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.

项目摘要在所有乳腺癌亚型中，三重阴性乳腺癌（TNBC）的预后和生存最差目前可用的标准疗法，代表未满足的治疗挑战。显着的异质性（具有六个普遍定义的亚组），缺乏FDA批准的靶向疗法，是主要的原因导致预后不良和高死亡率率不足，并阻止了共同的识别分子靶标和靶向治疗的发展。为了应对这一挑战，我们进行了广泛的分析乳腺癌患者数据库，发现真核伸长因子2-激酶的表达（EF2K）编码不寻常的α激酶的基因对TNBC患者的存活率具有巨大的影响。值得注意的是，EF2K表达较低的TNBC患者没有死亡率长达10年。更重要的是，我们发现在大多数TNBC患者中，EF2K高度表达了，并且表明这是一个重要的 TNBC肿瘤发生，侵袭和进展的驱动力；并将其验证为使用的潜在分子靶标多种临床前动物模型中的遗传沉默技术。根据我们的初步研究，我们假设EF2K代表针对TNBC的致命弱点，如果有效地针对目标，它将具有一个对患者生存的巨大影响。考虑到EF2K敲除小鼠很健康，没有迹象毒性，EF2K靶向的疗法预计将是安全的。但是，目前没有具体或有效的靶向EF2K的抑制剂。这是与包括药剂师在内的调查人员团队合作的和计算化学家，我们最近合成了一个严重的EF2K潜在小分子抑制剂基于计算建模并确定了显着抑制EF2K活性的铅化合物。基于在铅化合物上，我们进一步设计和合成了一百多个第二代小说化合物并鉴定出有效抑制ef2k的更潜在抑制剂在长效中配制时，浓度并在TNBC肿瘤中表现出显着的体内效率单脂基纳米颗粒，没有观察到的毒性作用。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 TNBC高度具体的策略。我们的长期目标是开发安全，高效的疗法并翻译他们去诊所的TNBC患者，他们缺乏针对性的治疗选择。