NEXT GENERATION APPROACHES TO BREAST CANCER USING IMAGE GUIDED DRUG DELIVERY

使用图像引导药物输送的下一代乳腺癌治疗方法

• 批准号: 8450023
• 负责人: Gregory M Lanza
• 金额: $ 45.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450023
• 关键词: Acute; Adjuvant Therapy; Adverse effects; Angiogenesis Inhibitors; Angiogenic Factor; Apoptosis; Bioluminescence; Breast; Breast Carcinoma; Cancer Patient; Clinic; Clinical; Clinical Trials; Data; Dependence; Dose; Drug Delivery Systems; Endothelium; Exhibits; Fatty acid glycerol esters; Fluorescence; Image; Injection of therapeutic agent; Ligands; Lipase; Location; Magnetic Resonance Imaging; Maintenance Therapy; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Mammary Neoplasms; Mammary gland; Metastatic Neoplasm to the Bone; Modeling; Myeloid Cells; Neoplasm Metastasis; Nuclear; Oryctolagus cuniculus; Osteoclasts; Osteolysis; Paclitaxel; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Play; Prodrugs; Recommendation; Recruitment Activity; Resistance; Role; Safety; Solid Neoplasm; Staging; System; TRANCE protein; Therapeutic; Treatment Cost; Tumor Angiogenesis; Tumor Burden; Tumor necrosis factor receptor 11b; Tyrosine Kinase Inhibitor; Visceral; Woman; Xenograft Model; Zoledronic Acid; angiogenesis; antiangiogenesis therapy; base; bevacizumab; bioluminescence imaging; bisphosphonate; bone; chemotherapy; compare effectiveness; cytotoxic; density; fumagillin; implantation; improved; malignant breast neoplasm; molecular imaging; nanomedicine; nanoparticle; neovascular; neovasculature; next generation; receptor; response; soft tissue; theranostics; therapeutic angiogenesis; treatment response; tumor; tumor growth; tumor progression

Angiogenesis is a critical feature of malignant tumor growth and metastasis and anti-angiogenesis targeting has improved survival in numerous solid tumor malignancies. However, anti-angiogenesis therapy cannot be expected to be equally effective across tumor types, sizes, locations, stages and grades. The utility of antiangiogenesis treatment with bevacizumab in breast cancer has been hotly debated in the press and scientific forums based on recent clinical trial data, however, current clinical recommendations affirm bevacizumab as an appropriate therapeutic option in combination with paclitaxel for metastatic breast cancer. In this proposal, we hypothesize that the identification of breast cancers with active neoangiogenesis will enhance the efficacy of targeted antiangiogenesis therapy. We contend that a compelling clinical need exists for quantitative molecular imaging to identify and follow breast cancer patients likely to respond to anti-angiogenic treatment. Although anti-VEGF monoclonal and receptor tyrosine kinase inhibitor drugs are approved in the clinic as antiangiogenic treatments, costing >$100,000/patient and exhibiting well documented adverse effects, alternative theranostic nanomedicine approaches specifically targeting neovessel endothelium with minute doses of highly potent, compounds, such as fumagillin, may represent an improved approach. We hypothesize that the efficacy of theranostic nanoparticles targeted to neovessel endothelium will reflect tumor dependence on angiogenesis for progression. We further hypothesize that the benefits of theranostic antiangiogenic nanoparticles can be enhanced using non-cross resistant anti-angiogeneic compounds,such as amino-bisphosphonates that have direct and indirect cytotoxic effects on neoangiogenesis and tumor-recruited myeloid cells that secrete pro-angiogeneic factors. Osteoprotegerin (OPG) receptor activator of nuclear factor-kB (RANK) and RANK ligand (RANKL) pathway plays a central role in bone destruction through osteoclast differentiation and osteolysis due to bone metastasis, which occurs in 70% of women with breast cancer. While amino-bisphosphonates (N-BP) and RANKL-Ab disrupt the OPG-RANK-RANKL system, inhibiting osteoclast formation or function, they can also induce apoptosis and antiangiogenesis in some cancers, including breast. We hypothesize that acute nanomedicine-based antiangiogenic therapy combined with N-BP treatment would be effective as pre-adjuvant and maintenance therapy. The specific aims of this study are: Aim 1. Compare the effectiveness of anti-angiogenesis and tumor progression with bevacizumab versus ¿v¿3- fumagillin-prodrug nanoparticles in soft tissue, visceral, and metastases and correlate treatment response with pretreatment tumor size and neovasculature character. Aim 2. Determine the efficacy of N-BP in combination with theranostic nanoparticles targeted to neovessel endothelium on breast cancer tumor growth, metastasis and survival.

血管生成是恶性肿瘤生长和转移和抗血管生成的关键特征 在许多实体瘤恶性肿瘤中的生存率提高了。但是，抗血管生成治疗不能是 预计将在肿瘤类型，大小，位置，阶段和成绩中同样有效。实用性 在媒体上，对乳腺癌的抗血管生成治疗一直在乳腺癌中进行了激烈的争论， 但是，基于最近的临床试验数据的科学论坛，当前的临床建议确认 贝伐单抗作为合适的治疗选择与紫杉醇用于转移性乳腺癌。 在此提案中，我们假设鉴定具有活性新血管生成的乳腺癌 将提高靶向抗血管生成疗法的效率。我们认为一个引人注目的临床 存在定量分子成像的需要，以识别和跟随可能的乳腺癌患者 应对抗血管生成治疗。虽然抗VEGF单克隆和受体酪氨酸激酶 抑制剂药物在诊所被批准为抗血管生成治疗，成本> 100,000美元/患者， 表现出良好的不良反应，替代性疗法纳米医学方法 用微小剂量的高剂量靶向Neovesl内皮，例如Fumagillin，可能 代表改进的方法。我们假设，针对的疗法纳米颗粒的效率 Neovesl内皮将反映肿瘤对进展的血管生成的依赖。我们进一步 假设可以使用非交叉来增强疗法抗血管生成纳米颗粒的益处 耐药性抗血盟化合物，例如具有直接和间接细胞毒性的氨基三膦酸盐 对新血管生成和肿瘤恢复的影响，髓样细胞分泌促血管生成因子。 核因子-KB（RANK）和RANK配体（RANKL）途径的骨蛋白酶（OPG）受体激活剂 通过破骨细胞分化和骨溶解在骨骼破坏中起着核心作用 转移发生在70％的乳腺癌女性中。而氨基三膦酸盐（N-BP）和 RANKL-AB破坏OPG秩秩系统，抑制破骨细胞的形成或功能，它们也可以 在包括乳房在内的某些癌症中诱导凋亡和抗血管生成。我们假设急性 基于纳米医学的抗血管生成疗法与N-BP治疗相结合将有效作为辅助治疗 和维护疗法。这项研究的具体目的是： 目标1。将抗血管生成和肿瘤进展的有效性与贝伐单抗的有效性 与3-富马素产生的纳米颗粒在软组织，内脏和转移中，并相关 治疗肿瘤大小和新生血管形的治疗反应。 AIM 2。确定N-BP与针对性的近静脉纳米颗粒的效率 Neovesel内皮对乳腺癌肿瘤生长，转移和生存。