Augmented homologous recombination as a mechanism of acquired temozolomide resistance in glioblastoma

增强同源重组作为胶质母细胞瘤获得性替莫唑胺耐药的机制

• 批准号: 9325481
• 负责人: Sandeep Burma
• 金额: $ 21.14万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325481
• 关键词: Adjuvant; Adult; Alkylating Agents; Attenuated; Brain Neoplasms; Cell Line; Clinical Trials; Cyclin-Dependent Kinases; DNA; DNA Double Strand Break; Drug resistance; EXO1 gene; Enzymes; Excision; Exhibits; Exonuclease; Genetic; Glioblastoma; Goals; Human Characteristics; Laboratories; MGMT gene; Methods; Mismatch Repair; Modality; Modeling; Molecular; Mus; Operative Surgical Procedures; Pathway interactions; Patients; Primary Brain Neoplasms; Publishing; Radiation; Radiation therapy; Radio; Recurrence; Recurrent tumor; Refractory; Resistance; Sum; Testing; Therapeutic; Treatment Protocols; Work; base; cancer cell; chemotherapy; combat; homologous recombination; improved; inhibitor/antagonist; mortality; neoplastic cell; novel; novel therapeutic intervention; overexpression; pre-clinical; recombinational repair; repaired; response; standard of care; temozolomide; therapy development; therapy resistant; tumor

Project Summary/Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults and is universally fatal. These tumors are refractory to all conventional therapeutic modalities - surgical resection, radiotherapy and chemotherapy- resulting in a mortality rate of over 90% at 2 years. The only improvement in GBM therapy came from addition of the DNA alkylating agent temzolomide (TMZ) tor treatment regimens. Although TMZ is now routinely administered, concurrently with radiation and as an adjuvant, gains in survival are modest (2-3 months) as these tumors eventually develop therapy-driven resistance and always recur. In order to improve GBM therapy further, it is important to understand how initial and acquired genetic and molecular changes occurring in these tumors modulate the response to TMZ. Loss of mismatch repair (MMR) and re-expression of MGMT enzyme are two mechanisms that underlie some but not all of the chemoresistance exhibited by GBMs. Work done in our and other laboratories has shown that TMZ induces secondary “one-ended” DNA double- strand breaks (DSBs) that are very toxic, and which can be correctly repaired only by the homologous recombination (HR) pathway. Exciting unpublished results from our lab reveal that protracted TMZ treatment of orthotopic GBM tumors in mice results in acquired resistance due to heightened HR repair of TMZ-induced DSBs. Moreover, we have recently published results demonstrating that HR repair is stimulated by cyclin- dependent kinases (CDKs 1&2), which opens up the possibility of combating acquired TMZ resistance with CDK inhibitors. We hypothesize that augmented HR may underlie GBM chemoresistance and recurrence and that targeting HR using CDK inhibitors (that are currently validated in clinical trials) might be a viable strategy for re-sensitizing recurrent GBMs to TMZ. We propose to test our hypothesis in pre-clinical mouse GBM models that closely mimic the characteristics of human GBM. In sum, the goals of the proposed project are to understand if augmented HR is a bona fide mechanism of acquired chemoresistance in GBM, and whether CDK inhibitors can be used to dampen HR thereby sensitizing recurrent tumors to TMZ.

项目总结/摘要 胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性脑肿瘤，通常是致命的。 这些肿瘤是难治的所有传统的治疗方式-手术切除，放疗和化疗。 化疗-导致2年死亡率超过90%。GBM治疗的唯一进步 来自于在治疗方案中加入DNA烷化剂替莫唑胺（TMZ）。虽然TMZ 现在常规施用，与放射同时施用并作为辅助，存活率的增加是适度的（2-3 几个月），因为这些肿瘤最终会产生治疗驱动的耐药性，并且总是复发。为了提高 GBM治疗进一步，重要的是要了解初始和获得性遗传和分子变化 发生在这些肿瘤调节TMZ的反应。错配修复（MMR）的丢失和 MGMT酶是GBM表现出的一些但不是全部化学抗性的基础的两种机制。 在我们和其他实验室所做的工作表明，TMZ诱导二级“一端”DNA双链， 链断裂（DSB）是非常有毒的，只能通过同源的 重组（HR）途径。我们实验室未发表的令人兴奋的结果表明， 小鼠中的原位GBM肿瘤由于TMZ诱导的HR修复增强而导致获得性抗性 DSB。此外，我们最近发表的结果表明，HR修复是由细胞周期蛋白刺激的， 依赖性激酶（CDKs 1和2），这开辟了对抗获得性TMZ耐药性的可能性， CDK抑制剂。我们假设HR增加可能是GBM化疗耐药性和复发的基础， 使用CDK抑制剂（目前已在临床试验中得到验证）靶向HR可能是一种可行的策略 让复发性GBM对TMZ重新敏感我们建议在临床前小鼠GBM中检验我们的假设 这些模型非常接近人类GBM的特征。总而言之，拟议项目的目标是 了解HR增加是否是GBM获得性耐药的真正机制，以及是否 CDK抑制剂可用于抑制HR，从而使复发性肿瘤对TMZ敏感。