An Integrated Approach to the Validation of Novel Gastric Cancer Oncogenes

验证新型胃癌癌基因的综合方法

• 批准号: 8728788
• 负责人: Lincoln D. Nadauld
• 金额: $ 13.56万
• 依托单位: IHC HEALTH SERVICES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728788
• 关键词: Address; Adenoviruses; Air; Alleles; Appointment; Attention; Authorization documentation; Biological Models; Cancer Biology; Cancer Center; Cancer Etiology; Cancer Model; Cancer Patient; Cells; Cellular biology; Cessation of life; Characteristics; Chimeric Proteins; Clinic; Collaborations; Development; Diffuse; Disease; Doctor of Philosophy; E-Cadherin; Environmental Risk Factor; Epithelium; Estrogen Receptors; Evaluation; Event; FGFR2 gene; Fibroblast Growth Factor Receptors; Genes; Genetic; Genetically Engineered Mouse; Genome; Genomics; Goals; Health; Helicobacter Infections; Helicobacter pylori; Human; Human Genetics; In Vitro; Inherited; Institutional Review Boards; Intestines; Investigation; Knockout Mice; Laboratories; Lead; Liquid substance; LoxP-flanked allele; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Medical Oncologist; Medical Oncology; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Biology; Mus; Mutation; Neonatal; Oncogenes; Oncogenic; Organ; Pathogenesis; Pathology; Patients; Physicians; Predisposition; Prevalence; Primary Carcinoma; Protocols documentation; Receptor Protein-Tyrosine Kinases; Reporting; Research; Research Personnel; Retroviridae; Role; Sampling; Science; Scientist; Second Primary Neoplasms; Solid Neoplasm; Somatic Mutation; Stem cells; Stomach; Stomach Neoplasms; Syndrome; System; Tamoxifen; Time; Training; Transgenic Mice; Translational Research; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Universities; Validation; Woman; Work; genome analysis; genome sequencing; in vitro Model; in vivo; inhibitor/antagonist; innovation; insight; interest; intestinal epithelium; malignant stomach neoplasm; medical schools; meetings; men; new technology; new therapeutic target; novel; novel therapeutics; offspring; oncology; recombinase; research study; skills; small molecule; tool; tumor; tumorigenesis

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.

描述（由申请人提供）：胃癌是全球第四大常见恶性肿瘤，也是全球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有助于胃肿瘤的发生。例如，种系 E-钙粘蛋白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，环境获得幽门螺杆菌感染是散发性肠型胃癌的主要原因。由于缺乏足够的模型系统、对导致胃癌的体细胞突变的不完整研究以及对胃干细胞区室在肿瘤发生中的作用的评估不充分，胃癌的研究一直受到阻碍。在我的初步努力中，我开发了一种强大的原代胃外植体培养系统，该系统能够实现胃上皮的长期繁殖和多谱系分化，从而可以进一步成功地进行致癌转化，从而代表了首次在体外环境中从原代胃上皮发展出浸润性癌。我在该项目中提出的项目和实验包括一种综合和协作方法，旨在 1) 开发强大的体外胃癌模型，2) 验证人类胃癌中的一种新型癌基因扩增 (FGFR2) 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) 确认胃干细胞区室在胃癌发展中的作用 癌症。该项目整合了细胞生物学、人类遗传学和小鼠敲除方法，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学位培训的肿瘤内科医生，我对包括胃癌在内的实体瘤的分子发病机制有着深厚而长期的兴趣。我建议在斯坦福大学医学院 Calvin Kuo 博士的实验室进行指导性研究，以培养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·福特博士和具有基因组学、癌症生物学和转化研究专业知识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，这些基因将成为新型疗法和先前开发的小分子抑制剂应用的直接目标。我打算在郭博士的指导下，将90%的精力投入到实验室的这个项目中。剩下的时间我将与我的合作导师 James Ford 博士一起在斯坦福癌症中心的胃肠道肿瘤诊所工作，除了接受教学培训、参加全国会议以及准备描述我的工作的演示文稿和手稿外，我还将继续在那里看望胃癌患者。我的目标仍然是获得肿瘤内科的任命，担任终身教授学术医师科学家，从事能够为临床带来新颖治疗选择的创新研究。