Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer

CRC是由重要器官转移引起的肿瘤相关死亡的第三大原因。CRC 患者的存活率高度依赖于诊断时的癌症分期， 尽管近年来在临床治疗方面取得了一些进展，但其发病率仍仅为13%。 癌症转移的病人。值得注意的是， 治疗对转移有很大贡献，因为约90%的转移性癌症患者也 对治疗有抵抗力因此，开发用于抑制CRC的新的靶向疗法， 进展和转移是必要和紧迫的。 在这方面，我们实验室的广泛临床前和临床研究，以及其他 实验室，现在已经证实了上调的claudin-1表达的因果作用， 促进CRC转移。在一项检查大型CRC患者队列的综合分析中， 细胞系和小鼠模型，我们已经报道了一个高度显着的关联， claudin-1表达与结直肠癌转移的关系对这些发现的机制研究 揭示了claudin-1与原癌基因Src的物理结合，促进CRC转移。所以 目前还不存在已知的封闭蛋白-1的小分子抑制剂。采用严格的分析设计， 包括体外和体内试验，我们鉴定了一种claudin-1特异性抑制剂。进一步的类似物是 合成，我们现在已经缩小了我们的搜索到一个新的和特定的小分子 抑制剂PDS-0330，用于有效抑制CLDN 1依赖性CRC进展。这些数据 已经导致了该提议的中心假设，即PDS-0330可以抑制CLDN 1/Src 联合抑制CRC进展和转移。在本拨款建议中，我们将优化 PDS-0330类似物的效力、药代动力学性质，以开发新的工具化合物。我们 还将确定结合特异性并表征PDS-0330的结合表位以抑制 结肠癌进展。最后，我们将确定PDS 0330在抑制Claudin-1中的功效。 1-小鼠和侵袭性CRC类器官模型中的依赖表型。

CRC is the third leading cause of tumor-related deaths attributed to vital organ metastasis. CRC patient survival is highly dependent on the cancer staging at the time of diagnosis and, despite the recent progresses made in the clinical management of this disease, it remains a meagre 13% for the patients diagnosed with cancer metastasis. Remarkably, resistance to the anti-cancer therapy contributes heavily to the metastasis as ~90% of patients with metastatic cancer are also resistant to the therapies. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is essential and urgent. In this regard, extensive preclinical and clinical studies from our laboratory, and of other laboratories, have now validated a causal role for the upregulated claudin-1 expression in promoting CRC metastasis. In a comprehensive analysis examining a large CRC-patient cohort, cell lines and mouse models, we have reported a highly significant association of the deregulated claudin-1 expression with CRC metastasis. Mechanistic investigations into these findings revealed physical binding of claudin-1 with proto-oncogene Src, in promoting CRC metastasis. So far, no known small molecule inhibitor for claudin-1 exists. Using a rigorous analytical design that included in vitro and in vivo testing, we identified a claudin-1 specific inhibitor. Further analogs were synthesized, we now have narrowed down our search to a novel and specific small molecule inhibitor, PDS-0330, for efficient inhibition of the CLDN1 dependent CRC progression. These data have led to the central hypothesis of this proposal that PDS-0330 can inhibit CLDN1/Src association to inhibit CRC progression and metastasis. In this grant proposal, we will optimize the potency, pharmacokinetic properties of PDS-0330 analogs to develop novel tool compounds. We will also determine binding specificity and characterize the binding epitope of PDS-0330 to inhibit colon cancer progression. Finally, we will determine the efficacy of PDS0330 in inhibiting Claudin- 1-dependent phenotypes in mouse and organoid model of aggressive CRC.