Hyperspectral Microendscopy to Monitor VEGF During Pancreatic Cancer Therapy

高光谱显微内窥镜监测胰腺癌治疗期间的 VEGF

• 批准号: 8003695
• 负责人: Bryan Quilty Spring
• 金额: $ 4.76万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003695
• 关键词: Address; Avastin; Caliber; Cell Proliferation; Cell Survival; Coupled; Cytotoxic Chemotherapy; Detection; Disease; Dose; Fiber Optics; Fluorescence; Genes; Goals; Growth Factor; Image; In Situ; Investigation; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; Medicine; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Nanotechnology; Neoplasm Metastasis; Outcome; Photochemotherapy; Play; Production; Radiation therapy; Recurrence; Relative (related person); Research; Role; Signal Transduction; Survival Rate; System; Therapeutic; Therapeutic Agents; Time; Tissues; Treatment Protocols; Treatment outcome; Vascular Endothelial Growth Factors; Work; base; cancer cell; cancer therapy; cell type; chemotherapy; cytokine; design; extracellular; flexibility; fluorescence imaging; fluorophore; improved; minimally invasive; molecular imaging; nanoparticle; neoplastic cell; optical imaging; outcome forecast; pancreatic neoplasm; public health relevance; receptor; response; spatiotemporal; tool; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer (PanCa) is a devastating disease with the lowest 5-year survival rate of all malignancies (<5%); therefore, there is a desperate need for improved treatment regimens. Pancreatic cancer cells and other cancer cell types up-regulate their expression of specific genes during therapy to promote tumor cell proliferation and survival. For example, cancer cells can increase production of cellular signaling factors, such as cytokine growth factors and their receptors. Vascular endothelial growth factor (VEGF) exemplifies the multitude of cytokines that play a role in tumor survival and metastasis. The Hasan group and others have shown that VEGF expression is up-regulated by cancer cells in response to subcurative cytotoxic therapies, such as chemotherapy, radiotherapy and photodynamic therapy (PDT). This tumor response often leads to disease recurrence and increased metastasis, paradoxical to the goals of therapy. During investigation for strategies to mitigate this effect, the Hasan group has found that secreted VEGF levels are elevated during a short time window following PDT. This result underscores the importance for developing tools to monitor cytokines online during cancer therapy. The overall goal of the proposed research is to capture the spatiotemporal dynamics of tumoral VEGF expression in an orthotopic, murine PanCa tumor model during combined PDT and anti-VEGF therapy. This study will also investigate the enhanced treatment outocome found using a newly developed nanoparticle to target the intracellular pool of VEGF. Our first aim is to construct a minimally invasive, quantitative molecular imaging system. A flexible, submillimeter-diameter fiber-optic imaging bundle will be used to access and image pancreatic tumors in situ. This probe will be coupled to a hyperspectral fluorescence detection system to facilitate rigorous quantification of relative changes in secreted VEGF levels. That is, each pixel of the image will contain a fluorescence emission spectrum and each pixel will be analyzed to isolate the anti-VEGF monoclonal antibody-fluorophore conjugate fluorescence (the imaging agent we will employ to visualize VEGF) from the tissue autofluorescence. The proposed design will enable frequent imaging during longitudinal studies. Based on the recorded VEGF expression and secretion dynamics, we will implement timed delivery and optimal dosing of an anti-VEGF therapeutic agent targeted to the appropriate tissue compartments (using the nanoconstruct to target intracellular VEGF and free Avastin to target extracellular VEGF) to optimally block VEGF activity. This work will ases the potential for image-guided PanCa therapy to improve treatment outcomes, and will investigate the mechanism of impoved therapeutic outcome using nanotechnology to target and neutralize intracellular pools of cytokine growth factors. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating disease with one of the worst prognoses in medicine. This project aims to improve pancreatic cancer treatment by addressing the spatiotemporal dynamics of key molecular mediators of tumor survival and proliferation. This project integrates new image-guidance and nanotechnology platforms to deliver therapeutic agents at the "right time" and to the "right place" for optimal inhibition of cancer cell survival and metastasis.

描述（由申请人提供）：胰腺癌（PANCA）是一种毁灭性疾病，所有恶性肿瘤的5年生存率最低（<5％）；因此，迫切需要改善治疗方案。胰腺癌细胞和其他癌细胞类型上调其在治疗过程中特定基因的表达，以促进肿瘤细胞增殖和存活。例如，癌细胞可以增加细胞信号传导因子的产生，例如细胞因子生长因子及其受体。血管内皮生长因子（VEGF）体现了在肿瘤存活和转移中起作用的多种细胞因子。 Hasan组和其他人表明，VEGF表达被癌细胞响应于亚生成性细胞毒性疗法（例如化学疗法，放疗和光动力疗法（PDT））上调。这种肿瘤反应通常会导致疾病复发并增加转移，这是治疗目标的悖论。在调查以减轻这种影响的策略期间，哈桑集团发现，在PDT之后的短时间窗口中，分泌的VEGF水平升高。该结果强调了开发工具在癌症治疗期间在线监测细胞因子的重要性。 拟议的研究的总体目标是捕获在PDT和抗VEGF疗法的原位，鼠PANCA肿瘤模型中肿瘤VEGF表达的时空动力学。这项研究还将研究使用新开发的纳米颗粒来靶向VEGF的增强治疗的外焦组。我们的第一个目的是构建一种微创的定量分子成像系统。柔性的，亚毫米至直径的光纤成像束将用于原位访问和图像胰腺肿瘤。该探针将与高光谱荧光检测系统耦合，以促进分泌VEGF水平的相对变化的严格量化。也就是说，图像的每个像素将包含荧光发射光谱，并且将分析每个像素以分离抗VEGF单克隆抗体 - 氟氟氟此类偶联物荧光（成像剂（我们将用于可视化VEGF）与组织自动荧光的成像剂。提出的设计将在纵向研究中频繁进行成像。根据记录的VEGF表达和分泌动力学，我们将实施针对适当的组织室的抗VEGF治疗剂的定时输送和最佳剂量（使用纳米结构来靶向细胞内VEGF和游离avastin，以靶向靶向细胞外VEGGF），以最佳地阻止VEVGF活性。这项工作将使图像引导的PANCA治疗改善治疗结果的潜力，并将使用纳米技术来研究障碍性治疗结果的机制，以靶向和中和细胞因子生长因子的细胞内池。 公共卫生相关性：胰腺癌是一种毁灭性的疾病，医学中最糟糕的预后之一。该项目旨在通过解决肿瘤存活和增殖的关键分子介质的时空动力学来改善胰腺癌治疗。该项目集成了新的图像指导和纳米技术平台，以在“正确的时间”和“正确的位置”提供治疗剂，以最佳抑制癌细胞的存活和转移。