Biological Basis of Imaging Biomarkers in Colorectal Cancer

描述（由申请人提供）：本拟议研究的目的是评估和验证用于评估结直肠癌（CRC）治疗反应的新兴非侵入性成像生物标志物的生物学基础。目前评估治疗反应的影像学标准是根据实体肿瘤反应评估标准（RECIST）指南的解剖学信息。这些标准，仅仅是基于肿瘤大小的减少，没有利用细胞和分子信息，现在可以通过当代成像方法。重要的是，由于相关的细胞和分子变化可能先于大小变化并在治疗数小时内发生，RECIST标准和传统成像方法通常不足以评估早期肿瘤反应。这些局限性，加上使用复杂的分子靶向治疗方案来治疗癌症的临床相关性日益增加，突出了加速能够报告肿瘤细胞对治疗的细胞和分子反应的新型成像方法的翻译的迫切需要。目前，新成像方法临床翻译的主要障碍是缺乏在相关生物学背景下进行的适当验证研究。本文提出的研究建立在广泛的临床前和临床数据的基础上，这些数据是通过我们参与胃肠道研究卓越特别计划（GI SPORE）和人类癌症小鼠模型联盟（MMHCC）获得的，旨在阐明和验证影响特定癌症成像生物标志物的潜在生物学因素和分子事件。在这些研究中，我们建议全面验证三种报告细胞增殖和凋亡方面的平移成像指标，即[18F]-FLT PET成像，通过MRI （ADC-MRI）进行表观扩散系数成像和[99mTc]-Annexin-V SPECT成像。细胞增殖和凋亡是已知在癌细胞中失调的关键生物学过程；因此，这些过程的非侵入性纵向成像评估在预测和量化治疗反应方面可能具有特别的价值。所提出的成像生物标志物的验证将在分子靶向治疗晚期结直肠癌的背景下进行，这是我们在临床前和临床环境中拥有丰富经验的领域。为了实现这些目标，我们确定了两个具体目标。目的1-探索非侵入性成像生物标志物与人类结直肠癌临床前小鼠模型中调节细胞周期和凋亡的离散基因组和蛋白质组学分子事件之间的定量关系。目标2-探索用小分子和蛋白质组学成像质谱和组织学注册三维多参数成像数据集的效用，以便在成像阵列中逐体素的基础上进行定量生物标志物验证。公共卫生相关性：本研究的目的是评估和验证用于评估结直肠癌（CRC）治疗反应的新兴非侵入性成像生物标志物的生物学基础。目前，新成像方法临床翻译的主要障碍是缺乏在相关生物学背景下进行的适当验证研究。我们建议全面验证[18F]-FLT PET成像、通过MRI （ADC-MRI）绘制表观扩散系数和[99mTc]-Annexin-V SPECT成像作为准确评估CRC分子靶向治疗疗效的指标。

DESCRIPTION (provided by applicant): The goal of this proposed research is to evaluate and validate the biological basis of emerging non-invasive imaging biomarkers for use in evaluation of treatment response in colorectal cancer (CRC). Current imaging criteria for evaluating therapeutic response are based upon anatomical information according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. These criteria, which are solely based on a reduction in tumor size, do not take advantage of cellular and molecular information now available through contemporary imaging methodology. Importantly, since relevant cellular and molecular changes may precede changes in size and occur within hours of treatment, RECIST criteria and conventional imaging methods are frequently inadequate for assessing early tumor response. These limitations, coupled with the increasing clinical relevance of employing complex, molecularly targeted therapeutic regimens to treat cancer, highlight a critical need to accelerate the translation of novel imaging approaches that are capable of reporting cellular and molecular responses of tumor cells to therapy. Presently, a major impediment to the clinical translation of novel imaging methodology is a lack of appropriate validation studies conducted within relevant biological contexts. The investigations proposed herein build upon extensive preclinical and clinical data accessible through our participation in both the Gastrointestinal Special Program of Research Excellence (GI SPORE) and the Mouse Models of Human Cancers Consortium (MMHCC) and aim to elucidate and validate the underlying biological factors and molecular events that affect specific cancer imaging biomarkers. In these studies, we propose comprehensive validation of three translational imaging metrics that report aspects of cellular proliferation and apoptosis, namely [18F]-FLT PET imaging, apparent diffusion coefficient mapping via MRI (ADC-MRI), and [99mTc]-Annexin-V SPECT imaging. Cellular proliferation and apoptosis are critical biological processes known to be dysregulated in cancer cells; thus non-invasive, longitudinal imaging assessments of these processes could be of particular value in predicting and quantifying response to therapy. Validation of the proposed imaging biomarkers will be performed within the context of molecularly targeted therapy for treatment of advanced CRC, a field where we have considerable Institutional experience within preclinical and clinical settings. To accomplish these goals, we have identified two specific aims. Aim 1- To explore quantitative relationships between non-invasive imaging biomarkers and discrete genomic and proteomic molecular events that regulate cell cycle and apoptosis in preclinical mouse models of human colorectal cancer. Aim 2- To explore the utility of registering three-dimensional, multi-parametric imaging data sets with small-molecule and proteomic imaging mass spectrometry and histology for quantitative biomarker validation on a voxel-by-voxel basis within imaging arrays. PUBLIC HEALTH RELEVANCE: The goal of this proposed research is to evaluate and validate the biological basis of emerging non-invasive imaging biomarkers for use in evaluation of treatment response in colorectal cancer (CRC). Presently, a major impediment to the clinical translation of novel imaging methodology is a lack of appropriate validation studies conducted within relevant biological contexts. We propose comprehensive validation of [18F]-FLT PET imaging, apparent diffusion coefficient mapping via MRI (ADC-MRI), and [99mTc]-Annexin-V SPECT imaging as metrics to accurately assess the efficacy of molecularly targeted therapy in CRC.