An Integrated Approach to the Validation of Novel Gastric Cancer Oncogenes

描述（由申请人提供）：胃癌是全球第四大常见恶性肿瘤，也是男性和女性癌症死亡的第二大原因。遗传和环境因素被认为是胃肿瘤发生的重要因素。例如，种系E-钙粘蛋白突变导致遗传性弥漫性胃癌，一种遗传性癌症易感综合征。同时，H.幽门螺杆菌感染是散发性胃癌的主要原因。胃癌的研究一直受到缺乏足够的模型系统，导致胃癌的体细胞突变的不完整的调查，以及胃干细胞室在肿瘤发生中的作用的评价不足的阻碍。在我的初步努力中，我已经开发了一个强大的原代胃外植体培养系统，使胃上皮的长期繁殖和多系分化，可以进一步经历成功的致癌转化，从而代表了有史以来第一次在体外环境中从原代胃上皮发展成浸润性癌。我在这个项目中提出的项目和实验包括一个综合和协作的方法，旨在1）开发一个强大的体外胃癌模型，2）验证一种新的癌基因扩增（FGFR 2）在人类胃癌和评估这一发现在散发性和家族性胃癌中的患病率，3）确认胃干细胞室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，以深入了解胃癌肿瘤发生，特别是E-钙粘蛋白依赖性肿瘤发生。 作为一名接受过分子生物学和肿瘤学博士培训的医学肿瘤学家，我对实体瘤（包括胃癌）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的卡尔文郭博士的实验室进行指导研究，以发展成为一名成功的独立研究者所需的技能和能力。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、癌症生物学和转化研究方面具有专长的监督委员会的指导。我相信这个项目将导致新的胃癌癌基因的鉴定，这些癌基因将成为新疗法的直接靶点，并用于先前开发的小分子抑制剂的应用。我打算在郭博士的指导下，在实验室里把90%的精力投入到这个项目上。我的剩余时间将与我的共同导师James福特博士一起在斯坦福大学癌症中心的GI肿瘤诊所工作，在那里我将继续看到胃癌患者，除了追求教学培训，参加国家会议和准备介绍和手稿描述我的工作。我的目标仍然是在医学肿瘤科获得任命，作为一个终身制的学术医生科学家谁追求创新的研究能够带来新的治疗方案的诊所。

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.