Spatial-Temporal Imaging of Cell Proliferation & Hypoxia

描述（由申请人提供）：在我们的初步研究中，我们在放射治疗过程中跟踪细胞增殖的时空分布，在治疗前发现肿瘤异质性。此外，在治疗期间观察到肿瘤中增殖能力的显着重新分布，包括显着和意想不到的加速再生。放射治疗的进展，如调强放疗，提供了根据物理一致性定制放射治疗的能力。结合区域生物信息，特别是其在治疗过程中的变化，可以导致治疗适应。同样，早期评估化疗的疗效并导致癌症管理的改善。时空响应对图像引导干预提出了重大挑战；以及对当前治疗实践进行重大改进的潜力。定量变化和更好地了解肿瘤动力学是阻碍治疗适应的主要未知因素。我们的研究将集中在这两个方面。我们的主要目标是：1)估计两种肿瘤类型的细胞增殖和缺氧在肿瘤间和肿瘤内的异质性，并量化其在癌症治疗过程中的时空变化；2)开发和测试在癌症治疗过程中肿瘤和周围关键结构中细胞增殖和缺氧分布的时空定量监测方法。FLT将作为增殖标志物，Cu-ATSM将作为缺氧标志物用于体内PET成像。PET成像结果将与选定活检样本的免疫组织化学分析相关联，以进一步验证使用的放射性药物。将开发先进的图像共配准技术（如刚体、可变形配准）和空间统计方法（如Moran、G统计），并应用于建立适当水平的图像和数据分析。我们的方法将在更大的动物肿瘤模型（狗）上发展，由于它的大尺寸和与人类的生物学相似性，这是一个很好的研究模型。两种自发的狗肿瘤类型——软组织肉瘤（用放疗治疗）和非霍奇金淋巴瘤（用化疗治疗）将被研究。除了证明J的可行性之外，本试点研究中收集的数据将用于执行良好的接地功率计算，以用于未来更大规模的研究并转化为人类。通过结合增殖与缺氧同时监测（FLT/Cu-ATSM）分布和先进的图像分析，我们假设时空量化其大小，以及这两个参数的变化，可以为癌症治疗的分子图像指导提供定量依据。

DESCRIPTION (provided by applicant): From our preliminary studies, in which we followed spatial-temporal distribution of cell proliferation through the course of radiation treatment, tumor heterogeneity was detected before the treatment. In addition, a significant re-distribution of the proliferative capacity was observed in the tumor during the treatment, including significant and unexpected accelerated repopulation. Advances in radiation treatment delivery, such as intensity-modulated radiotherapy, provide the ability to customize radiation delivery based on physical conformity. Incorporation of regional biologic information, especially its changes during therapy, could lead to treatment adaptation. Similarly, early assessment of chemotherapy efficacy and lead to improved cancer management. The spatio-temporal response represents significant challenges for image-guided interventions; and the potential for significant improvement of the current treatment practice. Quantification of the changes and better understanding of tumor kinetics are the main unknowns preventing treatment adaptation. Our research will be focused in these two areas. Our main goals in this project are: 1) to estimate inter- and intra-tumor heterogeneity of cell proliferation and hypoxia for two tumor types and quantify its spatio-temporal change during cancer therapy and 2) to develop and test the methodology for quantitative monitoring of spatio- temporal cell proliferation and hypoxia distribution in the tumor and surrounding critical structures during cancer therapy. FLT will be used as a proliferation marker and Cu-ATSM as a hypoxia marker for in-vivo PET imaging. The PET imaging results will be correlated to immunohistochemical analyses of selected biopsy samples to further validate the used radiopharmaceuticals. Advanced image co-registration techniques (e.g., rigid body, deformable registration) and spatial statistics methods (e.g., Moran, G statistics) will be developed and applied to establish appropriate level of image and data analyses. Our methodology will be developed on larger animal tumor models (dogs), which are an excellent research model due to its large size and biological similarity to humans. Two spontaneous dog tumor types - soft tissue sarcoma (treated with radiotherapy) and non-Hodgkin's lymphoma (treated with chemotherapy) will be investigated. In addition to proving J feasibility, the data collected in this pilot study will be used to perform well-grounded power calculations for a future larger study and translation to humans. By combining concurrent monitoring of proliferation and hypoxia (FLT/Cu-ATSM) distributions and advanced image analyses, we hypothesize that spatio-al temporal quantification of the magnitude, and the change of both parameters, can provide quantitative basis for molecular image guidance of cancer therapy.