Precision Genetic RNAi Medicines to Treat Metastatic Triple-Negative Breast Cancer (TNBC)

摘要 转移性三阴性乳腺癌是最具侵袭性和破坏性的乳腺癌 癌症，主要影响年轻女性和有色人种女性。不幸的是，护理标准 化疗和手术对TNBC患者的生存影响很小。TNBC有一个令人沮丧的 5年存活率为40%，占美国乳腺癌死亡人数的30%。最近 联合免疫治疗(抗PD-L1单抗+NaB-紫杉醇)获得FDA批准； 然而，在1年时，它只增加了2个月的无进展生存期。备择 抗体-药物结合物(ADC)治疗TNBC是不可行的，因为缺乏 独有的细胞表面标记与靶点，导致不可避免的缺陷，杀死正常细胞表达 靶向受体。因此，有很大的临床需求尚未满足开发新的精确基因。 能够靶向和杀伤TNBC肿瘤细胞的药物。TNBC是由扩增驱动的， 驱动细胞生长的cMYC主癌基因转录因子的过度表达和失控 新陈代谢，生长，增殖，存活，上皮-间充质转化，永生化， 转化、耐药、血管生成和转移。转录因子，包括cMYC， 对小分子抑制剂具有高度的顽固性。然而，cMYC可以通过精确遗传来靶向 RNAi药物。尽管RNAi在治疗肝脏疾病方面前景看好，但由于其~40 带负电荷的磷酸，siRNA RNAi疗法不能进入大多数细胞类型，包括癌症 细胞和大小(14 KDa)，需要投递剂。尽管目前的肝外siRNA 使用脂质和合成纳米颗粒的递送方法显示出解决递送问题的优点， 它们的总尺寸(100兆道尔顿)导致了不可避免的差(低)扩散系数， 降低了他们治疗TNBC的潜力。因此，虽然RNAi具有针对cMYC的巨大潜力， 目前还没有可行的方法来提供RNAi疗法来治疗TNBC。我们的项目将会发展 针对其他疾病的下一代抗体RNAi结合物(ARC)精密遗传药物 在TNBC中发现不可抑制的cmyc癌基因，并整合我们新的通用内体逃逸结构域 (UEEDs)。内体逃逸是传递siRNA和uEED的限速步骤 以一种无毒的方式解决这个问题。我们将使用患者来源的小鼠模型来测试这种方法 来自TNBC患者的异种移植(PDX)。我们假设以cmyc主癌基因为靶点 抗体-RNAi偶联物(ARCS)将诱导致命的RNAi反应，选择性地杀死TNBC肿瘤 基于cMYC癌基因成瘾的细胞，而不损害正常细胞。

ABSTRACT Metastatic Triple-Negative Breast Cancer (TNBC) is the most aggressive and devastating form of breast cancer, predominantly affecting younger women and women of color. Unfortunately, standard of care chemotherapeutic and surgery have done little to impact TNBC patient survival. TNBC has a dismal 40% survival rate at 5 years and accounts for 30% of all breast cancer deaths in the US. A recent immunotherapy combination (atezolizumab [anti-PD-L1] plus nab-paclitaxel) was FDA approved; however, it only increased progression-free survival by 2 months at the 1-year mark. Alternative approaches of Antibody-Drug Conjugates (ADCs) to treat TNBC are unfeasible because of the lack of an exclusive cell surface marker to target, leading to the inescapable deficit of killing normal cells expressing the targeted receptor. Thus, there is a great unmet clinical need to develop new precision genetic medicines capable of targeting and killing TNBC tumor cells. TNBC is driven by the amplification, overexpression and deregulation of the cMYC master oncogene transcription factor that drives cellular metabolism, growth, proliferation, survival, epithelial-mesenchymal transition (EMT), immortalization, transformation, drug resistance, angiogenesis and metastasis. Transcription factors, including cMYC, are highly recalcitrant to small molecule inhibitors. However, cMYC can be targeted by precision genetic RNAi medicines. Despite RNAi's promising therapeutic features to treat liver disorders, due to their ~40 negatively charged phosphates, siRNA RNAi therapeutics cannot enter most cell types, including cancer cells and size (14 kDa), on their own and require a delivery agent. Although current extra-hepatic siRNA delivery approaches using lipid and synthetic nanoparticles show merit to address the delivery problem, their overall size (100 Mega-Daltons) results in an inescapably poor (low) diffusion coefficient that diminishes their potential to treat TNBC. Consequently, while RNAi has great potential to target cMYC, there is currently no viable approach to deliver RNAi therapeutics to treat TNBC. Our project will develop next-generation Antibody RNAi conjugate (ARC) precision genetic medicines that target the otherwise undruggable cMYC oncogene in TNBC and incorporate our novel Universal Endosomal Escape Domains (uEEDs). Endosomal escape is the rate-limiting step for delivery of siRNAs and uEEDs directly address this problem in a non-toxic manner. We will test this approach using mouse models from patient-derived xenografts (PDX) from TNBC patients. We hypothesize that targeting the cMYC master oncogene using Antibody-RNAi Conjugates (ARCs) will induce a lethal RNAi response that selectively kills TNBC tumor cells based on their cMYC oncogene addiction, while leaving normal cells unharmed.