An Integrated Approach to the Validation of Novel Gastric Cancer Oncogenes

描述(申请人提供)：胃癌是全球第四大常见恶性肿瘤，也是导致男性和女性癌症死亡的第二大原因。遗传因素和环境因素都被认为与胃肿瘤的发生有关。例如，胚系E-钙粘附素突变会导致遗传性弥漫性胃癌，这是一种遗传性癌症易感综合征。同时，环境获得性幽门螺杆菌感染是散发性肠型胃癌的主要原因。由于缺乏适当的模型系统，对导致胃癌的体细胞突变的研究不完整，以及对胃干细胞在肿瘤发生中的作用评估不足，胃癌的研究一直受到阻碍。在我的初步工作中，我已经建立了一个强大的原代胃外植体培养系统，该系统能够使胃上皮细胞长期繁殖和多谱系分化，并进一步经历成功的致癌转化，从而代表了在体外环境下首次从原代胃上皮发展为浸润性癌。我在这个项目中提出的项目和实验包括一种整合和协作的方法，旨在1)建立一个强大的体外胃癌模型，2)验证一种新的癌基因扩增(FGFR2)在人类胃癌中的表达，并评估这一发现在散发性和家族性胃癌中的患病率，以及3)确认胃干细胞在胃癌发展中的作用。该项目整合了细胞生物学、人类遗传学和小鼠基因敲除方法，以深入了解胃癌的发生，特别是E-钙粘附素依赖的肿瘤发生。 作为一名拥有分子生物学和肿瘤学博士学位的内科肿瘤学家，我对包括胃癌在内的实体肿瘤的分子发病机制有着深刻而长期的兴趣。我建议在斯坦福大学医学院郭加文博士的实验室进行有指导的研究，以培养成为一名成功的独立研究员所需的技能和能力。除了郭博士的科学指导外，我还将接受詹姆斯·福特博士和一个在基因组学、癌症生物学和翻译研究方面拥有专业知识的监督委员会的指导。我相信这个项目将导致识别新的胃癌癌基因，这些基因将成为新的治疗方法和先前开发的小分子抑制剂应用的直接靶点。我打算在郭博士的指导下，将我90%的精力投入到这个实验室的项目中。我剩下的时间将在斯坦福癌症中心的胃肠肿瘤诊所与我的共同导师詹姆斯·福特博士一起工作，在那里，我将继续看望胃癌患者，此外，我还将继续接受教学培训，参加全国会议，并准备介绍我工作的演示文稿和手稿。我的目标仍然是在医学肿瘤科获得一个职位，成为一名终身教职的学术内科科学家，从事能够为临床带来新的治疗选择的创新研究。

DESCRIPTION (provided by applicant): Gastric cancer is the fourth most common malignancy and the second leading cause of cancer death amongst men and women worldwide. Both genetic and environmental factors are proposed to contribute to gastric tumorigenesis. For example, germline E-cadherin mutations result in Hereditary Diffuse Gastric Cancer, an inherited cancer predisposition syndrome. Meanwhile, environmental acquisition of H. pylori infection is a major cause of sporadic intestinal-type gastric cancer. The study of gastric cancer has been hampered by the lack of adequate model systems, an incomplete investigation of the somatic mutations that contribute to gastric cancer, and an insufficient evaluation of the gastric stem cell compartment's role in tumorigenesis. In my preliminary efforts I have developed a robust primary gastric explant culture system that enables the long-term propagation and multi-lineage differentiation of gastric epithelium that can further undergo successful oncogenic transformation, thus representing the first-ever development of invasive carcinoma from primary gastric epithelium in the in vitro setting. The project and experiments I propose in this project encompass an integrated and collaborative approach aimed at 1) developing a robust in vitro gastric cancer model, 2) validating a novel oncogene amplification (FGFR2) in human gastric cancer and assessing the prevalence of this finding in sporadic and familial gastric cancers, and 3) confirming the roles of the gastric stem cell compartment in the development of gastric cancer. This project integrates cell biology, human genetics and mouse knockout approaches to gain insight into gastric cancer tumorigenesis and specifically, E-cadherin-dependent tumorigenesis. As a Medical Oncologist with PhD training in molecular biology and oncological science, I have a deep and long-standing interest in the molecular pathogenesis of solid tumors including gastric cancer. I propose to pursue mentored research in the laboratory of Dr. Calvin Kuo at the Stanford University Medical School in order to develop the required skills and ability to become a successful, independent investigator. In addition to scientific mentoring by Dr. Kuo, I will receive guidance by Dr. James Ford and a supervisory committee with expertise in genomics, cancer biology and translational research. I believe this project will lead to the identification o new gastric cancer oncogenes that will become immediate targets for novel therapeutics and for application of previously-developed small molecule inhibitors. I intend to devote 90% of my effort to this project in the laboratory under the mentorship of Dr. Kuo. The remainder of my time will be spent working with Dr. James Ford, my co-mentor, in the GI Oncology Clinic at the Stanford Cancer Center where I will continue to see gastric cancer patients in addition to pursuing didactic training, attending national meetings and preparing presentations and manuscripts describing my work. My goal remains to obtain an appointment in a Division of Medical Oncology as a tenure-track academic physician scientist who pursues innovative research capable of bringing novel therapeutic options to the clinic.