Establishing therapeutic efficacy and uncovering mechanisms of tumor suppression

描述(申请人提供)：我的研究重点是阐明限制恶性肿瘤的细胞和分子机制。众所周知，细胞具有内在和外在的肿瘤抑制机制，这些机制是由几个关键的肿瘤抑制基因协调的。然而，在已建立的肿瘤中，无法随意恢复肿瘤抑制功能，阻碍了我们对其功能的理解。在这个K99/R00奖项中提出的项目概述了新型小鼠模型的创建和实施，这些模型允许以特定于组织和时间的方式控制基因失活和基因恢复。 我在Burkitt淋巴瘤模型中研究端粒功能障碍的后果的经验，以及我最近在阐明在几种不同人类癌症模型中恢复p53肿瘤抑制基因的体内效应的努力，决定了在这一应用中提议的研究。这些研究项目巩固了我对从事研究人类癌症进展的基本组成部分的职业的兴趣。我对肿瘤抑制生物学的渴望需要开发新的遗传系统，在这种系统中，肿瘤抑制基因的功能可以被灭活，然后再恢复。我们在这里提出的系统利用了固有的小鼠模型和基因定义的人类癌细胞。对这些系统的比较分析将通过利用相关的体内环境和研究人类癌症的相关组织来加强对肿瘤抑制基本机制的发现。麻省理工学院科赫研究所的设施，以及我的导师贾克斯博士可以提供的专业知识，对于这个项目的成功实施将是无价的。 这些实验的目标是：突出这些肿瘤抑制通路作为根除癌症手段的治疗潜力，确定肿瘤抑制基因抑制各种肿瘤类型的癌症形成或进展的相关机制，揭示在肿瘤抑制基因恢复时释放的生物程序，以及确定治疗干预的特定新靶点。 麻省理工学院贾克斯实验室和周边地区的研究环境为科学讨论、合作和培训提供了无与伦比的机会。目前，我指导一名本科生和一名技术助理，他们直接与我一起进行与我的研究相关的实验。这是一次令人难以置信的经历，它将赋予我管理独立实验室的许多必要技能。麻省理工学院、博德研究所和哈佛医学院的科学界提供了无数的研讨会和工作坊，将继续促进我的科学发展。 我的近期目标是开发本申请中描述的研究平台，并展示其解开迄今尚未确定的抑制肿瘤的分子和细胞机制的潜力。我打算启动一个独立的研究计划，通过研究各种重要肿瘤类型中的多个肿瘤抑制基因，来利用这些体内系统。从长远来看，我相信这些实验将为我的研究计划的发展提供一个基础。我期待着教育和招收和我一样热爱癌症研究的学生和博士后。 公共卫生相关性：在各种人类癌症中，相对较少的关键肿瘤抑制通路发生突变。不幸的是，我们对这些基因在每种肿瘤类型中控制的相关肿瘤抑制程序知之甚少。此外，还缺乏在体内研究这些功能的工具。我的目标是开发小鼠和人类细胞模型，以询问已建立的癌症中肿瘤抑制基因的功能，并研究肿瘤回归计划，希望更好地了解肿瘤生物学，确定新的治疗靶点。

DESCRIPTION (provided by applicant): My research is focused on elucidating the cellular and molecular mechanisms that constrain malignant cancers. It is known that cells possess intrinsic and extrinsic tumor- suppressor mechanisms that are orchestrated by a handful of key tumor-suppressor genes. However, the inability to restore tumor suppressor function at will in established tumors has hampered our understanding of their functions. The project proposed within this K99/R00 award outlines the creation and implementation of novel mouse models that allow gene inactivation and gene restoration to be controlled in a tissue-specific and temporal manner. The research proposed within this application has been shaped by my experiences studying the consequences of telomere dysfunction in a model of Burkitt's lymphoma and by my recent efforts to elucidate the in vivo effects of restoring the p53 tumor-suppressor gene in several models of diverse human cancers. These research projects solidified my interests in pursuing a career studying the fundamental components of human cancer progression. My desire to interrogate the biology of tumor-suppression requires the development of novel genetic systems in which tumor-suppressor gene function can be inactivated and then subsequently restored. The systems that we propose herein utilize autochthonous mouse models and genetically defined human cancer cells. Comparative analysis of these systems will enhance discovery of fundamental mechanisms of tumor suppression by capitalizing on the relevant in vivo setting and the relevant organism in which to study human cancer. The facilities at the Koch Institute at MIT, and the expertise that my mentor, Dr. Jacks, can provide wil be invaluable for successful implementation of this project. The goals of these experiments outlined within are: to highlight the therapeutic potential of targeting these tumor-suppressor pathways as a means to eradicate cancer, to identify relevant mechanisms by which tumor-suppressor genes inhibit cancer formation or progression in a variety of tumor types, to uncover biological programs unleashed upon tumor-suppressor gene restoration, and to identify specific novel targets for therapeutic intervention. The research environment in the Jacks Laboratory, MIT, and the surrounding area offers unmatched opportunities for scientific discussion, collaboration, and training. Currently, I supervise an undergraduate student and a technical assistant that work directly with me on experiments pertaining to my research. This is an incredible experience that will endow me with many of the necessary skills to manage an independent laboratory. The scientific community at MIT, the Broad Institute, and Harvard Medical School offers countless seminars and workshops that will continue to foster my scientific development. My immediate goals are to develop the research platform described in this application and to demonstrate its potential to unlock heretofore uncharacterized molecular and cellular mechanisms of tumor suppression. It is my intention to start an independent research program that will capitalize on these in vivo systems by studying multiple tumor-suppressor genes in a variety of important tumor types. For the long-term, I am confident that these experiments will provide a foundation on which my research program can grow. I look forward to educating and recruiting students and postdocs that share my passion for cancer research. PUBLIC HEALTH RELEVANCE: Relatively few key tumor-suppressor pathways are mutated in a variety of human cancers. Unfortunately, we have very little understanding of the relevant tumor-suppressor programs that these genes control in each tumor type. Further, tools to interrogate these functions in vivo are lacking. My goals are to develop mouse and human cell models to interrogate tumor-suppressor gene function in established cancers, and study tumor regression programs in the hopes to better understand tumor biology and identify novel therapeutic targets.