Photon-counting X-ray and Optical Tomography for Preclinical Cancer Research

用于临床前癌症研究的光子计数 X 射线和光学断层扫描

• 批准号: 10017171
• 负责人: Margarida Barroso
• 金额: $ 55.47万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017171
• 关键词: 3D Print; Address; Algorithms; Anatomy; Animal Model; Animals; Biological Assay; Biological Markers; Biological Models; Blood Vessels; Calcium; Cancer cell line; Cancerous; Cells; Chemicals; Collaborations; Complex; Contrast Media; Data Set; Detection; Development; Diagnostic radiologic examination; Dimerization; Disease; Drug Delivery Systems; Drug Targeting; Ensure; Epidermal Growth Factor Receptor; Exhibits; FDA approved; Family; Fluorescence; Fluorescence Resonance Energy Transfer; Functional Imaging; Gadolinium; Goals; Hemoglobin; Heterogeneity; Histopathology; Homodimerization; Human; Hybrids; Image; Immunohistochemistry; Individual; Industrialization; Iodine; Joints; Label; Ligands; Light; Lighting; Lipids; Location; Malignant Neoplasms; Mammary Neoplasms; Maps; Marketing; Measures; Metabolic; Metabolism; Molecular; Molecular Probes; Monitor; Multimodal Imaging; Mus; Mutation; Noise; Optical Tomography; Optics; Oxygen; Pathologic; Patients; Penetration; Pertuzumab; Pharmaceutical Preparations; Photons; Physiological; Pre-Clinical Model; Predictive Value; Property; Records; Resistance; Resolution; Roentgen Rays; Role; Rotation; Scanning; Side; Signal Transduction; Site; Source; Structure; System; Systems Integration; Technology Transfer; Therapeutic; Time; Tissue Differentiation; Tissues; Translations; Trastuzumab; Tumor Volume; Water; X-Ray Computed Tomography; Xenograft procedure; anticancer research; benign state; bone; capsule; commercialization; contrast enhanced; drug discovery; genome sequencing; high dimensionality; image reconstruction; imaging modality; imaging platform; improved; in vivo; inhibiting antibody; interest; malignant breast neoplasm; malignant state; metabolic rate; microCT; novel imaging technology; optical imaging; outcome forecast; photon-counting detector; pre-clinical; preclinical imaging; preclinical study; prognostic value; prototype; receptor; receptor expression; reconstruction; response; spatiotemporal; targeted treatment; tomography; tool; treatment response; tumor; tumor heterogeneity; tumor xenograft

Photon-counting X-ray and Optical Tomography for Preclinical Cancer Research ABSTRACT Preclinical imaging is a critical tool in cancer research. Since cancer exhibits very complex spatiotemporal features, there is a strong need for the development of novel imaging technologies to characterize cancerous tissues and their microenvironments. For this purpose, multimodal imaging has the best potential to provide anatomical, functional and molecular information concurrently in live and intact animals. Of our primary interest, human epidermal growth factor receptor 2 (HER2) expression has prognostic and predictive values in breast cancer. Currently, therapeutic monoclonal anti-HER2 antibodies that inhibit receptor dimerization are FDA- approved. However, an increasingly more complex view of the role of HER2 in breast cancer has emerged from genome sequencing that highlights the importance of inter- and intra-tumor heterogeneity in therapy resistance. Thus, there is a clear need for a non-invasive preclinical imaging modality that is capable of monitoring the interplay between HER2 receptor expression level, targeted drug delivery, and tumor response. The overall goal of this project is to develop a hybrid x-ray and optical prototype for High-dimensional Optical Tomography (HOT) Guided-by Energy-resolved Micro-CT (GEM), visualize and quantitate breast tumor heterogeneity, HER2 expression and dimerization, and therapeutic response in preclinical models. On the x- ray side, photon-counting micro-CT records individual x-ray photons and their energy levels, and enables chemically-specific material decomposition. As a result, a mouse anatomy can be represented in terms of water, lipid, bone, Calcium, Iodine, and Gadolinium. On the optical side, optical molecular tomography maps the distribution of functional biomarkers and molecular probes. Of great importance to targeted therapy, with in vivo Macroscopy Fluorescence Lifetime Förster Resonance Energy Transfer (MFLI-FRET) imaging, our recent results demonstrate that quantitative MFLI-FRET signals correlate strongly with intracellular drug delivery at the pathological site as validated via ex vivo immunohistochemistry analysis. Synergistically, basis materials resolved with photon-counting micro-CT can be related to unique optical properties, and used to correct a heterogeneous optical background for quantitative optical molecular tomography. Furthermore, contrast- enhanced micro-CT can identify regions of interest to regularize optical molecular tomography. The specific aims are to (1) prototype a hybrid HOTGEM system for comprehensive and synergistic x-ray and optical imaging, (2) develop joint methods for image reconstruction from datasets in multi-contrasts collected with the HOTGEM system, and (3) characterize breast cancer in xenograft systems with varying levels of HER2 and HER2-activating mutations using the HOTGEM system. Upon completion, the proposed HOTGEM system will have been validated to offer 50µm x-ray resolution for material decomposition and 100µm optical resolution for target localization in co-registration within 30 minutes for each hybrid in vivo scan, demonstrated to be a breakthrough for tomographic HER2 imaging, and ready for technology transfer and commercial translation.

用于临床前癌症研究的光子计数 X 射线和光学断层扫描 抽象的 由于癌症表现出非常复杂的时空特征，因此临床前成像是癌症研究的重要工具。 特征，强烈需要开发新颖的成像技术来表征癌症 为此，多模态成像最有潜力提供。 我们主要感兴趣的是活体和完整动物的解剖、功能和分子信息。 人表皮生长因子受体2（HER2）表达对乳腺具有预后和预测价值 目前，抑制受体二聚化的治疗性单克隆抗 HER2 抗体已获得 FDA 批准。 然而，对于 HER2 在乳腺癌中的作用，出现了越来越复杂的观点。 基因组测序强调了肿瘤间和肿瘤内异质性在治疗中的重要性 因此，显然需要一种能够检测耐药性的非侵入性临床前成像方式。 监测 HER2 受体表达水平、靶向药物输送和肿瘤反应之间的相互作用。 该项目的总体目标是开发用于高维光学的混合 X 射线和光学原型 断层扫描 (HOT) 能量分辨微型 CT (GEM) 引导下，对乳腺肿瘤进行可视化和定量 异质性、HER2 表达和二聚化以及临床前模型中的治疗反应。 在射线侧，光子计数微型 CT 记录单个 X 射线光子及其能量水平，并能够 因此，小鼠的解剖结构可以用以下形式表示： 水、脂质、骨骼、钙、碘和钆 在光学方面，光学分子断层扫描图。 功能性生物标志物和分子探针的分布对于靶向治疗非常重要。 体内宏观荧光寿命福斯特共振能量转移（MFLI-FRET）成像，我们最近 结果表明，定量 MFLI-FRET 信号与细胞内药物递送密切相关 通过离体免疫组织化学分析验证的病理部位，基础材料。 通过光子计数微型 CT 解决的问题可以与独特的光学特性相关，并用于校正 用于定量光学分子断层扫描的异质光学背景。此外，对比度 增强型微型 CT 可以识别感兴趣区域以规范光学分子断层扫描。 目标是 (1) 构建混合 HOTGEM 系统原型，以实现全面且协同的 X 射线和光学 成像，（2）开发联合方法，从使用多对比收集的数据集进行图像重建 HOTGEM 系统，以及 (3) 表征具有不同水平 HER2 和 HER2 的异种移植系统中的乳腺癌 使用 HOTGEM 系统进行 HER2 激活突变 完成后，拟议的 HOTGEM 系统将。 经验证可为材料分解提供 50 µm X 射线分辨率，并为材料分解提供 100 µm 光学分辨率 每次混合体内扫描 30 分钟内共同配准目标定位，被证明是 断层扫描 HER2 成像的突破，并为技术转让和商业转化做好准备。