microRNA-21 Blockade of Triple Negative Breast Cancer

microRNA-21 阻断三阴性乳腺癌

• 批准号: 9765665
• 负责人: Yuan-Yuan Jin
• 金额: $ 29.98万
• 依托单位: BOUND THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765665
• 关键词: 4T1; African; Anabolism; Angiogenesis Inhibitors; Apoptosis; BRCA1 gene; Binding; Biodistribution; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Breast Cancer therapy; CD47 gene; Cell Proliferation; Cell Surface Proteins; Cells; Clinical; Data; Disease-Free Survival; Dissociation; Drug Delivery Systems; Drug Kinetics; Endocytosis; Epidermal Growth Factor Receptor; Estrogen Receptors; Future; Gene Expression; Genetic Code; Growth; Hepatocyte; Hepatotoxicity; Hispanics; Human; IGF1 gene; Immune checkpoint inhibitor; Immunization; Immunocompetent; Infusion procedures; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Japan; Kidney; Kinetics; Label; Laboratory mice; Lead; Legal patent; Ligands; Liver; Low Density Lipoprotein Receptor; Luciferases; Malignant Neoplasms; Measures; Medicaid; Medicine; Messenger RNA; MicroRNAs; Mucin 1 protein; Mus; Mutation; Myotonic Dystrophy; Neoplasm Metastasis; Nucleic Acids; Outcome; PDCD1LG1 gene; PTEN gene; Peptide Nucleic Acids; Peptides; Pharmaceutical Preparations; Phase; Poly(ADP-ribose) Polymerases; Progesterone Receptors; Proprotein Convertases; Protein Kinase; Proteins; RNA; RNA Splicing; RNA-Induced Silencing Complex; Radiation; Rare Diseases; Receptor Signaling; Regulation; Research; Resistance; Safety; Saline; Serum; Serum Markers; Small Business Technology Transfer Research; Sterility; Subtilisins; T cell response; Technology; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Tumor Suppressor Proteins; Vertebral column; Weight; Woman; Work; Xenograft procedure; base; bevacizumab; cancer cell; cell growth; chemotherapy; commercialization; cost; design; disorder subtype; immune activation; immune checkpoint; in vivo; inhibitor/antagonist; malignant breast neoplasm; migration; molecular subtypes; molecular targeted therapies; mouse model; mutant; novel; novel therapeutics; nuclease; off-patent; orthotopic breast cancer; overexpression; patient subsets; peptide analog; preclinical study; receptor; receptor mediated endocytosis; response; side effect; standard of care; transcriptome; triple-negative invasive breast carcinoma; tumor; tumor growth; uptake; western diet; young woman

Triple negative breast cancer (TNBC) is an orphan disease that attacks 46,000 US women every year. TNBC cells lack human estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2 (Her2), the targets of existing medicines. TNBC recurs after standard-of-care chemotherapy and radiation, killing its victims within 4 years. New promising therapies such as poly(ADP-ribose) polymerase (PARP) inhibitors only benefit a small subset of patients with BRCA1/2 mutations. Thus, TNBC shows a critical need for molecularly-targeted therapy. Most TNBC cells and associated stroma show high microRNA 21 (miR-21), which decreases tumor suppressor proteins that keep cell growth in check. A molecularly-targeted therapeutic to block miR-21 in TNBC is our objective. Premise: We have designed a strong miR-21 blocking agent using aminomethyl bridged nucleic acid (BNA), with strong basepairing, Tm >80°C, low toxicity, and serum stability, conjugated to a peptide ligand for endocytosis by the insulin-like growth factor 1 receptor (IGF1R). 42% of TNBC tumors show constitutive IGF1R signaling. The peptide ligand for IGF1R provides a unique strategy for delivering miR-21 blocker specifically into the TNBC cells. Our agent basepairs with miR-21 in the RNA- induced silencing complex (RISC), freeing target mRNAs from miR-21 attack. Our miR-21 BNA elevated tumor suppressor proteins, suppressed immune checkpoint gene expression, increased apoptosis, slowed proliferation and migration in multiple TNBC lines. BNA-peptide in sterile saline can be administered by infusion. Our strategy optimizes cancer cell-specific delivery to block proliferation and immune checkpoints, covered by a pending PCT patent application, licensed by Bound Therapeutics LLC. Hypothesis: Our unique design for short microRNA blockers conjugated to a receptor ligand will direct TNBC cell uptake and slow the growth of TNBC orthotopic xenografts with minimal toxicity. Aim 1: Measure the effects of the lead miR-21 blocker on proliferation, apoptosis, invasion, and cellular expression of miR-21 target mRNAs and checkpoint proteins in 5 molecular subtypes of TNBC cells. Measure tumor response and immune activation by the lead miR-21 blocker in TNBC 4T1-luciferase orthotopic xenografts in immunocompetent syngeneic mice. Predicted results: Significant inhibition of tumor growth and immune checkpoints, and elevation of T-cell response. Aim 2: Measure toxicity of the lead miR-21 blocker in human hepatocytes by transcriptome analysis. Measure toxicity of the lead miR-21 blocker in mice by liver and kidney serum markers and weight. Measure on-target and off-target transcriptome effects, pharmacokinetics, and biodistribution of the lead miR-21 blocker in the mouse model. Predicted results: Minimal toxicity to human hepatocytes and murine host cells. Impact: We seek proof-of-concept to derisk the commercialization of a BNA-peptide TNBC therapeutic, enabling a full preclinical study of potency, T-cell response, toxicology, and pharmacokinetics, prior to IND and a Phase I single agent safety trial. We expect that miRNA blockade will significantly increase TNBC patient survival.

三重阴性乳腺癌（TNBC）是一种孤儿疾病，每年攻击46,000名美国女性。 TNBC 细胞缺乏人类雌激素受体，孕酮受体和表皮生长因子受体2（HER2）， 现有药物的靶标。 TNBC在护理标准的化学疗法和放射线后复发，杀死其 受害者在4年内。新承诺疗法，例如聚（ADP-核糖）聚合酶（PARP）抑制剂 受益于一小部分BRCA1/2突变患者。这，TNBC表现出对 分子靶向疗法。大多数TNBC细胞和相关的基质显示高microRNA 21（miR-21）， 这会减少抑制细胞生长的肿瘤抑制蛋白。分子靶向的疗法 在TNBC中阻止miR-21是我们的目标。前提：我们已经设计了强大的miR-21阻断剂 氨基甲基桥接的核酸（BNA），具有强底台，TM> 80°C，低毒性和血清稳定性， 通过胰岛素样生长因子1受体（IGF1R）共轭与肽配体进行内吞作用。 42％ TNBC肿瘤显示组成型IGF1R信号传导。 IGF1R的胡椒配体为 将miR-21阻滞剂专门传递到TNBC细胞中。我们的代理底托在RNA-中用miR-21 诱导沉默复合物（RISC），使目标mRNA免于miR-21攻击。我们的miR-21 bna升高肿瘤 抑制蛋白，抑制免疫检查点基因表达，凋亡增加，减慢 多个TNBC线的增殖和迁移。无菌盐水中的BNA肽可以通过 输液。我们的策略优化了癌细胞特异性输送以阻止增殖和免疫检查点， 由已待定的PCT专利申请涵盖，并获得Bound Therapeutics LLC的许可。假设：我们的独特 连接到接收器配体的短微洋阻滞剂的设计将引导TNBC细胞吸收并减慢 TNBC原位Xenographichographicics的生长具有最小的毒性。目标1：测量铅miR-21的效果 miR-21靶标mRNA和检查点的增殖，凋亡，侵袭和细胞表达的阻滞剂 TNBC细胞的5个分子亚型中的蛋白质。测量铅的肿瘤反应和免疫激活 TNBC 4T1-荧光素酶原位Xenographogricatics中的miR-21阻滞剂在免疫能力合成小鼠中。预测 结果：显着抑制肿瘤生长和免疫定位点，以及T细胞反应的升高。目的 2：通过转录组分析测量人肝细胞中铅miR-21阻滞剂的毒性。措施 肝脏和肾脏血清标记和重量在小鼠中铅miR-21阻滞剂的毒性。测量目标 以及脱靶转录组效应，药代动力学和铅miR-21阻滞剂的生物分布 鼠标模型。预测结果：对人肝细胞和鼠宿主细胞的毒性最小。影响：我们 寻求概念证明，以使BNA肽TNBC疗法的商业化驱散 在IND和A期之前，对效力，T细胞反应，毒理学和药代动力学的临床前研究 单代理安全试验。我们预计miRNA封锁将显着增加TNBC患者的存活。