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: 8546315
• 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/8546315
• 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; 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）：胃癌是全球男性和女性中癌症死亡的第四大最常见的恶性肿瘤，也是第二大主要原因。提出遗传和环境因素有助于胃肿瘤发生。例如，种系电子钙粘蛋白突变导致遗传性弥漫性胃癌，一种遗传性的癌症易感综合征。同时，幽门螺杆菌感染的环境获取是零星肠道胃癌的主要原因。缺乏适当的模型系统，对促成胃癌的体细胞突变的不完整研究以及对胃干细胞室在肿瘤发生中的作用的评估不足的研究，对胃癌的研究受到了阻碍。在我的初步努力中，我开发了一种强大的原发性胃外植体培养系统，该系统能够长期传播和多轮胃上皮分化，这可以进一步经历成功的致癌转化，从而代表了在Vitro环境中初级胃皮细胞中首次开发侵入性癌的发育。我在该项目中提出的项目和实验涵盖了一种旨在以1）为目标的综合和协作方法，该方法是针对1）开发一种健壮的体外胃癌模型，2）在人类胃癌中验证一种新型的致癌基因扩增（FGFR2），并评估这一发现中这种发现的普遍性 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，具体来说是E-钙粘蛋白依赖性肿瘤发生。 作为分子生物学和肿瘤学的博士学位培训的医学肿瘤学家，我对包括胃癌在内的实体瘤的分子发病机理有深深的兴趣。我建议在斯坦福大学医学院的Calvin Kuo博士实验室中进行指导的研究，以发展成为成功的独立研究人员所需的技能和能力。除了Kuo博士的科学指导外，我还将获得詹姆斯·福特（James Ford）博士的指导，并获得了具有基因组学，癌症生物学和转化研究专业知识的监督委员会的指导。我相信该项目将导致识别新的胃癌癌基因，这些胃癌癌基因将成为新型治疗剂的直接靶标，并用于应用先前发达的小分子抑制剂。我打算在Kuo博士的指导下将我的90％的努力用于实验室。我的剩余时间将用于与我的院长詹姆斯·福特（James Ford）博士一起在斯坦福癌症中心的GI肿瘤学诊所工作，除了进行教学培训，参加全国会议，准备演讲和手稿描述我的工作外，我还将继续看到胃癌患者。我的目标仍然是在医学肿瘤学部门任命为终身学术医师科学家，他从事创新的研究，能够将新颖的治疗选择带到诊所。