Novel Targeted Therapeutics for Breast Cancer

乳腺癌新型靶向治疗

基本信息

批准号：
10207553
负责人：
Bulent Ozpolat
金额：
$ 37.06万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207553
关键词：
Animal Model Binding Biological Assay Breast Cancer Cell Breast Cancer Model Breast Cancer Patient CCL2 gene Cancer Cell Growth Cell Proliferation Cells Chemicals Clinic Clinical Trials Collaborations Computer Models Crystallization Cyclin D1 Databases Development Docking Dose Drug Kinetics Drug or chemical Tissue Distribution EEF2 gene ERBB2 gene Epidermal Growth Factor Estrogen Antagonists Estrogens Evaluation FDA approved FOXM1 gene Family Foundations Future Generations Genes Genetic Goals Half-Life Heterogeneity Homology Modeling Hormones Hydrophobicity In Vitro Kinetics Knockout Mice Lead Light Lipids Mammary Neoplasms Methods Modeling Molecular Molecular Profiling Molecular Target Mus Mutate Nature Neoplasm Metastasis Oncogenic PTK2 gene Patients Pharmacodynamics Pharmacology Phenotype Phosphotransferases Pre-Clinical Model Primary Neoplasm Progesterone Prognosis Prognostic Marker Protein Kinase RNA Interference Relapse Research Personnel Resistance Schedule Signal Pathway Signal Transduction Small Interfering RNA Structure Subgroup Survival Rate System TP53 gene Tamoxifen Technology Testing Therapeutic Toxic effect Translating Translations Treatment Efficacy Treatment Failure Tumor Suppression Tumor-associated macrophages Vascular Endothelial Growth Factors advanced disease aptamer base c-myc Genes calmodulin-dependent protein kinase III cancer subtypes chemotherapy clinically relevant clinically significant design effective therapy improved in silico in vivo inhibitor/antagonist kinase inhibitor lung metastatic malignant breast neoplasm member mortality nanomolar nanoparticle nanoparticle delivery new therapeutic target novel overexpression patient derived xenograft model potential biomarker pre-clinical preclinical evaluation preclinical safety preclinical study prevent receptor response screening small molecule small molecule inhibitor targeted delivery targeted treatment therapeutic target therapeutically effective transcription factor triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

Project Summary Triple negative breast cancer (TNBC) has the worst prognosis and survival in all breast cancer subtypes with currently available standard therapies, representing an unmet therapeutic challenge. Significant heterogeneity (with six genetically defined subgroups) and a lack of FDA-approved targeted therapeutics and are the major reasons contributing to poor prognosis and high mortality rates and have prevented identification of common molecular targets and development of targeted therapeutics. To meet this challenge, we extensively analyzed breast cancer patient databases and discovered that expression of Eukaryotic Elongation Factor 2-Kinase (EF2K) gene encoding an unusual alpha kinase has a dramatic effect on survival rates of TNBC patients. Remarkably, TNBC patients with low EF2K expression had no mortality up to 10 years. More importantly, we found that EF2K is highly overexpressed in the majority of TNBC patients and showed that it is an important driver for TNBC tumorigenesis, invasion and progression; and validated it as a potential molecular target using genetic silencing technology in multiple preclinical animal models. Based on our preliminary studies, we hypothesize that EF2K represents an Achilles’ heel for targeting TNBC and if effectively targeted, it will have a tremendous impact on patient survival. Considering that EF2K knock-out mice are healthy and have no signs of toxicity, EF2K-targeted therapies are expected to be safe. However, currently there is no specific or potent inhibitors for targeting EF2K. Thus, in collaboration with a team of investigators, including medicinal chemists and computational chemists, we recently synthesized a serious of potential small molecule inhibitors of EF2K based on computational modeling and identified a lead compound that significantly inhibits EF2K activity. Based on the lead compound, we further designed and synthesized more than a hundred of second generation of novel compounds and identified a more potent inhibitor that is effective in inhibiting EF2K at with nanomolar concentrations and demonstrated remarkable in vivo efficacy in TNBC tumors when formulated in long-acting single-lipid based nanoparticles, with no observed toxic effects. In this proposed project, we will characterize and optimize the EF2K-inhibitor based therapy using clinically relevant TNBC models with the goal of developing highly specific strategies for TNBC. Our long-term goal is to develop safe, highly effective therapies and translate them to the clinic for TNBC patients, who lack targeted treatment options.

项目概要在所有乳腺癌亚型中，三阴性乳腺癌 (TNBC) 的预后和生存率最差目前可用的标准疗法，代表着未满足的治疗挑战。（有六个基因定义的亚组）和缺乏 FDA 批准的靶向治疗药物是主要的导致不良预后和高死亡率的原因，并阻碍了常见常见疾病的识别为了应对这一挑战，我们广泛分析了分子靶点和靶向治疗的发展。乳腺癌患者数据库，发现真核延伸因子 2-激酶的表达 (EF2K) 基因编码一种不寻常的 α 激酶，对 TNBC 患者的生存率具有显着影响。值得注意的是，EF2K 低表达的 TNBC 患者长达 10 年没有死亡。发现 EF2K 在大多数 TNBC 患者中高度过表达，并表明它是一个重要的 TNBC 肿瘤发生、侵袭和进展的驱动因素；并使用以下方法验证其作为潜在的分子靶点：基于我们的初步研究，我们在多种临床前动物模型中进行了基因沉默技术。表示 EF2K 是瞄准 TNBC 的致命弱点，如果有效瞄准，它将具有考虑到 EF2K 敲除小鼠是健康的并且没有任何迹象，这对患者的生存产生了巨大的影响。 EF2K 靶向治疗预计是安全的，但目前尚无特异性或有效的治疗方法。因此，我们与包括药物化学家在内的研究团队合作。和计算化学家，我们最近合成了一系列潜在的 EF2K 小分子抑制剂基于计算模型，并确定了一种显着抑制 EF2K 活性的先导化合物。以先导化合物为基础，我们进一步设计合成了一百多个第二代新型化合物化合物并确定了一种更有效的抑制剂，可以在纳摩尔浓度下有效抑制 EF2K 当以长效形式配制时，在 TNBC 肿瘤中表现出显着的体内功效基于单脂质的纳米粒子，没有观察到毒性作用在这个拟议的项目中，我们将表征。并使用临床相关的 TNBC 模型优化基于 EF2K 抑制剂的治疗，目标是开发我们的长期目标是开发安全、高效的疗法并转化为针对 TNBC 的高度具体的策略。他们前往针对 TNBC 患者的诊所，这些患者缺乏针对性的治疗选择。