Case GI SPORE

总体摘要/摘要 这一案例GI孢子更新申请提供了一个尖端的专业研究计划 胃肠道恶性肿瘤的卓越表现，重点是结直肠癌和腺癌 食管。这一综合计划建立在病例综合癌症中心的资源基础上 提出4个翻译研究项目，为胃肠道癌症患者带来新的分子进展。一个 一系列3项核心资源为这些项目提供支持，并为 胃肠道癌症的基因翻译研究。我们进一步发展了一套全面的基础设施，以确定 来自整个病例的基础科学和临床研究人员的新发展研究项目 癌症中心。凭借我们在培养强调翻译的新教师方面的良好记录 对于胃肠道癌症的研究，我们还制定了一个有针对性的职业提升计划，以进一步推动 并招募到孢子学院的翻译研究干部。4个孢子翻译研究项目 构成治疗胃肠道癌症的新的前沿方法，包括：i)靶向15-前列腺素脱氢酶 结肠癌抑癌通路用于预测癌症风险和预测对化学预防的反应 阿司匹林，以及新的结肠癌预防和治疗策略的开发(项目1，Dr。 Markowitz，Li和Berger)；ii)阐明突变签名的基础和临床意义 非裔美国人结肠癌(项目2，Willis，Li和Wang博士)；iii)发展结肠癌的分子标记 和非内窥镜检测Barrett‘s食道癌和早期食管腺癌(项目3，Dr. Chak、Guda和Markowitz)；以及iv)PIK3CA突变结肠癌个体化治疗的发展 使用谷氨酰胺代谢的靶向抑制剂(项目4，Wang博士和Meropol博士)。这些项目是建造的 关于孢子的第一个资助期取得的重大进展，包括：i)在《科学》杂志上发表了15-PGDH 调节结肠隐窝干细胞；ii)在《科学转化医学》上发表个人的15-PGDH 阿司匹林的水平决定了服用阿司匹林是否会降低患结肠癌的风险；iii)发表在《美国医学会会刊》上 美国国家科学院优先针对结直肠癌体细胞突变的基因 非裔美国人；iv)出版《癌症流行病学、生物标志物和预防》封面 检测食管刷中的甲基化波形蛋白DNA可以检测到90%以上的Barrett‘s食道和 食管腺癌；v)在《自然通讯》上发表PIK3CA突变癌是 对谷氨酰胺上瘾，对谷氨酰胺代谢抑制剂敏感。这些项目的优势在于 为评估胃肠道癌症生物标记物新药而开发的特殊人群和科学资源 发现福尔马林固定的肿瘤样本的下一代测序，以及对巴雷特食道的研究。 这些调查人员的力量和他们可支配的资源将确保这一计划导致重大 重要的翻译进展。

OVERALL SUMMARY/ABSTRACT This Case GI SPORE renewal application provides for a cutting edged Specialized Program of Research Excellence in gastrointestinal malignancies with emphasis on colorectal cancers and adenocarcinoma of the esophagus. This comprehensive program builds on the resources of the Case Comprehensive Cancer Center to propose 4 translational Research Projects to bring new molecular advances to patients with GI Cancers. A series of 3 core resources support these projects and also establish a strong programmatic infrastructure for translational research in GI cancers. We have further developed a comprehensive infrastructure for identifying new Developmental Research Projects from basic science and clinical investigators from across the Case Cancer Center. Drawing on our strong track record of developing new faculty who emphasize translational research in GI cancers, we have also developed a targeted Career Enhancement Program to further advance and recruit to the translational research cadre of SPORE faculty. The 4 SPORE translational research projects constitute novel and cutting edge approaches to GI cancers and include studies of: i) Targeting the 15-PGDH colon cancer tumor suppressor pathway for prediction of cancer risk, prediction of response to chemoprevention with aspirin, and development of new colon cancer prevention and treatment strategies (Project 1, Drs. Markowitz, Li, and Berger); ii) Elucidating the basis for and the clinical significance of a mutational signature of African American colon cancer (Project 2, Drs. Willis, Li, and Wang); iii) Development of molecular markers of and non-endoscopic detection of Barrett's esophagus and early esophageal adenocarcinomas (Project 3, Drs. Chak, Guda, and Markowitz); and iv) Development of personalized treatment of PIK3CA mutant colon cancers using targeted inhibitors of glutamine metabolism (Project 4, Drs. Wang and Meropol). These projects are built on major advances from the SPORE's first funding period that include: i) publication in Science that 15-PGDH regulates colon crypt stem cells; ii) publication in Science Translational Medicine that individual's 15-PGDH levels regulate whether taking aspirin will or will not reduce their colon cancer risk; iii) publication in Proceedings of the National Academy of Sciences of genes preferentially targeted for somatic mutations in colorectal cancers of African Americans; iv) publication on the cover of Cancer Epidemiology, Biomarkers and Prevention that testing for methylated vimentin DNA in esophageal brushings could detect over 90% of Barrett's esophagus and esophageal adenocarcinomas; v) publication in Nature Communications that PIK3CA mutant cancers are addicted to glutamine and sensitive to inhibitors of glutamine metabolism. These projects are advantaged by special populations and scientific resources developed for evaluation of GI cancer biomarkers, new drug discovery, Next-Generation sequencing of formalin fixed tumor samples, and studies of Barrett's esophagus. The strength of these investigators and the resources at their disposal will insure this program leads to significant important translational advances.