Targeted Therapy of Triple Negative Breast Cancer Using Theranostic Nanoparticles

使用治疗诊断纳米颗粒靶向治疗三阴性乳腺癌

• 批准号: 8700565
• 负责人: Lily Yang
• 金额: $ 5.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700565
• 关键词: Address; Adjuvant Therapy; Animal Model; Biodistribution; Cancer Patient; Cell Line; Cell surface; Clinical; Clinical Management; Clinical Protocols; Clinical Trials; DNA Damage; Data; Detection; Development; Diagnostic; Disease-Free Survival; Distant; Distant Metastasis; Dose; Doxorubicin; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug resistance; Dyes; ERBB2 gene; Effectiveness; Encapsulated; Endothelial Cells; Epidermal Growth Factor Receptor; Estrogens; Excision; Figs - dietary; Gene Expression Profiling; Generations; Goals; Hormonal; Human; Image; Image-Guided Surgery; Imaging Device; Incidence; Individual; Label; Lead; Lesion; Magnetic Resonance Imaging; Magnetism; Mammary Neoplasms; Mammary gland; Measures; Modeling; Molecular Target; Monitor; Mus; Neoadjuvant Therapy; Newly Diagnosed; Normal tissue morphology; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Poly(ADP-ribose) Polymerases; Progesterone; Protocols documentation; Recurrence; Research Project Grants; Residual Tumors; Residual state; Roche brand of trastuzumab; Serological; Signal Transduction; Specificity; Staging; System; Tamoxifen; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Uses; Tissue Sample; Tissues; Toxic effect; Tumor Tissue; Urokinase Plasminogen Activator Receptor; antiangiogenesis therapy; cDNA Arrays; chemotherapy; cohort; dosage; effective therapy; gemcitabine; image guided therapy; imaging modality; improved; in vitro testing; inhibitor/antagonist; iron oxide; macrophage; malignant breast neoplasm; nanoparticle; nanotherapy; neoplastic cell; novel; optical imaging; outcome forecast; preclinical study; prevent; receptor; receptor expression; response; targeted delivery; theranostics; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): Of the 1 million cases of newly diagnosed breast cancer worldwide each year, over 170,000 cases are a distinct type of triple-negative breast cancer (TNBC). TNBC lacks expression of estrogen (ER), progesterone (PR) and Her-2/neu. It is not a candidate for two common therapies for breast cancer: hormonal (tamoxifen) and Her-2 targeted (Herceptin) therapy. TNBC is usually found at the late stage and has a higher likelihood of local and distant recurrence and a poor prognosis. The goal of this study is to develop a complete therapeutic approach that merges targeted preoperative adjuvant therapy and image-guided treatment and surgery for preventing local recurrence and distant metastasis. Our team has developed a multifunctional nanoparticle platform that carries therapeutic agents, targets tumor cells and stromal tissues, and produces optical and MR imaging signals. We demonstrated the ability of targeted tumor imaging, tumor growth inhibition, and anti- angiogenesis effects in TNBC animal models. In the proposed study, we will develop receptor-targeted and near infrared dye labeled-magnetic iron oxide nanoparticles (IONPs). These nanoparticles will carry DNA damaging drugs without or with a poly ADP ribose polymerase (PARP) inhibitor for treatment of TNBC, MRI monitoring of drug delivery and response, and optical image-guided surgery. We hypothesize that targeted delivery of high concentrations of the combined therapeutic agents using theranostic nanoparticles and timely assessment of drug delivery and response to the treatment could lead to enhanced therapeutic effects in drug resistant tumor cells, while minimizing systemic toxicity. Image-guided surgery following the targeted therapy allows removal of small drug-resistant residual tumor lesions, which could prevent the development of local recurrence and distant metastasis. First, urokinase plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) will be validated as molecular targets for targeted therapeutics using two large cohorts (>3000 cases) of breast cancer tissues (Aim 1). We will produce a new generation of theranostic nanoparticles with enhanced drug delivery into the tumor by avoiding macrophage uptake and increasing in drug loading and release. We will determine biodistribution, and the effects of targeted therapy, MRI-guided drug delivery and evaluating response in TNBC animal models using different theranostic IONPs to select the lead theranostic IONPs for further preclinical studies (Aim 2). We will use the mice bearing orthotopic TNBC to study the effects of integration of preoperative targeted neoadjuvant therapy, monitoring therapeutic responses by non-invasive MRI, and intraoperative optical imaging of tumor lesions after administration of the theranostic IONPs on the incidences of local and distant recurrence as well as overall survival of the mice (Aim 3). We will examine systemic toxicity, and pharmacokinetics/pharmacodynamics of the selected lead theranostic IONPs in normal and tumor bearing mice (Aim 4). Clinical impact: The proposed study addresses the urgent need in clinical management of TNBC to improve the survival of patients afflicted with TNBC.

描述（由申请人提供）：全世界每年新诊断出的 100 万例乳腺癌中，超过 170,000 例是一种独特类型的三阴性乳腺癌 (TNBC)。 TNBC 缺乏雌激素 (ER)、孕激素 (PR) 和 Her-2/neu 的表达。它不适合两种常见的乳腺癌疗法：激素疗法（他莫昔芬）和 Her-2 靶向疗法（赫赛汀）。 TNBC通常发现于晚期，局部和远处复发的可能性较高，预后较差。本研究的目标是开发一种完整的治疗方法，将术前靶向辅助治疗与图像引导治疗和手术相结合，以预防局部复发和远处转移。我们的团队开发了一种多功能纳米颗粒平台，该平台可携带治疗剂、靶向肿瘤细胞和基质组织，并产生光学和磁共振成像信号。我们在 TNBC 动物模型中展示了靶向肿瘤成像、肿瘤生长抑制和抗血管生成作用的能力。在拟议的研究中，我们将开发针对受体的近红外染料标记的磁性氧化铁纳米颗粒（IONP）。这些纳米颗粒将携带 DNA 损伤药物，无论是否含有聚 ADP 核糖聚合酶 (PARP) 抑制剂，用于治疗 TNBC、药物输送和反应的 MRI 监测以及光学图像引导手术。我们假设，使用治疗诊断纳米颗粒靶向输送高浓度的联合治疗剂，并及时评估药物输送和治疗反应，可能会增强耐药肿瘤细胞的治疗效果，同时最大限度地减少全身毒性。靶向治疗后的图像引导手术可以切除小的耐药残留肿瘤病灶，这可以防止局部复发和远处转移的发展。首先，将使用两个大型乳腺癌组织队列（>3000 例）验证尿激酶纤溶酶原激活剂受体 (uPAR) 和表皮生长因子受体 (EGFR) 作为靶向治疗的分子靶标（目标 1）。我们将生产新一代治疗诊断纳米颗粒，通过避免巨噬细胞摄取并增加药物负载和释放，增强药物输送到肿瘤中。我们将使用不同的治疗诊断 IONP 确定 TNBC 动物模型中的生物分布、靶向治疗的效果、MRI 引导的药物递送和评估反应，以选择主要的治疗诊断 IONP 进行进一步的临床前研究（目标 2）。我们将使用携带原位 TNBC 的小鼠来研究术前靶向新辅助治疗的整合、通过非侵入性 MRI 监测治疗反应以及给予治疗诊断 IONP 后肿瘤病灶的术中光学成像对局部和远处复发发生率的影响以及小鼠的总体存活率（目标 3）。我们将检查正常和荷瘤小鼠中选定的先导治疗诊断 IONP 的全身毒性和药代动力学/药效学（目标 4）。临床影响：拟议的研究解决了 TNBC 临床管理的迫切需求，以提高 TNBC 患者的生存率。