Hyperspectral and Structural Microscopy Platform for Therapy of Resistant Cancer

用于治疗耐药性癌症的高光谱和结构显微镜平台

• 批准号: 8034979
• 负责人: Conor Lee Evans
• 金额: $ 17.41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034979
• 关键词: Address; Amaze; Apoptosis; Basic Cancer Research; Cancer Biology; Cancer Patient; Cause of Death; Cell Hypoxia; Cells; Cessation of life; Clinical; Complex; Confocal Microscopy; Detection; Development; Diffusion; Disease; Disease Resistance; Disseminated Malignant Neoplasm; Environment; Faculty; Foundations; Future; Goals; Gold; Grant; Heterogeneity; Hour; Hypoxia; Image; Imagery; Imaging Device; Imaging technology; In Situ; In Vitro; Knowledge; Label; Lasers; Lateral; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Measurement; Metastatic Lesion; Methods; Microscope; Microscopic; Microscopy; Modality; Modeling; Molecular; Molecular Probes; Molecular Profiling; Monitor; Nature; Necrosis; Nodule; Noise; Optical Coherence Tomography; Optics; Patients; Pharmaceutical Preparations; Photochemotherapy; Plant Roots; Primary Neoplasm; Property; Research; Research Personnel; Resistance; Resolution; Resources; Retinal blind spot; Sampling; Scanning; Screening procedure; Signal Transduction; Staging; Staining method; System; Technology; Therapeutic; Therapeutic Human Experimentation; Time; Tissue Sample; Translating; Treatment Factor; Validation; Work; anticancer research; base; bench to bedside; cancer imaging; cancer therapy; cell fixing; cellular imaging; design; experience; fluorophore; human disease; improved; in vitro Model; in vivo; innovation; instrument; molecular imaging; oncology; programs; resistance factors; response; spatiotemporal; therapy resistant; three-dimensional modeling; tissue phantom; tool; translational approach; translational medicine; treatment response; treatment strategy; tumor; uptake

DESCRIPTION (provided by applicant): Although much progress has been made in detecting and treating cancer, disseminated metastatic disease remains the leading cause of death in cancer patients. Frustratingly little is known regarding how these deadly lesions respond to and eventually resist treatment in vivo due to their widespread nature, often sub-clinical sizes, and highly heterogeneous microenvironments. The lack of appropriate imaging tools to understand and overcome treatment resistance on the microscale in metastatic cancer represents a major unmet need in both cancer research and therapeutics. To address this critical challenge, this application introduces an innovative microscopic technological paradigm for visualizing and understanding the microscale treatment response and resistance factors found in disseminated metastatic cancer. The goal of this work is to develop a high- throughput, live-cell, molecular and structural optical microscopy platform capable of visualizing and monitoring therapeutic response in micrometastatic lesions in vitro at both the cellular and nodular levels. Such an imaging platform will enable a bottom-up approach for basic cancer and cancer therapeutics research by building a detailed spatiotemporal picture of cancer therapy from single cells all the way to the whole tumor. Based upon the complementary molecular and structural imaging technologies of hyperspectral microscopy and optical coherence tomography (OCT), the automated multiplexed therapy-imaging platform will enable long-term cellular and nodular-level studies that map the 3D distribution of molecular treatment factors within a structural context. The new real-time, tunable, near-IR optimized hyperspectral microscopy system will allow for 3D, multi-fluorophore, live-cell imaging of treatment resistance factors deep in tumor nodules. For longitudinal microscale visualization of the complex structural changes caused by treatment, the non- perturbative and label-free time-lapse OCT (TL-OCT) modality will be integrated along with the hyperspectral microscope. Applicable to many metastatic cancers, this new imaging platform will be validated using a physiologically relevant, repeatable, and multiplexed in vitro 3D model of micrometastatic ovarian cancer for imaging-based screens. In the first application of this approach, the multimodal technological platform for cancer biology research will focus on visualizing and correlating several crucial treatment resistance factors, such as drug uptake and diffusion, hypoxia, and pH, with treatment response. This imaging-based approach to systematically and quantitatively characterize cancer therapy response and resistance represents a departure from traditional methods that miss crucial molecular and structural information. These technologies can be readily translated for imaging patient tissue samples ex vivo, or in situ microendoscopically, for image-guided therapeutic planning. By building our knowledge of treatment response and resistance at the microscale, this innovative imaging platform forms the foundation of a transformative, new investigator-led research program aiming to improve current cancer therapeutics and defeat treatment-resistant metastatic disease. PUBLIC HEALTH RELEVANCE: Cancer that becomes metastatic is too often fatal due to the spread of numerous microscopic lesions that grow to be treatment resistant. The goal of this application is to address the root causes of treatment resistance in cancer through an innovative microscale imaging approach capable of visualizing the crucial molecular and structural factors involved in therapeutic response. By building an understanding of how deadly lesions escape therapy from the cellular level to the whole tumor, and using this knowledge to defeat treatment-resistant disease, the technology developed in this application aims to significantly improve the lives of patients suffering from advanced metastatic cancer.

描述（由申请人提供）：尽管在检测和治疗癌症方面取得了很大进展，但播散性转移性疾病仍然是癌症患者死亡的主要原因。令人沮丧的是，关于这些致命的病变如何响应并最终抵抗体内治疗，由于其广泛的性质，通常是亚临床大小和高度异质性的微环境，我们知之甚少。缺乏适当的成像工具来理解和克服转移性癌症中微尺度上的治疗抗性代表了癌症研究和治疗中的主要未满足的需求。为了应对这一关键挑战，该应用程序引入了一种创新的微观技术范式，用于可视化和理解在播散性转移性癌症中发现的微尺度治疗反应和耐药因素。这项工作的目标是开发一种高通量、活细胞、分子和结构光学显微镜平台，能够在细胞和结节水平上可视化和监测体外微转移病灶的治疗反应。这样的成像平台将通过构建从单细胞到整个肿瘤的癌症治疗的详细时空图像，为基础癌症和癌症治疗研究提供自下而上的方法。 基于高光谱显微镜和光学相干断层扫描（OCT）的互补分子和结构成像技术，自动化多路复用治疗成像平台将实现长期的细胞和结节水平的研究，绘制结构背景下分子治疗因素的3D分布。新的实时、可调、近红外优化的高光谱显微镜系统将允许对肿瘤结节深处的治疗抗性因子进行3D、多荧光团、活细胞成像。对于治疗引起的复杂结构变化的纵向微观可视化，将沿着高光谱显微镜集成非扰动和无标记延时OCT（TL-OCT）模式。适用于许多转移性癌症，这种新的成像平台将使用生理相关的，可重复的和多路复用的微转移性卵巢癌体外3D模型进行验证，以进行基于成像的筛选。在这种方法的首次应用中，癌症生物学研究的多模式技术平台将专注于可视化和关联几个关键的治疗抵抗因素，如药物吸收和扩散，缺氧和pH值，与治疗反应。这种基于成像的方法系统地和定量地表征癌症治疗反应和耐药性，代表了对传统方法的偏离，这些方法错过了关键的分子和结构信息。这些技术可以很容易地转化为离体或原位显微内窥镜下成像患者组织样本，用于图像引导的治疗计划。通过建立我们在微观尺度上对治疗反应和耐药性的了解，这个创新的成像平台构成了一个变革性的、新的、由癌症研究者主导的研究项目的基础，该项目旨在改善当前的癌症治疗方法，并击败耐药性转移性疾病。 公共卫生相关性：转移性癌症往往是致命的，因为许多微小病变的扩散会对治疗产生抗药性。该应用的目标是通过一种创新的微尺度成像方法来解决癌症治疗耐药性的根本原因，该方法能够可视化治疗反应中涉及的关键分子和结构因素。通过了解致命病变如何从细胞水平逃脱治疗到整个肿瘤，并利用这些知识击败耐药疾病，该应用中开发的技术旨在显着改善晚期转移性癌症患者的生活。