New Models of Human Cancer

人类癌症的新模型

• 批准号: 6634112
• 负责人: WILLIAM C HAHN
• 金额: $ 15.74万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634112
• 关键词: athymic mouse; breast neoplasms; disease /disorder model; enzyme activity; lung neoplasms; metastasis; model design /development; neoplasm /cancer genetics; neoplasm /cancer invasiveness; oncogenes; prostate neoplasms; telomerase

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.

癌细胞是通过基因突变的逐步积累从正常的前体产生的。这些致癌的改变赋予了恶性细胞不受限制地生长、无视正常组织边界、获取营养供应和转移的能力。尽管对来自患者的癌细胞的研究已经阐明了肿瘤学的许多基本原理，但很难用他的方法来定义引发癌症的关键变化。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细微变化。作为博士后，我已经阐明了端粒酶活性的作用是癌症持续增长所必需的。通过控制端粒酶、致癌基因和肿瘤抑制因子，我将正常的人类细胞转化为致瘤性细胞，从而首次创造出具有明确遗传结构的人类肿瘤细胞。这些观察结果构成了本应用程序中提出的研究的基础，将端粒酶作为人类癌症新模型系统的重要组成部分。我建议创建新的基于细胞的普通上皮细胞模型，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，并从患者样本和临床结果数据中获得信息，为癌症分子分期的新方法奠定基础。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使我有机会利用罗伯特·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，并在我向独立研究者过渡的关键时刻扩大我的研究经验。