NEXT GENERATION APPROACHES TO BREAST CANCER USING IMAGE GUIDED DRUG DELIVERY

血管生成是恶性肿瘤生长转移和抗血管生成靶向的重要特征 提高了许多实体肿瘤恶性肿瘤的存活率。然而，抗血管生成治疗不能 预计对肿瘤类型、大小、位置、分期和分级都同样有效。的效用 贝伐单抗在乳腺癌中的抗血管生成治疗一直是新闻界和 然而，基于最近临床试验数据的科学论坛，当前的临床建议肯定了 贝伐单抗联合紫杉醇治疗转移性乳腺癌 在这项建议中，我们假设具有活跃新生血管生成的乳腺癌的识别 将提高靶向抗血管生成治疗的疗效。我们认为一个令人信服的临床 需要定量分子成像来识别和跟踪乳腺癌患者可能 对抗血管生成治疗有反应。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为抗血管生成治疗，成本为每名患者100,000美元， 表现出良好的不良反应，替代治疗鼻腔纳米药物的方法 以新生血管内皮细胞为靶点的小剂量高效力化合物，如福马西林，可能 代表了一种改进的方法。我们假设，靶向治疗的纳米颗粒的疗效 新生血管内皮细胞将反映肿瘤进展对血管生成的依赖。我们进一步 假设注射用抗血管生成纳米粒的益处可以通过非交叉来增强 抗药性抗血管生成化合物，如具有直接和间接细胞毒性的氨基双膦酸盐 对新血管生成和肿瘤募集的髓系细胞分泌促血管生成因子的影响。 骨保护素(OPG)受体核因子-kB激活因子(RANK)和RANKL途径 通过破骨细胞分化和骨溶解在骨破坏中起中心作用 转移，这发生在70%的乳腺癌女性患者中。而氨基双膦(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 在包括乳腺癌在内的某些癌症中诱导细胞凋亡和抗血管生成。我们假设这是急性的 基于纳米药物的抗血管生成治疗联合N-BP治疗将是有效的前辅助治疗 和维持性治疗。这项研究的具体目的是： 目的1.比较贝伐单抗抗血管生成和肿瘤进展的效果 软组织、内脏和转移中的3-烟美西林前药纳米粒的对比及相关性 治疗反应与治疗前肿瘤大小和新生血管特征有关。 目的2.确定N-BP与靶向治疗的纳米粒联合的疗效。 新生血管内皮细胞对乳腺癌生长、转移和生存的影响。

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.