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.

尽管在结直肠癌(CRC)治疗和早期发现方面取得了进展，但结直肠癌的负担 非洲裔美国人(AA)的比例仍然很高。在所有的结直肠癌中，AAS的发病率最高 美国的种族团体。与高加索美国人(CA)相比，高加索美国人约有25% 更高的结直肠癌发病率和约50%的结直肠癌死亡率。此外，早期的CRC发病相对来说 在AAS和高级别CRC患者中很常见，术后5年的总生存率 AAS的手术费用比CA低三倍。最近的研究表明，基因突变 APC和β-连环蛋白与AAS的高发有关。然而，这些机制 儿童权利公约中的种族差异背后的攻击性很少被理解。 我们和其他人已经证明，claudin-1在结直肠癌中的表达经常是失调的。 此外，APC/Wnt/β-Catenin通路的改变(已知会促进结直肠癌) 与结直肠癌中claudin-1水平升高有关。我们的初步数据表明，AA 大肠癌患者Claudin-1的表达高于CA患者和结肠癌患者 Claudin-1的表达具有更多的肿瘤干细胞(CSCs)，有助于肿瘤的发生 攻击性和故态复萌。此外，最近的研究表明，CSCs，特别是 CD44+CD166CRC细胞可能是AAS−发生率高于CA的原因之一。这个 本附录的目的是评估claudin-1在结直肠癌中的种族差异中的作用。 攻击性，并形成与其分子决定因素相关的蛋白质特征。 我们还计划测试一种新的claudin-1抑制剂在攻击性患者中的疗效。 来自AA侵袭性结直肠癌患者的异种移植(PDX)。它的发展和表征 这种新型的claudin-1抑制剂得到了NCI父母资助(R01CA250383)的支持。整体而言 这个联合项目的目标是改善对侵袭性结直肠癌的预测和治疗。 AA通过靶向claudin-1。我们的假设是claudin-1在攻击性 再生障碍性贫血患者结直肠癌的特点Claudin-1相关的签名和抑制剂将是无价的 用于识别AA患者侵袭性CRC和降低CRC死亡率的工具。创新在于 在这项研究的新颖概念和“最先进”和尖端技术的使用中， 包括HyperionTM成像系统和PDX型号。具体目标1.确定分子 再生障碍性贫血与尖锐湿疣患者中Claudin-1调控的CRC决定因素的比较具体目标2. 确定Claudin-1抑制对AA和CA结直肠癌患者PDX的影响。这个 该项目的成功完成将产生与claudin-1相关的分子签名 预测AA患者的侵袭性疾病和针对CRC的claudin-1靶向治疗。