Targeting glioma stem cells by perturbation of telomere maintenance mechanisms

描述（由申请人提供）：拟议的研究是探索新的治疗机会，通过扰乱胶质瘤干细胞中的端粒维持机制来治愈恶性胶质瘤。恶性胶质瘤对治疗具有高度抗性，这主要是由于胶质瘤干细胞（GSC）的存在，其具有取之不尽的自我更新和增殖能力。我建议通过抑制端粒酶来靶向GSC，因为GSC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。目的一，我将探讨GSCs的反应，端粒酶抑制与三个独立的模型系统。我还将测试抗端粒酶是否会使组合治疗方案中的常规放疗和化疗敏感。我之前的研究表明，抗端粒酶将通过ALT（端粒替代延长）机制导致耐药性，因此在目标2中，我将产生和表征依赖于ALT机制的GSC，并将探索靶向ALT弱点的可能性，以防止对抗端粒酶治疗的耐药性。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，因此在目标3中，我将研究端粒酶+和ALT+胶质瘤干细胞中端粒染色质重塑的机制。从这一目标中获得的信息将帮助我们了解GSC背景下ALT机制的性质，并提供针对ALT+ GSC的新治疗机会。这项拟议的研究将帮助我形成一个强大的研究计划，我将在学术/医学研究机构推出一个独立的教师职位。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，我将致力于提高我在管理实验室，指导博士后和学生，科学写作和演讲以及寻求合作等方面的技能，因为这些技能对我获得教师职位并成功成为PI至关重要。MD安德森癌症中心（MDACC）和罗纳德德平霍实验室为我实现这些目标提供了极好的培训环境。尽管DePinho博士现在是MDACC的总裁，他仍然承诺将投入2.5%的精力用于我的培训和职业发展。我还成立了一个特别咨询委员会，由黄绵琦博士、容伟钧博士和陈俊杰博士组成。他们不仅为我的研究提供技术支持，还指导我寻找教师职位，并成为一名成功的独立研究者。在K99/R 00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，即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，作为学术/医学研究机构的实验室负责人，并通过与其他科学家合作，作为团队成员开发新的癌症疗法，医生和制药公司。

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.