Integrated approach to study early and late events in colonic neoplasia: mouse to man

研究结肠肿瘤早期和晚期事件的综合方法：小鼠到人

• 批准号: 9904129
• 负责人: Robert J. Coffey
• 金额: $ 94.41万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904129
• 关键词: Address; Alleles; Antibodies; Apple; Cancer Center; Cancer Etiology; Cells; Cessation of life; Cetuximab; Clinical; Code; Colonic Adenoma; Colonoscopy; Colorectal Cancer; Diagnosis; Drug resistance; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Event; Goals; Human; Individual; KRAS2 gene; Ligands; Link; Malignant Neoplasms; Membrane; Modeling; Monitor; Mus; Neoplasms; Pathogenesis; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; RNA; Reporter; Resistance; Resolution; Resources; Role; Signal Transduction; Solid Neoplasm; Specialized Program of Research Excellence; System; Testing; Tumor Suppressor Proteins; Universities; Up-Regulation; WNT Signaling Pathway; Woman; Work; adenoma; anticancer research; base; cancer diagnosis; clinical implementation; exosome; imaging probe; man; men; mutant; neutralizing antibody; neutralizing monoclonal antibodies; novel; resistance mechanism; stem cells; therapeutic target; three dimensional cell culture; tool; tumor; tumor heterogeneity

The EGFR contributes to the pathogenesis of many human cancers, including colorectal cancer (CRC), which is the third most commonly diagnosed cancer and the third leading cause of cancer deaths in the US for both men and women. The EGFR has become a major therapeutic target in many cancers. The EGFR neutralizing monoclonal antibody, cetuximab, is approved for the treatment of advanced CRCs that contain wild-type KRAS; however, only 15% of individuals with wild-type KRAS CRC respond to cetuximab, and individuals with mutant KRAS CRC do not respond to cetuximab. The challenge in cancer research I propose to address is: why has EGFR blockade in CRC (and other solid tumors) had such modest clinical benefit. I propose that the inability to more effectively block the EGFR in CRC is due, at least in part, to three issues: 1) an incomplete understanding of the complexity of EGFR signaling triggered by its seven mammalian ligands; 2) inadequate predictive preclinical models and 3) the emergence of drug resistance. By addressing each of these three issues, the overall goal of this revised application is to significantly advance the diagnosis, treatment and monitoring of individuals with CRC. Our focus is CRC, viewed from the perspective of membrane-proximal EGFR-related events. We anticipate that advances we make will be applicable to other solid tumors in which EGFR signaling plays a prominent role. Based on our recent finding that the Egfr inhibitor, Lrig1, marks a distinct population of colonic stem cells and acts as a tumor suppressor, along with the use of unique reporter mice (Lrig1-Apple, Egfr-EmGFP), we propose to link key events in colonic neoplasia to stem cells and Egfr- related events. Our lab has developed a robust model of colonic neoplasia: within 50 days of inducing loss of one Apc allele in Lrig1-expressing colonic stem cells, multiple, highly dysplastic colonic adenomas arise that can be monitored by colonoscopy and novel PET imaging probes. These mice will be treated with the first available mouse Egfr neutralizing antibody. Findings in mouse adenomas will be related to human adenomas. Using MulltiOmyx and DISSECT, we will examine the tumor landscape at single cell resolution and deconstruct tumor heterogeneity. Using a newly developed 3D culture system, we have discovered a novel mode of cetuximab resistance via increased WNT signaling due to marked upregulation of a long con-coding RNA not previously linked to CRC. We will further elucidate the mechanism of this resistance and advance these findings clinically. We will further examine a new mode of signaling by EGFR and its ligands via exosomes and test whether EGFR-containing exosomes act as a decoy to reduce the amount of EGFR antibody delivered to tumors. We will harness the tools and resources at Vanderbilt University, Vanderbilt-Ingram Cancer Center and Vanderbilt's GI Specialized Programs of Research Excellence (SPORE) to advance this work.

EGFR 参与许多人类癌症的发病机制，包括结直肠癌 (CRC)， 是美国第三大最常诊断的癌症，也是美国癌症死亡的第三大原因 男女。 EGFR已成为许多癌症的主要治疗靶点。 EGFR 中和 单克隆抗体西妥昔单抗被批准用于治疗含有野生型的晚期结直肠癌 克拉斯；然而，只有 15% 的野生型 KRAS CRC 患者对西妥昔单抗有反应，而患有野生型 KRAS CRC 的患者对西妥昔单抗有反应。 突变型 KRAS CRC 对西妥昔单抗没有反应。我建议解决的癌症研究挑战是： 为什么 EGFR 阻断在 CRC（和其他实体瘤）中的临床获益如此有限？我建议 无法更有效地阻断 CRC 中的 EGFR，至少部分是由于以下三个问题：1）不完整 了解由七种哺乳动物配体触发的 EGFR 信号传导的复杂性； 2) 不足 预测临床前模型和3）耐药性的出现。通过解决这三个问题中的每一个 问题，此修订后的应用程序的总体目标是显着推进诊断、治疗和 监测 CRC 患者。我们关注的是CRC，从近膜角度看 EGFR 相关事件。我们预计我们取得的进展将适用于其他实体瘤，其中 EGFR 信号传导发挥着重要作用。根据我们最近的发现，Egfr 抑制剂 Lrig1 标志着 独特的结肠干细胞群，并作为肿瘤抑制因子，并使用独特的报告基因 小鼠（Lrig1-Apple、Egfr-EmGFP），我们建议将结肠肿瘤中的关键事件与干细胞和 Egfr- 相关事件。我们的实验室开发了一个强大的结肠肿瘤模型：在诱导损失后 50 天内 表达 Lrig1 的结肠干细胞中存在一个 Apc 等位基因，就会出现多发性高度发育不良的结肠腺瘤 可以通过结肠镜检查和新型 PET 成像探头进行监测。这些小鼠将接受第一次治疗 可用小鼠 Egfr 中和抗体。小鼠腺瘤的发现将与人类腺瘤相关。 使用 MultiOmyx 和 DISSECT，我们将以单细胞分辨率检查肿瘤景观并解构 肿瘤异质性。利用新开发的3D文化系统，我们发现了一种新的模式 由于长共编码 RNA 的显着上调，WNT 信号传导增加导致西妥昔单抗耐药 之前与 CRC 相关联。我们将进一步阐明这种抵抗的机制并推进这些研究 临床发现。我们将进一步研究 EGFR 及其配体通过外泌体和 测试含有 EGFR 的外泌体是否充当诱饵，以减少递送至体内的 EGFR 抗体的量 肿瘤。我们将利用范德比尔特大学、范德比尔特-英格拉姆癌症中心和 范德比尔特大学的 GI 卓越研究专业计划 (SPORE) 旨在推进这项工作。