Reversing Cellular immortality in cancer

 描述(申请人提供)：数十年的癌症研究导致在了解癌症基因功能方面取得重大突破，并在这些复杂疾病的诊断和治疗方面取得重要进展。尽管取得了这一进展，但大多数成年人的晚期癌症最终是难以治疗的，这些常见疾病的治愈仍然遥不可及。治疗晚期癌症的困难与许多变量有关，包括对癌症如何发生的不完全了解，癌症变化的复杂性，肿瘤的异质性，以及对中央癌症通路的分子基础只有部分了解。我在未来七年的研究计划旨在解决这些根本障碍的重要方面。我将讨论癌症产生的目标细胞群体--起源细胞--并确定这些早期开始如何与癌细胞最基本的特性之一--获得不朽的增殖特性--联系在一起。我将在潜水组织中鉴定新的表达端粒酶的干细胞群体，并确定它们与癌细胞来源的关系。我将探索通过端粒酶上调获得永生的机制，并揭示TERT启动子高度重复的突变促进肿瘤发生的方法。我将设计方法来破坏永生表型的维持，最终使癌细胞无法长期增殖或存活。总而言之，这一计划将带来对癌症起源的根本新见解，揭示有抱负的癌症如何绕过他们在癌症发生过程中遇到的关键瓶颈，并导致具有治疗许多最难治的人类癌症的潜力的新疗法。

 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.