8618
• 发表时间: 2016-05-10
• 期刊: Oncotarget
• 作者: Khalil S;Fabbri E;Santangelo A;Bezzerri V;Cantù C;Di Gennaro G;Finotti A;Ghimenton C;Eccher A;Dechecchi M;Scarpa A;Hirshman B;Chen C;Ferracin M;Negrini M;Gambari R;Cabrini G
• 通讯作者: Cabrini G