NEXT GENERATION APPROACHES TO BREAST CANCER USING IMAGE GUIDED DRUG DELIVERY

血管生成是恶性肿瘤生长和转移的重要特征，靶向抗血管生成是肿瘤治疗的关键 改善了许多恶性实体瘤的生存率。然而，抗血管生成疗法不能被应用于治疗。 预期在肿瘤类型、大小、位置、阶段和等级中同样有效。的效用 在乳腺癌中使用贝伐单抗的抗血管生成治疗在新闻界引起了激烈的争论， 然而，根据最近的临床试验数据，目前的临床建议肯定了 贝伐单抗作为与紫杉醇联合治疗转移性乳腺癌的适当治疗选择。 在这个建议中，我们假设，乳腺癌与活跃的新血管生成的鉴定， 将增强靶向抗血管生成治疗的功效。我们主张，一个令人信服的临床 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虽然抗VEGF单克隆抗体和受体酪氨酸激酶 抑制剂药物在临床上被批准作为抗血管生成治疗，成本> 100，000美元/患者， 表现出有据可查的不良反应，替代治疗诊断纳米医学方法，特别是 用小剂量的高效化合物如烟曲霉素靶向新血管内皮， 这是一种改进的方法。我们假设，治疗诊断纳米颗粒的疗效靶向于 新血管内皮将反映肿瘤进展对血管生成的依赖性。我们进一步 假设治疗诊断性抗血管生成纳米颗粒的益处可以使用非交叉免疫增强， 耐药的抗血管生成化合物，如具有直接和间接细胞毒性的氨基二膦酸盐 对新血管生成和分泌促血管生成因子的肿瘤募集骨髓细胞的影响。 骨保护素（OPG）受体核因子-kB（RANK）和RANK配体（RANKL）通路激活剂 在通过破骨细胞分化和骨溶解引起的骨破坏中起核心作用 转移，这发生在70%的女性乳腺癌患者中。而氨基二磷酸盐（N-BP）和 RANKL-Ab破坏OPG-RANK-RANKL系统，抑制破骨细胞形成或功能，它们还可以 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 基于纳米药物的抗血管生成疗法与N-BP治疗相结合将是有效的预辅助治疗。 和维持治疗这项研究的具体目标是： 目标1.比较贝伐单抗血管生成和肿瘤进展的有效性 在软组织、内脏和转移瘤中与3-烟曲霉素-前药纳米颗粒相比， 治疗反应与治疗前肿瘤大小和新生血管特征有关。 目标2.确定N-BP与治疗诊断纳米颗粒组合的疗效， 新生血管内皮对乳腺癌肿瘤生长、转移和存活的影响。

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.