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microRNA-21 Blockade of Triple Negative Breast Cancer

microRNA-21 阻断三阴性乳腺癌

基本信息

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
项目类别：
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

项目摘要

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.

三阴性乳腺癌（TNBC）是一种罕见的疾病，每年有46000名美国女性罹患此病。TNBC