New Models of Human Cancer

癌细胞通过逐步积累基因突变从正常前体产生。 这些致癌性改变赋予恶性细胞不受限制地生长、忽略正常组织边界、募集营养供应和转移的能力。尽管对来自患者的癌细胞的研究阐明了肿瘤学的许多基本原理，但引发癌症的关键变化很难用他的方法来定义。 癌症诊断和治疗的进一步进展需要更详细和精确地了解将正常细胞转化为癌细胞的微妙变化。作为博士后研究员，我阐明了端粒酶活性的作用是癌症持续生长所必需的。 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细胞，从而首次创造出具有明确遗传结构的人类肿瘤细胞。 这些观察结果形成了本申请中提出的使用端粒酶作为人类癌症新模型系统的重要组分的研究的基础。我建议创建新的基于细胞的模型，包括乳腺癌，前列腺癌和肺癌，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，这些分子系统的信息来自患者样本和临床结果数据，从而为癌症分子分期的新方法奠定基础。 总之，这些研究将使我能够确定启动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。一个指导研究科学家发展奖将为我提供机会，以利用博士罗伯特温伯格的指导和怀特黑德研究所的独特资源，以开发这些新的系统，并扩大我的研究经验，因为我使一个独立的调查员的关键过渡。

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.