Targeting glioma stem cells by perturbation of telomere maintenance mechanisms

通过扰动端粒维持机制靶向神经胶质瘤干细胞

• 批准号: 8928060
• 负责人: Jian Hu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928060
• 关键词: Acute; Adult; Adverse effects; Advisory Committees; Biological Models; Biology; Biometry; Brain Neoplasms; Cancer Biology; Cancer Center; Cell Survival; Cell division; Cells; Chromatin Remodeling Factor; Chromatin Structure; Chromosomes; Collaborations; DAXX gene; Data; Development; Drug Targeting; Environment; Enzymes; Faculty; Frequencies; Generations; Genetic; Genetic Recombination; Glial Fibrillary Acidic Protein; Glioma; Goals; Grant; Head; Human; Institution; Ionizing radiation; Laboratories; Lead; Length; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Medical Research; Mentors; Modeling; Multienzyme Complexes; Mus; Mutate; Mutation; Nature; Pathway interactions; Patients; Pharmacologic Substance; Physicians; Positioning Attribute; Postdoctoral Fellow; Proliferating; Radiation therapy; Recurrence; Regimen; Regulation; Relative (related person); Reporting; Research; Research Institute; Research Personnel; Resistance; Resistance development; Role; Sampling; Scientist; Somatic Cell; Stem cells; Students; Telomerase; Telomerase inhibition; Telomere Maintenance; Testing; Time; Training; Writing; cancer genomics; cancer stem cell; cancer therapy; career development; chemotherapy; chromatin remodeling; combinatorial; conventional therapy; design; effective therapy; histone modification; improved; killings; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; prevent; programs; resistance mechanism; response; screening; self-renewal; skills; stem cell biology; telomere; temozolomide; tumor

Project Summary The proposed study is to explore novel therapeutic opportunities to cure malignant gliomas by perturbing telomere maintenance mechanisms in glioma stem cells. Malignant gliomas are highly resistant to treatment largely due to the existence of glioma stem cells (GSCs), which possess inexhaustible ability to self-renew and proliferate. I propose to target GSCs by inhibiting telomerase because GSCs have higher level of telomerase activity than somatic cells and other non-GSC tumor cells. With Aim 1, I will explore GSCs' response to telomerase inhibition with three independent model systems. I will also test whether anti-telomerase sensitizes conventional radiation therapy and chemotherapy in combinatorial therapy regimens. My previous study showed that anti-telomerase will lead to resistance through ALT (Alternative Lengthening of Telomeres) mechanisms, so in Aim 2 I will generate and characterize GSCs that rely on ALT mechanisms and will explore the possibility to target the weakness of ALT in order to prevent the resistance in response to anti-telomerase therapy. More evidence is pointing to the important function of chromatin remodeling factors in the regulation of telomeres, so in Aim 3, I will investigate the mechanisms of telomeric chromatin remodeling in telomerase+ and ALT+ glioma stem cells. The information obtained from this aim will help us understand the natures of ALT mechanisms in the GSC context and provide new therapeutic opportunities to target ALT+ GSCs. This proposed study will help me to form a strong research program, with which I will launch an independent faculty position in an academic/medical research institution. To that end, my immediate goals are to continue sharpening my technical skills in mouse genetics, telomere biology and stem cell biology and expanding my skills in oncogenomics, biostatistics and translational biology. In terms of my career development, I will be devoted to improve my skills on managing lab, mentoring postdocs and students, scientific writing and presentation, and seeking for collaborations, among others, because these skills are all essential for me to land a faculty position and succeed as a PI. MD Anderson Cancer Center (MDACC) and the Ronald DePinho laboratory provide an excellent training environment for me to achieve these goals. Even though Dr. DePinho is President of MDACC now, he still promises to devote 2.5% effort to my training and career development. I have also formed an extraordinary advisory committee composed of Dr. Mien-Chie Huang, Dr. Wai-Kwan Yung and Dr. Junjie Chen. They will not only provide me technical support for my proposed study, but also guide me to look for a faculty position and succeed as an independent investigator. With the help of K99/R00 training grant, I will have a good start to achieve my long term goals, which are to continue exploring basic and translational problems in cancer biology, including telomere biology and cancer stem cell biology, as a lab head in an academic/medical research institute and to contribute in developing novel cancer therapies as a team player by collaborating with other scientists, physicians and pharmaceutical companies.

项目摘要 拟议的研究是探索新的治疗机会，以通过干扰来治愈恶性神经胶质瘤 神经胶质瘤干细胞中的端粒维持机制。恶性神经胶质瘤对治疗高度抗药性 很大程度上是由于存在神经胶质瘤干细胞（GSC），它们具有无尽的自我更新能力和 增生。我建议通过抑制端粒酶来靶向GSC，因为GSC具有较高的端粒酶水平 活性比体细胞和其他非GSC肿瘤细胞。使用AIM 1，我将探索GSCS对 三个独立模型系统的端粒酶抑制。我还将测试抗telomeromerase是否敏感 组合治疗方案中的常规放射疗法和化学疗法。我以前的研究 表明抗细胞瘤将通过ALT导致抗性（端粒的替代性延长） 机制，因此在AIM 2中，我将生成并表征依赖Alt机制的GSC，并将探索 靶向ALT弱点以防止抗抗细胞酶的抗性的可能性 治疗。更多证据表明，染色质重塑因子在调节中的重要功能 端粒，因此在AIM 3中，我将研究端粒染色质重塑端粒酶+的机理 和Alt+神经胶质瘤干细胞。从这个目标获得的信息将有助于我们了解ALT的本质 GSC环境中的机制，为靶向ALT+ GSC提供了新的治疗机会。这 拟议的研究将帮助我建立一项强大的研究计划，我将通过该计划启动独立教师 在学术/医学研究机构中的位置。为此，我的直接目标是继续 培养我在鼠标遗传学，端粒生物学和干细胞生物学方面的技术技能，并扩大我的 致癌基因组学，生物统计学和转化生物学的技能。就我的职业发展而言，我将 致力于提高我在管理实验室，指导博士后和学生的技能，科学写作和 演讲，并寻求合作等，因为这些技能对我来说都是至关重要的 在教师职位上占据一席之地，并成为PI。 MD安德森癌症中心（MDACC）和罗纳德·迪帕尼奥 实验室为我提供了极好的培训环境，以实现这些目标。即使Depinho博士 现在是MDACC总裁，他仍然承诺将努力为我的培训和职业发展提供2.5％的努力。我 还成立了一个由Mien-Chie Huang博士Wai-Kwan Yung博士组成的非凡咨询委员会 和Junjie Chen博士。他们不仅会为我的拟议研究提供技术支持，还可以指导我 寻找教师职位并成功成为独立研究者。在K99/R00培训的帮助下 格兰特（Grant），我将有一个良好的开始来实现我的长期目标，这将继续探索基本和 癌症生物学的翻译问题，包括端粒生物学和癌症干细胞生物学，作为实验室 领导学术/医学研究所，并为开发新型癌症疗法做出贡献 通过与其他科学家，医师和制药公司合作进行团队合作。