NEXT GENERATION APPROACHES TO BREAST CANCER USING IMAGE GUIDED DRUG DELIVERY

描述（由申请人提供）：血管生成是恶性肿瘤生长和转移的关键特征，靶向抗血管生成改善了许多实体瘤恶性肿瘤的生存率。然而，不能预期抗血管生成疗法在肿瘤类型、大小、位置、阶段和等级中同样有效。根据最近的临床试验数据，贝伐珠单抗在乳腺癌中的抗血管生成治疗效用在新闻界和科学论坛上引起了激烈的争论，然而，目前的临床建议确认贝伐珠单抗是转移性乳腺癌联合紫杉醇的适当治疗选择。在这个建议中，我们假设，乳腺癌与活跃的新血管生成的识别将提高靶向抗血管生成治疗的疗效。我们认为，一个迫切的临床需要存在定量分子成像，以确定和跟踪乳腺癌患者可能对抗血管生成治疗。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为抗血管生成治疗，成本>$100，000/患者并且表现出有据可查的不良反应，但是用微小剂量的高效化合物（例如烟曲霉素）特异性靶向新血管内皮的替代治疗诊断纳米医学方法可能代表改进的方法。我们假设靶向新生血管内皮的治疗诊断纳米颗粒的疗效将反映肿瘤进展对血管生成的依赖性。我们进一步假设，使用非交叉耐药的抗血管生成化合物，如对新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细胞毒性作用的氨基二膦酸盐，可以增强治疗诊断性抗血管生成纳米颗粒的益处。骨保护素（OPG）核因子-kB（RANK）和RANK配体（RANKL）通路的受体激活剂在通过破骨细胞分化的骨破坏和骨转移引起的骨质溶解中发挥核心作用，这发生在70%的乳腺癌女性中。虽然氨基二膦酸盐（N-BP）和RANKL-Ab破坏OPG-RANK-RANKL系统，抑制破骨细胞形成或功能，但它们也可在某些癌症（包括乳腺癌）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结合N-BP治疗将是有效的辅助前和维持治疗。本研究的具体目标是：目标1。比较贝伐单抗与av <$3-烟曲霉素-前体药物纳米颗粒在软组织、内脏和转移瘤中抗血管生成和肿瘤进展的有效性，并将治疗反应与治疗前肿瘤大小和新血管特征相关联。目标2.确定N-BP与靶向新生血管内皮的治疗诊断纳米颗粒组合对乳腺癌肿瘤生长、转移和存活的功效。 公共卫生相关性：血管生成，即新血管形成，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，不能预期抗血管生成疗法在肿瘤类型、大小、位置、阶段和等级上同样有效。我们假设，如果选择合适的患者，抗血管生成治疗和长期生存率可以显著提高乳腺癌。我们认为，迫切需要定量纳米医学方法来识别，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，但我们认为，这种方法的急性获益可以有效地维持软，内脏和骨癌的化合物对新生血管扩张的间接影响较轻，如氨基二膦酸盐。

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.