多模态MRI技术指导非小细胞肺癌个体化放疗生物靶区研究

The standard radiotherapy based on population evidence is unfit for non-small cell lung caner(NSCLC) with heterogeneity. Tumor heterogeneity is associated with disease progression and malignancy, and may have important effects on the results of treatment. Therefore, the discovery of novel radiotherapy strategies based on personal tumor heterogeneity is one of the hotspots in radiotherapy study. Multimodal magnetic resonance imaging (MRI) technology may be an emerging powerful tool for evaluation of tumor heterogeneity because of its unrivaled advantages of non invasiveness, three-dimensional, and dynamic display, which turns the personal radiotherapy into reality. MRI plays a pivotal role in the management of patients with cancer. This technique including proton MR spectroscopy (MRS), diffusion weighted imaging (DWI),pulmonary perfusion imaging using MRI (pMRI), dynamic contrast-enhanced MR(DCE-MR) and functional MRI (fMRI) may be an emerging powerful tool for evaluation of invasiveness and radiosensitivity of NSCLC. In order to overcome the disadvantages of the design of radiotherapy scheme based on population evidence,based on our previous study, we will use lung cancer cells, lung cancer animal models and clinical patients as the research objects in this study to make full use of the multimodal MRI functional imaging information by imaging - pathological specimens - molecular markers precise control study. We will also study the relationship between the imaging features, parameters or the biological index and tumor invasiveness, radiotherapy sensitivity and organs at risk by image fusion, pathological precise matching technology. Third, we will explore the method and relevant technical standards of multimodality MRI delineation of individual biological target,accurate prediction of tumor subregional radiotherapy sensitivity, invasion, and organs at risk based on multimodal MRI technology with accurate radiotherapy technology integration,and then draw the outline of biological target for individual biological intensity-modulated radiotherapy. This study will establish a new model of NSCLC biological radiotherapy to provide theoretical and practical basis for individualized radiotherapy.

基于群体化证据的放疗技术不适合存在巨大差异的非小细胞肺癌（NSCLC）患者，肿瘤异质性是决定NSCLC放疗个体差异的主要因素之一，根据肿瘤异质性勾画个体化生物靶区是目前研究热点之一。多模态磁共振（MRI）技术(包括常规MRI、波谱成像、扩散加权成像等)可以立体显示肿瘤异质性特征，克服CT影像局限性，使NSCLC个体化放疗成为可能。为克服基于群体化证据设计放疗方案的不足，本项目在前期研究基础上，拟以肺癌细胞、肺癌动物模型和临床患者为对象，通过影像-病理标本-分子指标精确匹配对照、图像融合等手段，充分挖掘多模态MRI显像信息，研究影像特征和成像参数与肺癌放疗敏感性指标、侵袭性和危及器官的关系，探索基于多模态MRI技术精确预测肿瘤内亚区域放疗敏感性、侵袭范围和危及器官的方法及技术标准，并据此勾画生物靶区进行个体化生物调强放疗。本研究将建立NSCLC生物放疗新模式，为个体化放疗提供理论和实践依据。

根据肿瘤异质性勾画个体化生物靶区是目前研究热点之一。多模态磁共振（MRI）技术可以立体显示肿瘤异质性特征，克服CT影像局限性，使NSCLC个体化放疗成为可能。为克服基于群体化证据设计放疗方案的不足，本项目前期研究显示多模态MRI显像技术能较好的显示肿瘤异质性，实现肺癌的个体化治疗，该项目拟通过影像-分子指标精确匹配对照、图像融合等手段，充分挖掘多模态MRI显像信息，研究影像特征和成像参数与肺癌放疗敏感性指标、侵袭性和危及器官的关系，探索建立基于多模态MRI技术精确预测肿瘤内亚区域放疗敏感性、侵袭范围和危及器官的方法及技术标准，并据此勾画生物靶区进行个体化生物调强放疗。在该研究中，分别从体内和体外研究了多模态MRI成像技术反映肿瘤生物学特性的能力。（1）在体内研究中，建立肺癌动物模型，进行多模态MRI检查，检测放疗敏感性和侵袭性。对比分析多模态 MRI 成像与肺癌动物模型放疗敏感性、侵袭性的关系；对小鼠进行多模态MRI检查，获取多模态MRI图像，组织病理学检测巨噬细胞数量和炎性指标等，分析对比放疗前后多模态 MRI成像的动态变化及其与分子病理结果的关系，证实多模态 MRI技术能准确评价肺功能；临床上利用多模态MRI技术，进行放疗敏感性和侵袭范围检测，评价肺癌放疗敏感性和侵袭范围，勾画靶区，判断预后及预测放疗副反应，为临床应用提供技术标准；（2）在体外研究中，对比检测不同剂量放疗的细胞株侵袭性和放疗敏感性及相关TLR7/TGF-β1信号通路关键基因表达变化，观察多模态MRI技术参数与分子指标的关系。研究发现：（1）多模态MRI技术能够评价NSCLC放疗敏感性和侵袭性，为临床开展个体化放疗提供实验依据；（2）多模态MRI技术能够评价肺功能和确定危及器官，根据多模态MRI显像确定肿瘤与危及器官的关系，从而达到降低正常肺剂量，减低毒副作用的目的；（3）多模态MRI技术能够构建NSCLC个体化放疗靶区，进而建立基于多模态MRI 技术的NSCLC 个体化放疗技术标准。本研究将进一步丰富肿瘤放疗理论，为临床治疗提供一种全新的方法，具有良好的临床应用前景。