Assessment of Tumor Early Response to Treatment by Diffusion MRI

描述（由申请人提供）：本申请要求资金支持辅导定量研究职业发展奖（K25）。候选人在物理学和成像科学方面接受过正式培训，并寻求成为癌症成像跨学科领域的独立研究者。已经制定了职业发展计划，其中包括关键的教学培训，实验室培训和其他职业发展活动，以确保候选人过渡到独立调查员。建议的教学和实验室培训包括癌症生物学，生物统计学，多种成像模式，临床癌症成像，并提出了一个渐进的计划，以培养候选人作为独立研究者的必要技能，包括赠款写作技能，指导技能，科学 评论，以及与研究伦理相关的其他主题。由来自不同领域的知名科学家组成的导师委员会将指导候选人在癌症研究领域建立一个独立的研究小组。拟议的研究旨在开发和验证先进的扩散加权磁共振成像（DW-MRI）技术，使用振荡梯度（OGSE）定量表征肿瘤病理生理学，并评估其作为潜在的非侵入性成像生物标志物的作用，以监测肿瘤对治疗的早期反应。目前，常规DW-MRI已广泛应用于转化和临床癌症研究，以监测肿瘤细胞密度的变化，从而评估治疗反应。然而，治疗肿瘤中的细胞密度变化是下游效应，反映了晚期肿瘤对治疗的反应。捕获治疗后细胞内的初始生理变化是一种潜在的更早和更特异的成像生物标志物，可能能够预测最终的治疗结果。因此，我们开发了一种新的OGSE技术，能够检测细胞内的微观结构的变化，从而能够探测细胞的生理状态。我们的目标是开发和验证OGSE方法作为癌症的潜在成像生物标志物。为了实现这一点，我们将在三种类型的癌症治疗模型中评估OGSE方法，这些模型在随后的细胞密度变化之前在治疗后表现出不同的三类亚细胞形态：1）具有多拷贝DNA内容物和细胞器的细胞-多倍性（>= 8 n）; 2）M期的DNA内容物和细胞器的拷贝加倍（4 n）;和3）细胞停滞在凋亡前状态-亚G 0期（2n）。特别是，我们将进行理论建模（目的I），体外细胞培养研究（目的II）和体内动物成像方法（目的III），以全面研究OGSE方法对抗癌治疗后特定细胞内微观结构变化的敏感性和特异性。如果成功，本提案中描述的方法将提供一种新的MR技术，能够非侵入性地提供肿瘤状态的特异性评估，并在治疗的早期阶段预测最终的治疗结果。

DESCRIPTION (provided by applicant): This application requests funds to support a Mentored Quantitative Research Career Development Award (K25). The candidate has formal training in physics and imaging sciences, and seeks to become an independent investigator in the interdisciplinary field of cancer imaging. A career development plan has been established that includes critical didactic training, laboratory training, and other career development activites that ensure the candidate's transition to an independent investigator. The proposed didactic and laboratory trainings include cancer biology, biostatistics, multiple imaging modalities, clinical cancer imaging, and a progressive plan is proposed for the candidate to develop necessary skills as an independent investigator, including grant writing skills, mentoring skills, scientific reviews, and other topics related to research ethics. A mentor committee formed by established scientist from different fields will guide the candidate to develop an independent research group in the field of cancer research. The proposed research seeks to develop and validate advanced diffusion-weighted magnetic resonance imaging (DW-MRI) techniques using oscillating gradients (OGSE) for quantitative characterization of tumor pathophysiology, and to assess their role as potential non-invasive imaging biomarkers to monitor tumor early response to treatment. Currently, the conventional DW-MRI has been widely adapted in translational and clinical cancer studies to monitor variations in tumor cell density in order to assess therapeutic response. However, the cell density change in treated tumors is a downstream effect, reflecting a late tumor response to treatment. Capturing initial physiological variations within cells following treatment is a potentially earlier and more specific imaging biomarker that may be capable of predicting ultimate therapeutic outcomes. We therefore have developed a new OGSE technique capable of detecting intracellular microstructural variations, and hence capable of probing physiological states of cells. We aim to develop and validate the OGSE method as a potential imaging biomarker in cancer. To accomplish this, we will evaluate the OGSE method in three types of cancer treatment models, exhibiting distinct three classes of subcellular morphology following treatment before subsequent changes in cell density: 1) cells with multiple copies of DNA contents and organelles - polyploidy (>=8n); 2) doubled copies of DNA contents and organelles in M phase (4n); and 3) cells arrested in pre-apoptotic states - sub-G0 phase (2n). In particular, we will perform theoretical modeling (Aim I), in vitro cell culture studies (Am II) and in vivo animal imaging methods (Aim III) to comprehensively investigate the sensitivity and specificity of the OGSE method to specific intracellular microstructural variations following anti-cancer treatment. If successful, the methods described in this proposal would provide a new MR technique that is capable of providing specific assessment of tumor status non-invasively and predicting ultimate therapeutic outcomes at early stage of treatment.