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，抗血管生成靶向治疗提高了许多实体瘤恶性肿瘤的存活率。然而，不能期望抗血管生成治疗在肿瘤类型、大小、位置、分期和分级上同样有效。根据最近的临床试验数据，贝伐单抗在乳腺癌抗血管生成治疗中的作用已经在媒体和科学论坛上进行了激烈的辩论，然而，目前的临床建议确认贝伐单抗与紫杉醇联合治疗转移性乳腺癌是一种合适的治疗方案。在这项建议中，我们假设，识别出新生血管生成活跃的乳腺癌将增强靶向抗血管生成治疗的疗效。我们认为，临床上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。尽管抗血管内皮生长因子单抗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，并表现出良好的不良反应，但替代的治疗纳米药物方法专门针对新生血管内皮细胞，使用微量的高强度化合物，如福马吉林，可能是一种改进的方法。我们假设，靶向新生血管内皮细胞的热疗纳米粒的疗效将反映肿瘤进展对血管生成的依赖。我们进一步假设，使用非交叉耐药的抗血管生成化合物，例如对新血管生成具有直接和间接细胞毒性作用的氨基双膦酸盐，以及分泌促血管生成因子的肿瘤招募的髓系细胞，可以增强抗血管生成纳米粒的益处。护骨素(OPG)核因子-kB受体激活物(RANK)及其配体(RANKL)通路在破骨细胞分化和骨转移所致的骨溶解中起核心作用，70%的乳腺癌患者发生骨转移。虽然氨基二磷酸盐(N-BP)和RANKL-Ab破坏了OPG-RANK-RANKL系统，抑制了破骨细胞的形成或功能，但它们也可以诱导某些癌症的细胞凋亡和抗血管生成，包括乳腺癌。我们假设，基于急性纳米药物的抗血管生成治疗与N-BP治疗相结合，将与前辅助治疗和维持治疗一样有效。本研究的具体目的是：1.比较贝伐单抗和av？3-fumaglin前药纳米粒在软组织、内脏和转移中的抗血管生成和肿瘤进展的效果，并与治疗前的肿瘤大小和新生血管特性进行相关性研究。目的2.探讨N-BP联合靶向血管内皮细胞的纳米微粒对乳腺癌生长、转移和生存的影响。 公共卫生相关性：血管生成，新的血管形成，是恶性肿瘤生长和转移的关键特征。然而，正如最近对乳腺癌所证明的那样，抗血管生成治疗不能期望在肿瘤类型、大小、位置、分期和分级上同样有效。我们假设，如果患者选择得当，乳腺癌的抗血管生成治疗和长期存活率可以显著提高。我们认为，存在对定量纳米医学方法的迫切需求，以识别、治疗和跟踪可能对治疗有反应的患者。虽然目前抗血管生成治疗与化疗联合使用是暂时的，但我们建议，对于软癌、内脏癌和骨癌，如果有化合物对新生血管扩张产生较轻微的间接影响，如氨基双膦酸类化合物，这种方法可以有效地维持这种方法的急性益处。