Targeting vulnerabilities in copper metabolism in the development of cancer therapies

针对癌症疗法开发中铜代谢的脆弱性

基本信息

批准号：
10461152
负责人：
MICHAEL J. PETRIS
金额：
$ 44.46万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
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：
2021-08-03 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10461152
关键词：
4T1 Address Affinity Animal Model Artificial Membranes Binding Binding Sites Biological Biological Assay Biological Availability Biological Markers Breast Cancer Model Breast Cancer Patient Cancer Model Cancer Patient Cancer cell line Cell Membrane Permeability Ceruloplasmin Chelating Agents Clinical Clinical Research Clinical Trials Computer Assisted Copper Detection Development Diet Dietary Copper Disease Progression Dose Drug Design Drug Kinetics ERBB2 gene Enzymes Evaluation Family Goals Growth Hot Spot In Vitro Intestines Lead Liver Microsomes MAP2K1 gene Malignant Neoplasms Maximum Tolerated Dose Mesothelioma Metabolic Metabolism Metastatic breast cancer Micronutrients Modeling Molecular Conformation Monitor Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Normal tissue morphology Oncogenic Oral Pathway interactions Patients Performance Permeability Pharmaceutical Preparations Pharmacodynamics Phase Phosphotransferases Pre-Clinical Model Primary Neoplasm Process Property Protein-Lysine 6-Oxidase Proteins Publishing Role Serum Structure Structure-Activity Relationship Testing Therapeutic Time Tissues Treatment Efficacy absorption analog anti-cancer base cancer cell cancer therapy cell motility chelation design experimental study functional group high risk population human model improved inhibitor innovation lead optimization lung cancer cell malignant breast neoplasm mouse model nanomolar neoplastic cell novel novel therapeutic intervention oxidation preclinical development screening small molecule small molecule inhibitor tautomer therapeutic target therapy development triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

PROJECT SUMMARY Although there have been important advances in the detection and treatment of cancer, there remains an urgent need to develop new therapeutic strategies. Copper (Cu) is an essential micronutrient that is required in higher amounts by cancer cells relative to normal tissues. Several enzymes with key roles in cancer require Cu for their activity, including lysyl oxidases and several oncogenic kinases (e.g., MEK1; ULK1). In pre-clinical models of cancer, many studies have shown that tumor growth and metastasis is suppressed by Cu chelators added to the diet. In clinical trials, Cu depletion via an oral Cu chelator was found to significantly slow disease progression in patients with mesothelioma, and significantly extend survival in breast cancer patients. While it is clear that Cu depletion is a promising anticancer strategy, there is a need to develop therapies that specifically target pathways of Cu delivery to oncogenic enzymes. In the current proposal, we pursue a highly innovative approach by targeting the Cu transporter, ATP7A. Our extensive preliminary studies validate ATP7A as a therapeutic target including: 1) Intestine-specific deletion of murine ATP7A lowers systemic copper status to levels shown to be therapeutic in cancer patients; 2) ATP7A is required to deliver copper to the family of lysyl oxidases, which have well-documented roles in metastasis; 3) Targeted deletion of ATP7A in breast and lung cancer cell lines reduces primary tumor growth and metastasis in mice; 4) Elevated ATP7A expression is significantly correlated with lower survival in cancer patients. Based on these findings, we hypothesize that a small molecule inhibitor of ATP7A will be therapeutic in cancer. Using computer-aided drug design, we have identified a hit molecule called MKV3 that binds to ATP7A with nanomolar affinity and inhibits ATP7A activity in cancer cell lines. Mice treated with MKV3 showed reduced activity of the serum Cu biomarker, ceruloplasmin, and reduced tumor growth. In this proposal, we will conduct structure guided optimization to identify MKV3 analogs with improved potency and drug like properties (Aim 1); conduct pharmacokinetic studies to identify MKV3 analogs that are suitable for pharmacodynamic studies (Aim 2); and evaluate the most favorable MKV3 analog in mouse models of breast cancer (Aim 3).

项目概要尽管在癌症的检测和治疗方面取得了重要进展，但仍然存在一些问题迫切需要开发新的治疗策略。铜 (Cu) 是人体必需的微量营养素相对于正常组织，癌细胞的含量更高。几种在癌症中起关键作用的酶需要 Cu 的活性，包括赖氨酰氧化酶和几种致癌激酶（例如 MEK1；ULK1）。在临床前在癌症模型中，许多研究表明铜螯合剂可抑制肿瘤生长和转移添加到饮食中。在临床试验中，发现通过口服铜螯合剂消除铜可以显着减缓疾病间皮瘤患者的进展，并显着延长乳腺癌患者的生存期。虽然它很明显，铜消耗是一种有前途的抗癌策略，因此需要开发能够专门针对铜传递至致癌酶的途径。在当前的提案中，我们追求高度通过针对铜转运蛋白 ATP7A 的创新方法。我们广泛的初步研究验证了 ATP7A 作为治疗靶点，包括：1) 肠道特异性小鼠 ATP7A 的缺失可将全身铜状态降低至对癌症患者具有治疗作用的水平； 2) 需要 ATP7A 将铜递送至赖氨酰氧化酶家族，赖氨酰氧化酶家族在转移; 3）乳腺癌和肺癌细胞系中ATP7A的靶向缺失可减少原发肿瘤的生长以及小鼠体内的转移； 4) ATP7A 表达升高与癌症生存率降低显着相关患者。基于这些发现，我们假设 ATP7A 的小分子抑制剂将是癌症治疗。使用计算机辅助药物设计，我们发现了一种名为 MKV3 的命中分子，以纳摩尔亲和力与 ATP7A 结合并抑制癌细胞系中的 ATP7A 活性。用 MKV3 治疗的小鼠显示血清铜生物标志物铜蓝蛋白的活性降低，并减少肿瘤生长。在这个建议，我们将进行结构引导优化，以识别具有改进效力的 MKV3 类似物，类似药物的特性（目标 1）；进行药代动力学研究以确定适合的 MKV3 类似物药效学研究（目标 2）；并评估小鼠乳腺模型中最有利的 MKV3 类似物癌症（目标 3）。