Establishing therapeutic efficacy and uncovering mechanisms of tumor suppression

描述（由申请人提供）：我的研究重点是阐明抑制恶性肿瘤的细胞和分子机制。已知细胞具有由少数关键肿瘤抑制基因协调的内在和外在肿瘤抑制机制。然而，在已建立的肿瘤中不能随意恢复肿瘤抑制功能阻碍了我们对其功能的理解。K99/R 00奖项中提出的项目概述了新型小鼠模型的创建和实施，这些模型允许以组织特异性和时间方式控制基因失活和基因恢复。 本申请中提出的研究已经形成了我的经验，研究端粒功能障碍的后果，在伯基特淋巴瘤模型和我最近的努力，以阐明在体内恢复p53肿瘤抑制基因在几个模型中的不同的人类癌症的影响。这些研究项目巩固了我对研究人类癌症进展的基本组成部分的兴趣。我想探究肿瘤抑制的生物学原理，这需要开发一种新的遗传系统，在这种系统中，肿瘤抑制基因的功能可以被灭活，然后随后恢复。我们在本文中提出的系统利用本地小鼠模型和遗传定义的人类癌细胞。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生物体来促进肿瘤抑制的基本机制的发现。麻省理工学院科赫研究所的设施，以及我的导师杰克斯博士的专业知识，对这个项目的成功实施将是无价的。 其中概述的这些实验的目标是：突出靶向这些肿瘤抑制途径作为根除癌症的手段的治疗潜力，鉴定肿瘤抑制基因在各种肿瘤类型中抑制癌症形成或进展的相关机制，揭示肿瘤抑制基因恢复后释放的生物学程序，以及 以确定治疗干预的特定新靶点。 在杰克实验室，麻省理工学院和周边地区的研究环境提供了科学讨论，合作和培训无与伦比的机会。目前，我监督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有关的实验。这是一个令人难以置信的经验，将赋予我许多必要的技能来管理一个独立的实验室。麻省理工学院、布罗德研究所和哈佛医学院的科学界提供了无数的研讨会和讲习班，这些研讨会和讲习班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，并展示其解锁迄今为止未表征的肿瘤抑制分子和细胞机制的潜力。我打算启动一个独立的研究项目，通过研究多种重要肿瘤类型中的多种肿瘤抑制基因，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提供一个发展的基础。我期待着教育和招募学生和博士后分享我对癌症研究的热情。 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途径发生突变。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，缺乏在体内询问这些功能的工具。我的目标是开发小鼠和人类细胞模型，以询问肿瘤抑制基因在已建立的癌症中的功能，并研究肿瘤消退计划，希望更好地了解肿瘤生物学并确定新的治疗靶点。

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.