Targeting glioma stem cells by perturbation of telomere maintenance mechanisms

描述（由申请人提供）：本研究旨在通过干扰胶质瘤干细胞的端粒维持机制，探索治疗恶性胶质瘤的新方法。恶性胶质瘤对治疗具有高度的耐药性，很大程度上是由于胶质瘤干细胞（glioma stem cells, GSCs）的存在，这种干细胞具有永不枯竭的自我更新和增殖能力。我建议通过抑制端粒酶来靶向GSCs，因为GSCs比体细胞和其他非gsc肿瘤细胞具有更高水平的端粒酶活性。在Aim 1中，我将通过三个独立的模型系统探索GSCs对端粒酶抑制的反应。我还将测试抗端粒酶是否会使常规放射治疗和化疗在联合治疗方案中增敏。我之前的研究表明，抗端粒酶会通过ALT （Alternative Lengthening of Telomeres）机制导致耐药性，因此在Aim 2中，我将生成并表征依赖于ALT机制的GSCs，并探索针对ALT弱点的可能性，以防止抗端粒酶治疗产生耐药性。越来越多的证据表明染色质重塑因子在端粒调控中的重要作用，因此在Aim 3中，我将研究端粒酶+和ALT+胶质瘤干细胞端粒染色质重塑的机制。从这一目的中获得的信息将有助于我们了解谷丙转化酶在GSC背景下的机制性质，并为靶向谷丙转化酶+ GSC提供新的治疗机会。这个建议的研究将帮助我形成一个强大的研究计划，我将启动一个独立的教师职位在学术/医学研究机构。为此，我的直接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，并扩大我在肿瘤基因组学、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，我将致力于提高自己的技能，管理实验室，指导博士后和学生，科学写作和演讲，寻求合作等，因为这些技能都是我获得教师职位和成功的PI所必需的。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培训环境。尽管DePinho博士现在是MDACC的主席，他仍然承诺为我的培训和职业发展投入2.5%的努力。我还成立了一个特别咨询委员会，由黄敏芝博士、容伟钧博士和陈俊杰博士组成。他们不仅会为我提出的研究提供技术支持，还会指导我寻找教师职位，并成功地成为一名独立研究者。在K99/R00培训基金的帮助下，我将有一个良好的开端来实现我的长期目标，这是继续探索癌症生物学的基础和转化问题，包括端粒生物学和癌症干细胞生物学，作为一个学术/医学研究机构的实验室负责人，并通过与其他科学家、医生和制药公司合作，作为一个团队成员，为开发新的癌症疗法做出贡献。

DESCRIPTION (provided by applicant): 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.