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：
10280230
负责人：
MICHAEL J. PETRIS
金额：
$ 46.74万
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/10280230
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/antagonist 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).

项目摘要尽管在癌症的检测和治疗方面取得了重要进展，但仍有迫切需要制定新的治疗策略。铜（Cu）是必需的微量营养素相对于正常组织，癌细胞的量较高。几种在癌症中具有关键作用的酶需要 Cu的活性，包括赖氨酸氧化酶和几种致癌激酶（例如MEK1； ULK1）。在临床前癌症模型，许多研究表明，肿瘤的生长和转移受到Cu螯合剂的抑制加入饮食。在临床试验中，发现通过口服Cu螯合剂耗尽的铜耗尽显着缓慢疾病间皮瘤患者的进展，并显着延长乳腺癌患者的存活率。同时很明显，铜耗尽是一种有希望的抗癌策略，有必要开发疗法特异性靶向CU递送到致癌酶的途径。在当前的建议中，我们追求一个高度通过靶向CU转运蛋白ATP7A来创新方法。我们广泛的初步研究将ATP7A验证为治疗靶点，包括：1）特定于肠少女ATP7A的缺失将系统性铜状态降低至癌症患者的治疗水平； 2）需要ATP7A将铜传递给赖氨酸氧化酶的家族，这些酶在转移; 3）针对乳腺癌和肺癌细胞系中ATP7A的靶向删除可降低原发性肿瘤的生长和小鼠转移； 4）ATP7A表达升高与癌症的生存率较低显着相关患者。根据这些发现，我们假设一个小分子抑制剂ATP7A将是癌症治疗。使用计算机辅助的药物设计，我们已经确定了一个名为MKV3的热门分子与纳摩尔亲和力与ATP7A结合，并抑制癌细胞系中的ATP7A活性。用MKV3处理的小鼠表明血清CU生物标志物，ceruloplasmin和肿瘤生长降低的活性降低。在这个提案，我们将进行指导优化的结构，以确定效力提高的MKV3类似物像属性一样的药物（AIM 1）；进行药代动力学研究以识别适合的MKV3类似物药效研究（AIM 2）；并评估乳房小鼠模型中最有利的MKV3类似物癌症（目标3）。