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

基本信息

批准号：
10576888
负责人：
PUNITA DHAWAN
金额：
$ 54.85万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10576888
关键词：
Anoikis Applications Grants Binding Biochemical Biology Biometry Cell Line Cells Cessation of life Chemicals Chemoresistance Clinical Management Clinical Research Colon Carcinoma Colorectal Cancer Colorectal Surgery Complex Crystallography Data Diabetic Nephropathy Diagnosis Diagnostic Neoplasm Staging Disease Management Disparate Disseminated Malignant Neoplasm Distant Drug Kinetics Ephrins Epitopes Fluorouracil Genetic Genetically Engineered Mouse Goals Hepatitis C In Vitro Invaded Investigation Knowledge Laboratories Libraries Liver Lung Malignant Neoplasms Mediating Microsomes Modeling Molecular Mus Neoplasm Metastasis Nonmetastatic Oncogenic Organ Organoids Outcome Pathology Patients Pharmaceutical Chemistry Pharmacologic Substance Phenotype Play Preclinical Testing Property Protein Isoforms Proteins Proto-Oncogenes Qualifying Reporting Resistance Risk Role Sampling Scientist Signal Pathway Signal Transduction Site Specificity Testing Therapeutic Time Toxic effect analog anticancer activity cancer cell cancer therapy claudin-1 protein cohort colon cancer metastasis colon cancer patients colon cancer progression colorectal cancer metastasis colorectal cancer progression colorectal cancer treatment design efficacy evaluation gut homeostasis improved in silico in vitro Model in vivo in vivo evaluation inhibitor metastatic colorectal mortality mouse model mutant novel novel therapeutics overexpression patient derived xenograft model preclinical study receptor side effect small molecule inhibitor src-Family Kinases targeted treatment therapy development therapy resistant tool translational potential tumor tumor growth tumor xenograft v-src Oncogenes

项目摘要

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.

CRC是归因于重要器官转移的肿瘤相关死亡的第三大原因。 CRC 患者的生存高度依赖于诊断时的癌症分期，尽管最近在该疾病的临床管理方面取得的进展，它仍然是13％对于诊断为癌症转移的患者。值得注意的是，对抗癌者的抵抗力治疗对转移有很大贡献，因为约90％的转移性癌患者也是对疗法有抵抗力。因此，开发新的和有针对性的疗法来抑制CRC 进展和转移是必不可少的和紧迫的。在这方面，我们的实验室以及其他的广泛临床前和临床研究实验室，现在已经验证了上调Claudin-1表达中的因果作用促进CRC转移。在研究大型CRC患者队列的全面分析中，细胞系和小鼠模型，我们报道了失控的高度显着关联 Claudin-1用CRC转移表达。对这些发现的机械调查揭示了claudin-1与原癌基因SRC的物理结合，在促进CRC转移方面。所以远处，不存在Claudin-1的小分子抑制剂。使用严格的分析设计包括体外和体内测试，我们确定了Claudin-1特异性抑制剂。进一步的类似物是合成的，我们现在将搜索范围缩小到一个新颖而特定的小分子抑制剂PDS-0330，以有效抑制CLDN1依赖性CRC进展。这些数据已经提出了该提议的中心假设，即PDS-0330可以抑制CLDN1/SRC 抑制CRC进展和转移的关联。在此赠款建议中，我们将优化 PDS-0330类似物的效力，药代动力学特性，以开发新型工具化合物。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PDS0330在抑制claudin-的功效侵袭性CRC的小鼠和类器官模型中的1依赖性表型。