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: 8186086
• 负责人: Gregory M Lanza
• 金额: $ 48.72万
• 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/8186086
• 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; 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

DESCRIPTION (provided by applicant): 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 av¿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. PUBLIC HEALTH RELEVANCE: Angiogenesis, new vessel formation, is a critical feature of malignant tumor growth and metastasis. However, as evidenced recently for breast cancer, anti-angiogenesis therapy cannot be expected to be equally effective across tumor types, sizes, locations, stages and grades. We hypothesize that antiangiogenic therapy and long-term survival could be significantly enhanced in breast cancer given proper patient selection. We contend that a compelling need exists for quantitative nanomedicine approaches to identify, treat and follow patients likely to respond to treatment. Although antiangiogenic therapy is currently used transiently in combination with chemotherapy, we suggest that the acute benefits of this approach could be maintained effectively for soft, visceral, and bone cancers with compounds exerting milder indirect effects on neovascular expansion, such as amino-bisphosphonates.

描述（申请人提供）：血管生成是恶性肿瘤生长和转移的关键特征，靶向抗血管生成已经提高了许多实体肿瘤恶性肿瘤的生存率。然而，抗血管生成治疗不能期望在不同肿瘤类型、大小、位置、分期和分级中都同样有效。基于最近的临床试验数据，贝伐珠单抗抗血管生成治疗在乳腺癌中的应用在媒体和科学论坛上一直存在激烈的争论，然而，目前的临床建议确认贝伐珠单抗与紫杉醇联合治疗转移性乳腺癌是合适的治疗选择。在这一建议中，我们假设发现活跃新生血管生成的乳腺癌将提高靶向抗血管生成治疗的疗效。我们认为，迫切需要定量分子成像来识别和跟踪可能对抗血管生成治疗有反应的乳腺癌患者。尽管抗vegf单克隆和受体酪氨酸激酶抑制剂药物在临床上被批准作为抗血管生成治疗药物，每名患者花费10万美元，并且有充分的不良反应，但替代治疗纳米药物方法专门针对新血管内皮，使用小剂量的高效化合物，如富马西林，可能是一种改进的方法。我们假设靶向新血管内皮的治疗纳米颗粒的疗效将反映肿瘤对血管生成的依赖性。我们进一步假设，治疗性抗血管生成纳米颗粒的益处可以通过使用非交叉抗性抗血管生成化合物来增强，例如氨基双磷酸盐，它对新生血管生成和分泌促血管生成因子的肿瘤募集骨髓细胞具有直接和间接的细胞毒性作用。骨保护素（OPG）受体激活物核因子- kb （RANK）和RANK配体（RANKL）途径通过破骨细胞分化和骨转移导致的骨破坏发挥核心作用，70%的乳腺癌女性发生骨转移。虽然氨基双膦酸盐（N-BP）和RANKL-Ab破坏OPG-RANK-RANKL系统，抑制破骨细胞的形成或功能，但它们也可以在包括乳腺癌在内的一些癌症中诱导细胞凋亡和抗血管生成。我们假设急性纳米药物为基础的抗血管生成治疗联合N-BP治疗将是有效的辅助前和维持治疗。本研究的具体目的是：目的1。比较贝伐单抗与av - 3-富马吉林前药纳米颗粒在软组织、内脏和转移瘤中的抗血管生成和肿瘤进展的有效性，并将治疗反应与预处理肿瘤大小和新生血管特征相关联。目标2。研究N-BP联合靶向新血管内皮的治疗性纳米颗粒对乳腺癌肿瘤生长、转移和生存的影响。