miRNAs:Safe and effective therapeutic adjuvants for treating drug resistant TNBC

miRNA：治疗耐药TNBC的安全有效的治疗佐剂

基本信息

批准号：
9212787
负责人：
Manjeet Kumar Rao
金额：
$ 34.59万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212787
关键词：
Address Adjuvant Adverse effects Affect Aftercare Age Age Reporting Antineoplastic Agents Biochemical Biological Assay Blood Breast Cancer Patient Breast Cancer survivor Cancer Center Cancer Model Cancer Patient Cardiotoxicity Cells Cessation of life Chromosomal Instability Clinical Trials Combined Modality Therapy Confocal Microscopy DNA Damage DNA Repair Data Detection Development Diagnosis Disease Dose Drug Delivery Systems Drug Sensitization Drug resistance Exhibits Fiber Funding Gene Targeting Genes Genomics Goals Hepatotoxicity High Prevalence Hispanics Immune system Immunofluorescence Immunologic Individual Lead Legal patent Libraries Ligand Binding Link Liposomes Malignant Neoplasms Mammary Neoplasms Measures Mediating Metastatic Neoplasm to the Lung Metastatic breast cancer MicroRNAs Microtubule-Associated Proteins Microtubules Mitotic spindle Modeling Mus Neoplasm Metastasis Normal tissue morphology Oligonucleotides Paclitaxel Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacotherapy Phase I Clinical Trials Play Population Positioning Attribute Privatization Process Proteins Quality of life Radiolabeled Regimen Regulation Relapse Reporter Reporter Genes Resistance Role Selection for Treatments Serum Siblings Signal Transduction Stress Structure Testing Therapeutic Toxic effect Treatment Efficacy Treatment Failure Treatment outcome Tumor Tissue Untranslated RNA Woman base biomaterial compatibility cancer therapy cellular sensitization chemotherapy cytotoxicity drug development drug sensitivity gene product improved individual patient inhibitor/antagonist innovation killings malignant breast neoplasm mouse model nanoparticle neoplastic cell new therapeutic target novel novel therapeutics outcome forecast overexpression pre-clinical preclinical study public health relevance response therapeutic evaluation therapy resistant tool treatment response triple-negative invasive breast carcinoma tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Approximately, 15-20% of all breast cancers account for triple negative breast cancers (TNBCs) that exhibit aggressive, distinct metastatic pattern and poor prognosis resulting in disproportionate number of breast cancer deaths. Despite, a better chemotherapy response rate in early-stages, >60% of patients with TNBCs develop chemoresistance leading to early relapse and shorter survival. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious cancer drugs. Recently, we have discovered that small non-coding RNAs-miRNAs play critical roles in mediating drug sensitivity/resistance in TNBCs. Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that uniquely sensitize drug resistant TNBCs to paclitaxel. Interestingly, our preliminary sensitizer miRNAs are expressed at significantly lower levels in relapsed metastatic TNBC patient sera compared to sera from their healthy siblings. Furthermore, using liposome- or biocompatible PLGA nanoparticle-based approaches, we show that systemic delivery of candidate miRNA suppresses breast cancer lung metastasis without any hepatotoxicity in preclinical mouse tumor models. These findings led us to hypothesize that tumor-specific miRNAs render selective cell cytotoxicity in a drug-specific manner, that these miRNAs may serve as detection markers for identifying patients those who might benefit most from specific drug treatment, and that these miRNAs may represent novel therapeutic tools for the treatment of the TNBCs. We propose three specific aims to test our hypothesis. In Aim 1, we will test the hypothesis that candidate miRNA sensitizes cellular response to taxol by targeting microtubule-associated proteins (MAPs). In Aim 2, we will test the hypothesis that candidate miRNA affects taxol response by targeting DNA damage surveillance pathway. In Aim 3, we will determine the therapeutic potential of candidate miRNAs in improving the efficacy of taxol for treating therapy resistant TNBC using tumor xenograft mouse model and syngeneic mouse model with intact immune system. We will also test the response of candidate miRNAs and taxol combination therapy using ex-vivo explants from therapy sensitive and therapy resistant TNBC patients. Successful completion of this study will set stage for a new paradigm of treating therapy resistant TNBCs using miRNA therapeutics. Recent miRNA-based clinical trials have begun to establish miRNA therapeutics as a feasible approach for treating diseases in general and cancer in particular. Since miRNAs function through subtle regulation of a large numbers of factors, and can be easily manipulated using synthetic oligos, they represent more attractive targets than the single gene or gene product that is the target of conventional cancer treatments, which are typically prone to drug resistance.

描述（由申请人提供）：大约 15-20% 的乳腺癌属于三阴性乳腺癌 (TNBC)，这些乳腺癌表现出侵袭性、独特的转移模式和不良预后，导致乳腺癌死亡人数不成比例。尽管早期化疗反应率较高，但超过 60% 的 TNBC 患者会出现化疗耐药，导致早期复发和生存期缩短。因此，了解这种耐药性的机制对于开发新的、有效的抗癌药物至关重要。最近，我们发现小非编码RNA-miRNA在介导TNBC的药物敏感性/耐药性中发挥着关键作用。通过高通量 miRNA 抑制剂库筛选，我们已经鉴定出能够独特地使耐药 TNBC 对紫杉醇敏感的 miRNA 抑制剂。有趣的是，与健康同胞的血清相比，我们的初步敏化 miRNA 在复发转移性 TNBC 患者血清中的表达水平显着较低。此外，使用基于脂质体或生物相容性 PLGA 纳米颗粒的方法，我们表明，候选 miRNA 的全身递送可抑制乳腺癌肺转移，而在临床前小鼠肿瘤模型中没有任何肝毒性。这些发现使我们推测肿瘤特异性 miRNA 以药物特异性方式产生选择性细胞毒性，这些 miRNA 可以作为检测标记来识别可能从特定药物治疗中受益最多的患者，并且这些 miRNA 可能代表新颖的用于治疗 TNBC 的治疗工具。我们提出三个具体目标来检验我们的假设。在目标 1 中，我们将测试以下假设：候选 miRNA 通过靶向微管相关蛋白 (MAP) 来增强细胞对紫杉醇的反应。在目标 2 中，我们将测试候选 miRNA 通过靶向 DNA 损伤监测途径影响紫杉醇反应的假设。在目标 3 中，我们将使用肿瘤异种移植小鼠模型和具有完整免疫系统的同基因小鼠模型来确定候选 miRNA 在提高紫杉醇治疗耐药 TNBC 疗效方面的治疗潜力。我们还将使用来自治疗敏感和治疗耐药的 TNBC 患者的离体外植体来测试候选 miRNA 和紫杉醇联合疗法的反应。这项研究的成功完成将为使用 miRNA 疗法治疗耐药 TNBC 的新范例奠定基础。最近基于 miRNA 的临床试验已开始将 miRNA 疗法确立为治疗一般疾病，特别是癌症的可行方法。由于 miRNA 通过大量因素的微妙调节发挥作用，并且可以使用合成寡核苷酸轻松操作，因此它们比作为传统癌症治疗目标的单基因或基因产物更具吸引力，而传统癌症治疗通常容易产生耐药性。