Novel Targeted Therapeutics for Breast Cancer

项目摘要 三阴性乳腺癌（TNBC）在所有乳腺癌亚型中具有最差的预后和存活率， 目前可用的标准疗法，代表未满足的治疗挑战。显著的异质性 (with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，并阻止了常见的 分子靶点和靶向治疗的发展。为了应对这一挑战，我们广泛分析了 乳腺癌患者数据库，发现真核细胞延伸因子2-激酶的表达 编码不寻常的α激酶的EF 2K基因对TNBC患者的存活率具有显著影响。 值得注意的是，EF 2K低表达的TNBC患者长达10年没有死亡率。更重要的是我们 发现EF 2K在大多数TNBC患者中高度过表达，并表明它是一种重要的免疫调节因子。 TNBC肿瘤发生、侵袭和进展的驱动因素;并使用 在多种临床前动物模型中的基因沉默技术。根据我们的初步研究， 假设EF 2K代表靶向TNBC的阿喀琉斯之踵，如果有效靶向，它将具有 对患者生存的巨大影响。考虑到EF 2K基因敲除小鼠是健康的，没有任何迹象表明， 由于EF 2K的毒性，预期EF 2K靶向治疗是安全的。然而，目前还没有具体或有效的 靶向EF 2K的抑制剂。因此，在与包括药物化学家在内的一组调查人员的合作下， 和计算化学家，我们最近合成了一系列潜在的EF 2K小分子抑制剂， 基于计算建模，并确定了一种显着抑制EF 2K活性的先导化合物。基于 在先导化合物的基础上，我们进一步设计合成了一百多个第二代新化合物， 化合物，并确定了一种更有效的抑制剂，有效地抑制EF 2K在纳摩尔 在TNBC肿瘤中，当以长效制剂配制时， 基于单脂质的纳米颗粒，没有观察到毒性作用。在这个项目中，我们将 并使用临床相关的TNBC模型优化基于EF 2K抑制剂的治疗， 针对TNBC的高度具体战略。我们的长期目标是开发安全、高效的治疗方法， 他们到诊所为TNBC患者，谁缺乏有针对性的治疗方案。

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.