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.

项目概要 拟议的研究旨在探索通过扰动来治愈恶性神经胶质瘤的新治疗机会 神经胶质瘤干细胞的端粒维持机制。恶性胶质瘤对治疗具有高度抵抗力 这很大程度上是由于神经胶质瘤干细胞（GSC）的存在，它具有无穷无尽的自我更新和更新能力 增生。我建议通过抑制端粒酶来靶向 GSC，因为 GSC 的端粒酶水平较高 活性高于体细胞和其他非 GSC 肿瘤细胞。对于目标 1，我将探讨 GSC 的应对措施 端粒酶抑制与三个独立的模型系统。我也会测试抗端粒酶是否致敏 常规放疗和化疗的组合治疗方案。我之前的学习 研究表明，抗端粒酶药物会通过 ALT（端粒替代延长）导致耐药性 机制，因此在目标 2 中，我将生成并表征依赖 ALT 机制的 GSC，并将探索 针对 ALT 弱点的可能性，以防止对抗端粒酶的抵抗 治疗。更多证据表明染色质重塑因子在调节 端粒，所以在目标3中，我将研究端粒酶+中端粒染色质重塑的机制 和 ALT+ 神经胶质瘤干细胞。从此目标获得的信息将帮助我们了解 ALT 的本质 GSC 背景下的机制，并为靶向 ALT+ GSC 提供新的治疗机会。这 拟议的研究将帮助我形成一个强大的研究计划，我将通过该计划建立一个独立的教师队伍 在学术/医学研究机构中的职位。为此，我的近期目标是继续 提高我在小鼠遗传学、端粒生物学和干细胞生物学方面的技术技能，并扩大我的研究范围 肿瘤基因组学、生物统计学和转化生物学方面的技能。在我的职业发展方面，我会 致力于提高我在管理实验室、指导博士后和学生、科学写作和 演示、寻求合作等等，因为这些技能对我来说都是必不可少的 获得教职并成为一名成功的 PI。 MD 安德森癌症中心 (MDACC) 和 Ronald DePinho 实验室为我实现这些目标提供了良好的训练环境。尽管德皮尼奥博士 现在是MDACC主席，他仍然承诺为我的培训和职业发展投入2.5%的努力。我 并成立了由黄勉杰博士、容伟均博士组成的特别顾问委员会 和陈俊杰博士。他们不仅会为我提出的研究提供技术支持，还会指导我 寻找教职并成为一名成功的独立调查员。借助K99/R00培训 授予，我将有一个良好的开端来实现我的长期目标，即继续探索基本和 作为实验室，癌症生物学的转化问题，包括端粒生物学和癌症干细胞生物学 作为学术/医学研究机构的负责人，并为开发新型癌症疗法做出贡献 与其他科学家、医生和制药公司合作，成为团队合作者。