Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer

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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.