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: 8450023
• 负责人: Gregory M Lanza
• 金额: $ 45.57万
• 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/8450023
• 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; bioluminescence imaging; 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

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.

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