Spatial-Temporal Imaging of Cell Proliferation & Hypoxia

描述（由申请人提供）：根据我们的初步研究，我们在放射治疗过程中跟踪细胞增殖的时空分布，在治疗前检测到肿瘤异质性。此外，在治疗期间在肿瘤中观察到增殖能力的显著再分布，包括显著和意外的加速再增殖。放射治疗输送的进步，例如调强放射治疗，提供了根据身体符合性定制放射输送的能力。局部生物信息的整合，特别是其在治疗过程中的变化，可能导致治疗适应。同样，早期评估化疗的疗效并改善癌症管理。时空响应代表了图像引导干预的重大挑战;以及显著改善当前治疗实践的潜力。定量的变化和更好地了解肿瘤动力学的主要未知因素，防止治疗适应。我们的研究将集中在这两个领域。我们在这个项目中的主要目标是：1）估计两种肿瘤类型的细胞增殖和缺氧的肿瘤间和肿瘤内异质性，并量化其在癌症治疗期间的时空变化; 2）开发和测试用于定量监测癌症治疗期间肿瘤和周围关键结构中的细胞增殖和缺氧时空分布的方法。FLT将用作体内PET成像的增殖标志物，Cu-ATSM将用作缺氧标志物。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，以进一步验证所用放射性药物。先进的图像配准技术（例如，刚体，可变形配准）和空间统计方法（例如，Moran，G统计）将被开发和应用，以建立适当的图像和数据分析水平。我们的方法将在较大的动物肿瘤模型（狗）上开发，由于其体积大且与人类生物学相似，因此是一种优秀的研究模型。将研究两种自发性犬肿瘤类型-软组织肉瘤（用放疗治疗）和非霍奇金淋巴瘤（用化疗治疗）。除了证明J的可行性外，本试点研究中收集的数据将用于为未来更大规模的研究和人类翻译进行充分的功率计算。通过结合增殖和缺氧（FLT/Cu-ATSM）分布的同步监测和先进的图像分析，我们假设时空定量的幅度，和两个参数的变化，可以提供定量的基础上，分子图像指导癌症治疗。

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.