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：胶质母细胞瘤是原发性脑癌的最常见形式，仍然是致命的 疾病。胶质母细胞瘤的护理标准涉及手术切除，然后进行辐射和 替莫酚化疗（TMZ）。虽然无进展生存（PFS）研究表明 80％的治疗患者在6个月时对TMZ有反应，这些患者中只有10％仍然存在 响应24个月。我们研究了TMZ期间的microRNA（miRNA）表达是否改变 治疗有助于获得的TMZ耐药性。为此，我们在匹配的前后介绍了miRNA TMZ处理的胶质母细胞瘤细胞系和临床标本。我们确定了一个miRNA，miR-181d，那是 在这两种情况下都因TMZ处理而下调，并深远影响了细胞TMZ 灵敏度。 miR-181d通常抑制对TMZ至关重要的多个DNA修复基因的表达 耐药性，包括甲基黄瓜甲烷甲基转移酶（MGMT）和同源重组（HR） 基因。 TMZ诱导的miR-181D降解上调这两个过程并有助于TMZ抗性。 该提案将将miRNA降解描述为一种获得的抵抗机制，并发展 针对这种抗药性的治疗。 AIM 1提出了表征A）分子机制的实验 DNA损伤响应触发miRNA降解和b）该过程与 获得的TMZ电阻。 AIM 2提出了实验a）表征mir-的遗传环境 181D降解有助于获得的TMZ耐药性，b）确定miR-181d调节过程 这有助于这种抵抗。 AIM 3建立在以下前提下 降解的细胞能力将抑制获得的TMZ耐药性；为此，我们提出了一个mirna 基于基因治疗方法来解决获得的TMZ抗性问题。创新： 提出的研究将TMZ诱导的miRNA降解作为获得的TMZ的新机制 阻力是一种创新的和迄今未开发的方法。此外，该提案开发了原始的 miRNA降解同时上调多个DNA修复过程的框架 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 反抗。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 通过在DNA修复，microRNA和逆转录病毒基因领域发展的原理 治疗。

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

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

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