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

治疗转移性三阴性乳腺癌 (TNBC) 的精准基因 RNAi 药物

• 批准号: 10573227
• 负责人: STEVEN F DOWDY
• 金额: $ 18.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573227
• 关键词: Address; Affect; Antibodies; Antibody-drug conjugates; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cell surface; Cessation of life; Charge; Clinical; Combination immunotherapy; Diffusion; Drug resistance; Endosomes; Engineering; Epithelium; Extrahepatic; FDA approved; Fatty acid glycerol esters; Genetic; Genetic Medicine; Growth; Lipids; Liver diseases; MDA MB 231; Medicine; Mesenchymal; Metabolism; Monoclonal Antibodies; Neoplasm Metastasis; Normal Cell; Oncogenes; Operative Surgical Procedures; Paclitaxel; Progression-Free Survivals; Proliferating; RNA Interference; RNA Interference Therapy; Sampling; Site; Small Interfering RNA; Survival Rate; Testing; Therapeutic; Transcription Factor Oncogene; aggressive breast cancer; angiogenesis; anti-PD-L1; c-myc Genes; cancer cell; cell growth; cell type; inorganic phosphate; malignant breast neoplasm; mammary; mouse model; nanoparticle; neoplastic cell; next generation; novel; oncogene addiction; overexpression; patient derived xenograft model; pre-clinical; precision genetics; promoter; receptor; response; siRNA delivery; small molecule inhibitor; standard of care; success; targeted treatment; theories; therapeutic target; transcription factor; triple-negative invasive breast carcinoma; tumorigenesis; women of color; young woman

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.

摘要 转移性三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性和破坏性的形式。 癌症，主要影响年轻女性和有色人种女性。不幸的是，标准治疗 化疗和手术对TNBC患者的存活率几乎没有影响。TNBC有一个惨淡的 5年生存率为40%，占美国所有乳腺癌死亡人数的30%。最近的一 免疫治疗组合（atezolizumab [抗PD-L1]加nab-紫杉醇）获得FDA批准; 然而，在1年时，它仅将无进展生存期增加了2个月。替代 治疗TNBC的抗体-药物缀合物（ADC）的方法是不可行的，因为缺乏有效的治疗方法。 特异性细胞表面标志物靶向，导致不可避免的缺陷，杀死正常细胞表达 目标受体。因此，存在开发新的精确遗传修饰的巨大未满足的临床需求。 能够靶向和杀死TNBC肿瘤细胞的药物。TNBC由扩增驱动， cMYC主癌基因转录因子的过度表达和失调， 代谢、生长、增殖、存活、上皮-间充质转化（EMT）、永生化， 转化、耐药性、血管生成和转移。转录因子，包括cMYC， 对小分子抑制剂是高度排斥的。然而，cMYC可以通过精确遗传学靶向 RNAi药物。尽管RNAi具有治疗肝脏疾病的有希望的治疗特征，但由于其~40 带负电荷的磷酸盐，SiRNA RNAi疗法无法进入大多数细胞类型，包括癌症 细胞和大小（14 kDa），并且需要递送剂。虽然目前肝外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）导致不可避免的差（低）扩散系数， 降低了它们治疗TNBC的潜力。因此，虽然RNAi具有靶向cMYC的巨大潜力， 目前没有可行的方法来递送RNAi治疗剂以治疗TNBC。我们的项目将发展 下一代抗体RNAi缀合物（ARC），针对其他基因的精确遗传药物 在TNBC中的cMYC癌基因，并纳入我们的新的通用内体逃逸结构域 （uEEDs）。内体逃逸是siRNA和uEEDs递送的限速步骤，其直接寻址 以无毒的方式解决这个问题。我们将使用来自患者来源的小鼠模型来测试这种方法。 异种移植物（PDX）。我们假设，使用靶向cMYC主癌基因， 抗体-RNAi缀合物（ARC）将诱导选择性杀死TNBC肿瘤的致死性RNAi应答。 cMYC癌基因成瘾的细胞，而不伤害正常细胞。