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

基本信息

批准号：
8848042
负责人：
Gregory M Lanza
金额：
$ 48.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848042
关键词：
4T1 Acute Adjuvant Therapy Adverse effects Angiogenesis Inhibitors Angiogenic Factor Apoptosis Bioluminescence Breast Breast Cancer Patient Breast Carcinoma Clinic Clinical Clinical Trials Data Dependence Dose Drug Delivery Systems Endothelium Exhibits Fatty acid glycerol esters Fluorescence 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 Metastatic breast cancer 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 image guided 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

项目摘要

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的关键特征，抗血管生成靶向治疗抗血管生成治疗可以改善多种实体瘤的生存率。预计对于不同的肿瘤类型、大小、位置、阶段和级别同样有效。使用贝伐珠单抗治疗乳腺癌的抗血管生成治疗在媒体和媒体上引起了激烈争论基于最近临床试验数据的科学论坛，然而，当前的临床建议肯定贝伐珠单抗与紫杉醇联合治疗转移性乳腺癌是一种合适的治疗选择。在此提案中，我们致力于鉴定具有活跃新生血管生成的乳腺癌我们认为，这将增强靶向抗血管生成治疗的疗效。需要定量分子成像来识别和跟踪可能患有乳腺癌的患者尽管抗 VEGF 单克隆抗体和受体酪氨酸激酶药物对抗血管生成治疗有反应。抑制剂药物在临床上被批准作为抗血管生成治疗，每个患者的费用> 100,000 美元表现出有据可查的副作用，替代治疗诊断纳米医学方法特别用小剂量的高效化合物（例如夫马洁林）靶向新血管内皮，可能我们捕捉到了一种代表治疗诊断纳米颗粒的功效的改进方法。新血管内皮将反映肿瘤进展对血管生成的依赖性。培养了使用非交叉可以增强治疗诊断抗血管生成纳米颗粒的益处耐药性抗血管生成化合物，例如具有直接和间接细胞毒性的氨基二膦酸盐对新血管生成和肿瘤招募的分泌促血管生成因子的骨髓细胞的影响。核因子 kB (RANK) 和 RANK 配体 (RANKL) 途径的骨保护素 (OPG) 受体激活剂通过破骨细胞分化和骨溶解作用在骨质破坏中发挥核心作用转移，70% 的乳腺癌女性会发生转移，而氨基二磷酸盐 (N-BP) 和 RANKL-Ab 破坏 OPG-RANK-RANKL 系统，抑制破骨细胞的形成或功能，它们还可以在某些癌症（包括乳腺癌）中诱导细胞凋亡和抗血管生成。基于纳米药物的抗血管生成治疗联合 N-BP 治疗作为预辅助治疗将是有效的本研究的具体目的是：目标 1. 比较贝伐珠单抗抗血管生成和肿瘤进展的有效性相对 v¿ 3-夫马洁林前药纳米颗粒在软组织、内脏和转移中的作用及其相关性治疗反应与治疗前肿瘤大小和新血管特征有关。目标 2. 确定 N-BP 与治疗诊断纳米颗粒相结合的功效新血管内皮对乳腺癌肿瘤生长、转移和存活的影响。