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

• 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
• 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

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%的乳腺癌为三阴性乳腺癌（TNBC），其表现出侵袭性、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。尽管在早期阶段有更好的化疗反应率，但>60%的TNBC患者会产生化疗耐药性，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癌症药物至关重要。最近，我们发现小的非编码RNA-miRNA在介导TNBC的药物敏感性/耐药性中起关键作用。通过高通量的miRNA抑制剂文库筛选，我们已经鉴定了独特地使耐药TNBC对紫杉醇敏感的miRNA抑制剂。有趣的是，与来自其健康同胞的血清相比，我们的初步致敏剂miRNA在复发转移性TNBC患者血清中以显著较低的水平表达。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的全身递送在临床前小鼠肿瘤模型中抑制乳腺癌肺转移而没有任何肝毒性。这些发现使我们假设肿瘤特异性miRNA以药物特异性方式提供选择性细胞毒性，这些miRNA可作为检测标记物用于鉴定可能从特定药物治疗中获益最多的患者，并且这些miRNA可代表治疗TNBC的新型治疗工具。我们提出了三个具体目标来检验我们的假设。在目标1中，我们将测试候选miRNA通过靶向微管相关蛋白（MAP）来敏化细胞对紫杉醇的反应的假设。目的2：验证候选miRNA通过靶向DNA损伤监测通路影响紫杉醇效应的假设。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在改善紫杉醇治疗耐药性TNBC的功效中的治疗潜力。我们还将使用来自治疗敏感性和治疗抗性TNBC患者的离体外植体测试候选miRNA和紫杉醇组合治疗的响应。这项研究的成功完成将为使用miRNA治疗剂治疗耐药性TNBC的新范例奠定基础。最近基于miRNA的临床试验已经开始将miRNA疗法确立为治疗一般疾病和特别是癌症的可行方法。由于miRNA通过对大量因子的微妙调节发挥作用，并且可以使用合成寡核苷酸容易地操纵，因此它们代表比作为常规癌症治疗靶点的单个基因或基因产物更有吸引力的靶点，常规癌症治疗通常易于产生耐药性。