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: 10361926
• 负责人: STEVEN F DOWDY
• 金额: $ 22.16万
• 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/10361926
• 关键词: Address; Affect; Antibodies; Antibody-drug conjugates; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cell Size; Cell surface; Cessation of life; Charge; Clinical; Combination immunotherapy; Diffusion; Drug resistance; Engineering; Epithelial; 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; RNA Interference; RNA Interference Therapy; Sampling; Site; Small Interfering RNA; Survival Rate; Testing; Therapeutic; Transcription Factor Oncogene; aggressive breast cancer; angiogenesis; anti-PD-L1; base; c-myc Genes; cancer cell; cell growth; cell type; dalton; 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.

抽象的 转移性三阴性乳腺癌 (TNBC) 是最具侵袭性和破坏性的乳腺癌形式 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 患者的生存影响甚微。 TNBC 的表现令人沮丧 5 年生存率为 40%，占美国所有乳腺癌死亡人数的 30%。最近的一个 免疫治疗组合（atezolizumab [抗 PD-L1] 加白蛋白结合型紫杉醇）获得 FDA 批准； 然而，它仅使 1 年无进展生存期延长了 2 个月。选择 由于缺乏有效的方法，抗体药物偶联物（ADC）治疗 TNBC 的方法是不可行的。 独特的细胞表面标记物作为目标，导致不可避免的杀死正常细胞表达的缺陷 目标受体。因此，开发新的精准遗传基因有很大的未满足的临床需求。 能够靶向并杀死 TNBC 肿瘤细胞的药物。 TNBC由放大驱动， 驱动细胞的 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、 对小分子抑制剂高度耐药。然而，cMYC 可以通过精准遗传来靶向 RNAi 药物。尽管 RNAi 在治疗肝脏疾病方面具有前景广阔的治疗功能，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)，独立且需要递送剂。虽然目前肝外 siRNA 使用脂质和合成纳米粒子的递送方法显示出解决递送问题的优点， 它们的整体尺寸（100兆道尔顿）导致不可避免的低（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， 目前尚无可行的方法来提供 RNAi 疗法来治疗 TNBC。我们的项目将发展 下一代抗体 RNAi 结合物 (ARC) 精准遗传药物，针对其他疾病 TNBC 中不可成药的 cMYC 癌基因，并纳入我们新颖的通用内体逃逸域 （uEED）。内体逃逸是 siRNA 和 uEED 直接递送的限速步骤 以无毒的方式解决这个问题。我们将使用来自患者的小鼠模型来测试这种方法 来自 TNBC 患者的异种移植物（PDX）。我们假设针对 cMYC 主癌基因使用 抗体-RNAi 缀合物 (ARC) 将诱导致命性 RNAi 反应，选择性杀死 TNBC 肿瘤 细胞基于其 cMYC 癌基因成瘾，同时保持正常细胞不受伤害。