Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer

CLDN1抑制对结肠癌化疗耐药和转移的影响

• 批准号: 10767698
• 负责人: PUNITA DHAWAN
• 金额: $ 23.84万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-12 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10767698
• 关键词: ALCAM gene; African American population; Biopsy; CD44 gene; Cells; Characteristics; Chemicals; Chemoresistance; Clinical; Colon; Colonic Neoplasms; Colorectal Cancer; Cytometry; Data; Development; Disease; Early Diagnosis; Ephrins; Epithelium; Funding; Future; Gene Silencing; Genetic; Goals; Growth; Incidence; Joints; LGR5 gene; Malignant Neoplasms; Mediating; Molecular; Molecular Profiling; Mutation; Neoplasm Metastasis; Nonmetastatic; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Proteins; Proto-Oncogenes; Relapse; Resistance; Role; Signal Pathway; System; Technology; Testing; Time; Tissues; United States; Western Blotting; Xenograft procedure; adenoma; aldehyde dehydrogenase 1; beta catenin; biomarker signature; cancer cell; cancer stem cell; cancer therapy; caucasian American; claudin-1 protein; clinical decision-making; clinical practice; colon cancer metastasis; colon cancer patients; colorectal cancer metastasis; colorectal cancer progression; colorectal cancer treatment; early onset colorectal cancer; effective therapy; efficacy testing; imaging system; improved; inhibitor; innovation; mortality; mouse model; multimodality; multiplexed imaging; novel; overexpression; parent grant; patient derived xenograft model; personalized decision; pre-clinical; racial difference; racial disparity; racial population; receptor; risk prediction; src-Family Kinases; stem cell biomarkers; targeted treatment; tool; treatment strategy; tumor; tumor growth

Despite advances in colorectal cancer (CRC) treatment and early detection, the burden of CRC on African Americans (AAs) remains high. AAs have the highest incidence of CRC among all racial groups in the United States. Compared with Caucasian Americans (CAs), AAs show ~25% higher CRC incidence and ~50% higher CRC mortality. Furthermore, early CRC onset is relatively common in AAs, and among patients with high-grade CRC, the 5-year overall survival after surgery is three times lower in AAs than in CAs. Recent studies have shown that mutations in APC and β-catenin are associated with the high incidence in AAs. Nevertheless, the mechanisms underlying the racial differences in CRC aggressiveness are poorly understood. We and others have demonstrated that claudin-1 expression is frequently dysregulated in CRC. Additionally, alterations in the APC/Wnt/β-catenin pathway (which are known to promote CRC) are correlated with increased claudin-1 levels in CRC. Our preliminary data demonstrate that AA patients with CRC have higher claudin-1 expression than CA patients and colon tumors with high claudin-1 expression have higher numbers of cancer stem cells (CSCs), contributing to tumor aggressiveness and relapse. Moreover, recent studies have shown that CSCs, specifically CD44+CD166− cells, may contribute to the higher incidence of CRC in AAs than in CAs. The purpose of this supplement is to evaluate the role of claudin-1 in racial disparities in CRC aggressiveness and to develop a protein signature in correlation with its molecular determinants. We also plan to test the efficacy of a novel claudin-1 inhibitor in aggressive patient-derived xenografts (PDXs) from AA patients with aggressive CRC. The development and characterization of this novel claudin-1 inhibitor are supported by an NCI parent grant (R01CA250383). The overall goal of this joint project is to improve the prediction and treatment of aggressive CRC tumors in AA by targeting claudin-1. Our hypothesis is that claudin-1 plays a key role in the aggressive features of CRC in AA patients. A claudin-1-associated signature and inhibitor will be invaluable tools for identifying aggressive CRCs and reducing CRC mortality in AA patients. Innovation lies in the novel concept of this study and the use of “state-of-the-art” and cutting-edge technologies, including HyperionTM Imaging System and PDX models. Specific Aim 1. Identify the molecular determinants of CRC modulated by claudin-1 in AA relative to that in CA patients. Specific Aim 2. Determine the effects of claudin-1 inhibition on PDXs from AA and CA patients with CRC. The successful completion of this project will yield a claudin-1-associated molecular signature to predict aggressive disease and a claudin-1-targeted therapy for CRC for AA patients.

尽管结直肠癌（CRC）治疗和早期检测进展，CRC的燃烧 关于非裔美国人（AAS）仍然很高。 AA在所有人中的CRC事件最高 美国种族群体。与白种人（CAS）相比，AAS显示约25％ CRC事件较高，CRC死亡率高约50％。此外，早期CRC发作相对 在AAS和高级CRC的患者中，常见于5年之后的总生存期 AAS的手术比CAS低三倍。最近的研究表明， APC和β-catenin与AAS中的高入射有关。然而，这些机制 CRC侵略性的种族差异的根本理解很少。 我们和其他人已经证明，在CRC中，Claudin-1表达经常失调。 另外，APC/Wnt/β-catenin途径的改变（已知可以促进CRC） 与CRC中的Claudin-1水平升高相关。我们的初步数据表明AA CRC患者的Claudin-1表达高于CA患者和较高的CA患者和结肠肿瘤 Claudin-1表达具有较高的癌症干细胞（CSC），导致肿瘤 侵略性和解脱。此外，最近的研究表明，CSC，特别是 CD44+CD166-细胞可能会导致AAS中CRC的高入射，而不是CAS中的CAS。这 该补充的目的是评估Claudin-1在CRC中种族分布中的作用 侵略性并发展与其分子确定剂相关的蛋白质特征。 我们还计划测试新型Claudin-1抑制剂在侵略性患者衍生中的效率 来自AA侵袭性CRC患者的异种移植物（PDX）。发展和特征 NCI父母赠款（R01CA250383）支持了这种新颖的Claudin-1抑制剂。总体 该联合项目的目标是改善对侵略性CRC肿瘤的预测和治疗 通过靶向claudin-1。我们的假设是Claudin-1在侵略性中起关键作用 AA患者CRC的功能。 Claudin-1相关的签名和抑制剂将是无价的 识别AA患者的CRC和CRC死亡率的工具。创新是谎言 在这项研究的新颖概念以及“最先进”和尖端技术的使用中 包括Hyperiontm成像系统和PDX模型。特定目标1。识别分子 CLADIN-1在AA中调节的CRC的决定因素相对于CA患者。具体目标2。 确定Claudin-1抑制对CRC和CA患者PDX的影响。这 该项目的成功完成将产生与Claudin-1相关的分子签名 预测针对AA患者的CRC的侵略性疾病和CLADIN-1靶向疗法。