Reversing Cellular immortality in cancer

逆转癌症中的细胞永生

基本信息

批准号：
8956267
负责人：
STEVEN E ARTANDI
金额：
$ 63.25万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-08 至 2022-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Decades of cancer research have led to major breakthroughs in understanding cancer gene function and to important advances in diagnosis and treatment of these complex diseases. Despite this progress, most advanced cancers in adults are ultimately refractory to treatment, and cures for these common conditions remain out of reach. The difficulty in treating advanced cancers relates to many variables, including an incomplete understanding of how cancer initiates, the complexity of the alterations in cancer, heterogeneity in tumors and only a partial understanding of the molecular underpinnings of central cancer pathways. My research program over the next seven years seeks to address important aspects of these fundamental roadblocks. I will address the target cell populations from which cancers emerge - the cell-of-origin - and determine how these early beginnings are linked to one of the most fundamental properties of cancer cells, the acquisition of immortal proliferative properties. I will identify new telomerase-expressing stem cell populations in divers tissues and determine how they relate to cancer cells-of-origin. I will probe the mechanisms by which immortality is acquired by telomerase upregulation and reveal the means by which highly recurrent mutations in the TERT promoter promote tumorigenesis. I will devise methods for disrupting maintenance of the immortal phenotype, ultimately rendering cancer cells incapable of long-term proliferation or survival. Together, this program will lead to fundamental new insights into the origins of cancer, reveal how aspiring cancers circumvent critical bottlenecks they encounter during carcinogenesis and lead to new therapies with potential to treat many of the most refractory human cancers.

描述（由适用提供）：数十年的癌症研究导致了了解癌症基因功能以及这些复杂疾病的诊断和治疗的重要进展。尽管取得了这种进展，但大多数成年人的高级癌症最终还是对治疗的难治性，并且治愈这些常见疾病仍然无法应付。治疗晚期癌症的困难与许多变量有关，包括对癌症的启动，癌症改变的复杂性，肿瘤异质性的复杂性以及仅部分理解中央癌症途径的分子基础的不完全理解。我未来七年的研究计划旨在解决这些基本障碍的重要方面。我将解决癌症出现的靶细胞群体 - 原始细胞 - 癌细胞 - 确定这些早期起点如何与癌细胞最基本的特性之一联系在一起，即不朽的增殖特性的获取。我将在潜水组织中确定新的表达端粒酶的干细胞群体，并确定它们与癌细胞之间的关系。我将探测端粒酶上调获得永生的机制，并揭示TERT启动子中高度复发突变促进肿瘤发生的手段。我将设计用于破坏不朽表型维持的方法，最终使癌细胞无法长期增殖或生存。该计划一起将导致对癌症起源的基本新见解，揭示有抱负的癌症如何规避他们在癌变期间遇到的关键瓶颈，并导致新疗法有可能治疗许多最耐用的人类癌症。