Biological Basis of Imaging Biomarkers in Colorectal Cancer

描述(申请人提供)：这项拟议研究的目标是评估和验证新出现的非侵入性成像生物标记物的生物学基础，用于评估结直肠癌(CRC)的治疗反应。目前用于评估治疗反应的影像标准是基于实体肿瘤反应评估标准(RECIST)指南中的解剖学信息。这些标准完全基于肿瘤大小的缩小，没有利用目前通过现代成像方法获得的细胞和分子信息。重要的是，由于相关的细胞和分子变化可能发生在大小变化之前，并在治疗后几个小时内发生，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，再加上使用复杂的、分子靶向的治疗方案治疗癌症的临床相关性日益增强，突显了加快转化能够报告肿瘤细胞和分子对治疗的细胞和分子反应的新的成像方法的迫切需要。目前，新的成像方法临床翻译的一个主要障碍是缺乏在相关生物学背景下进行的适当的验证性研究。本文建议的研究建立在我们通过参与胃肠道卓越研究特别计划(GI Spoke)和人类癌症小鼠模型联盟(MMHCC)获得的大量临床前和临床数据的基础上，旨在阐明和验证影响特定癌症成像生物标记物的潜在生物因素和分子事件。在这些研究中，我们建议对三种报告细胞增殖和凋亡方面的平移成像指标进行全面验证，即[18F]-Flt PET成像、通过MRI的表观扩散系数图(ADC-MRI)和[99mTc]-Annexin-V SPECT成像。细胞增殖和凋亡是已知在癌细胞中失控的关键生物学过程；因此，对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。建议的成像生物标记物的验证将在分子靶向治疗晚期结直肠癌的背景下进行，在这个领域，我们在临床前和临床环境中拥有丰富的机构经验。为了实现这些目标，我们确定了两个具体目标。目的1-探讨非侵入性成像生物标志物与调节细胞周期和细胞凋亡的离散基因组和蛋白质组分子事件之间的定量关系。目的2-探索将三维、多参数成像数据集与小分子和蛋白质组成像质谱学和组织学配准，用于成像阵列内逐个体素的定量生物标记物验证。

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.