New Models of Human Cancer

癌细胞是由正常的前体细胞通过逐步积累的基因突变形成的。这些致癌改变赋予了恶性细胞不受限制地生长、忽略正常组织边界、补充营养物质和转移的能力。尽管对来自患者的癌细胞的研究阐明了许多肿瘤学的基本原理，但用他的方法很难定义引发癌症的关键变化。癌症诊断和治疗的更多进展需要对将正常细胞转化为癌细胞的细微变化有更详细和更准确的了解。作为一名博士后，我已经阐明了端粒酶活性在癌症持续生长中所起的作用。通过操纵端粒酶、癌基因和肿瘤抑制因子，我已经将正常的人类细胞转化为致瘤性，从而首次创造出具有明确基因构成的人类肿瘤细胞。这些观察结果为本申请中提出的将端粒酶用作人类癌症新模型系统的重要组成部分的研究奠定了基础。我建议创建包括乳腺癌、前列腺癌和肺癌在内的常见上皮细胞的新的基于细胞的模型，并使用这些模型系统来定义将正常细胞转化为癌症的关键途径。我将使用这些模型系统来研究分子系统，研究来自患者样本和临床结果数据的信息，以产生一种新的癌症分子分期方法的基础。综上所述，这些研究将使我能够确定引发癌症的关键细胞内途径，并验证开发新的抗肿瘤药物的分子靶点。导师研究科学家发展奖将为我提供机会，利用罗伯特·温伯格博士的指导和怀特黑德研究所的独特资源来开发这些新系统，并在我向独立研究人员的关键转变过程中扩大我的研究经验。

The cancer cell arises from normal precursors through a step-wise accumulation of genetic mutations. These oncogenic alterations endow malignant cells with the ability to grow without restraint, to ignore normal tissue boundaries, to recruit a supply of nutrients, and to metastaize. Although the study of cancer cells derived from patients has elucidated many fundamental principles of oncology, the critical changes that initiate cancer have been difficult to define with his approach. Additional progress in the diagnosis and treatment of cancer requires a more detailed and precise understanding of the subtle alterations that transform normal cells into cancer cells. As a postdoctoral fellow I have elucidated the role of telomerase activity is required for the continued growth of cancer. Manipulating telomerase, oncogenes, and tumor suppressors, I have converted normal human cells to tumorigenicity, thereby creating human tumor cells with a defined genetic constitution for the first time. These observations form the foundation for the studies presented in this application to use telomerase as an important component of new model systems of human cancer. I propose to create new cell-based models of the common epithelial including breast, prostate, and lung cancer and to use these model systems to define the critical pathways that convert normal cells into cancer. I will use these model systems to study the molecular systems with information derived from patient samples and clinical outcome data to generate the foundations of a new approach to the molecular staging of cancer. Taken together, these studies will permit me to identify the crucial intracellular pathways that initiate cancer and to validate molecular targets to which to develop new anti-neoplastic agents. A Mentored Research Scientist Development Award will provide me the opportunity to take advantage of the mentorship of Dr. Robert Weinberg and the unique resources of the Whitehead Institute to develop these new systems and to broaden my research experiences as I make the crucial transition to an independent investigator.