Novel Targeted Therapeutics for Breast Cancer

乳腺癌新型靶向治疗

• 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
• 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

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 三阴性乳腺癌(TNBC)是所有乳腺癌亚型中预后和生存率最差的 目前可用的标准疗法，代表着一个尚未满足的治疗挑战。显著的异质性 (有六个基因定义的亚组)和缺乏FDA批准的靶向治疗，是主要的 导致预后不良和死亡率高的原因，并阻碍了对 分子靶点与靶向治疗的发展。为了迎接这一挑战，我们广泛分析了 乳腺癌患者数据库中发现真核细胞延伸因子2-激酶的表达 (EF2K)基因编码一种不寻常的α-激酶，对TNBC患者的存活率有显著影响。 值得注意的是，EF2K低表达的TNBC患者10年内无死亡。更重要的是，我们 发现EF2K在大多数TNBC患者中高度过度表达，并表明它是一种重要的 TNBC肿瘤发生、侵袭和进展的驱动因素；并验证其为潜在的分子靶点 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是针对TNBC的致命弱点，如果有效地针对，它将有一个 对患者生存的巨大影响。考虑到EF2K基因敲除小鼠是健康的，没有迹象表明 毒性，EF2K靶向治疗预计是安全的。然而，目前还没有具体的或有效的 靶向EF2K的抑制剂。因此，与包括药物化学家在内的一组调查人员合作 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 根据计算模型，确定了一种能显著抑制EF2K活性的先导化合物。基座 关于先导化合物，我们进一步设计和合成了一百多个第二代新奇 化合物，并确定了一种更有效的抑制EF2K-at的纳米分子 长效制剂对TNBC肿瘤的体内疗效显著 基于单一脂质的纳米颗粒，没有观察到毒性作用。在这个提议的项目中，我们将描述 并利用临床相关的TNBC模型优化基于EF2K抑制剂的治疗，目标是开发 针对TNBC的高度具体的战略。我们的长期目标是开发安全、高效的治疗方法并将 他们被送到缺乏针对性治疗选择的TNBC患者的诊所。