Are ACF Surrogate Markers for Chemoprevention?

ACF 替代标记物可用于化学预防吗？

• 批准号: 8278959
• 负责人: Daniel William Rosenberg
• 金额: $ 33.34万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278959
• 关键词: Aberrant DNA Methylation; Aberrant crypt foci; Address; Apoptosis; Attention; BRAF gene; Biological Markers; Cells; Characteristics; Chemoprevention; Clinical Research; Colon; Colon Carcinoma; Colonoscopy; Colorectal Cancer; CpG Island Methylator Phenotype; Cross-Sectional Studies; Data; Defect; Development; Disease; Distal; Epigenetic Process; Excision; Frequencies; Funding; Future; Goals; Growth; Histocompatibility Testing; Human; Hyperplasia; Image; Imaging Techniques; Incidence; Individual; Intestines; K-ras mouse model; KRAS2 gene; Lesion; Location; Malignant Neoplasms; Microsatellite Instability; Molecular; Molecular Abnormality; Molecular Analysis; Mucous Membrane; Mus; Mutant Strains Mice; Mutation; Neoplasms; Oncogene Activation; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Prevention; Proteomics; Recommendation; Relative (related person); Right-On; Risk; Risk Factors; Rodent Model; Role; Sampling; Screening procedure; Shapes; Side; Signal Pathway; Signal Transduction; Source; Staging; Surrogate Markers; Testing; Tissues; Work; adenoma; atorvastatin; cancer chemoprevention; cancer risk; cell type; clinical practice; colorectal cancer screening; follow-up; high risk; human subject; indexing; insight; molecular marker; mouse model; nanofluidic; neoplastic; novel; prenylation; regional difference; response; senescence; tumor progression

DESCRIPTION (provided by applicant): We propose a multi-disciplinary approach combining molecular analyses with funded clinical studies to evaluate aberrant crypt foci (ACF) and other diminutive lesions (<5 mm) for their significance in cancer development in the distal and proximal colon. We propose that distal colon ACF are self-limiting lesions and that few if any of these mainly hyperplastic lesions progress to neoplasia. Although ACF possess oncogenic mutations (e.g. BRAF or KRAS), we hypothesize that these lesions mobilize signaling pathways comparable to oncogene-induced senescence (OIS) pathways described in other cell and tissue types. We will approach this problem by using confocal imaging techniques and sensitive nanofluidic proteomics to examine the relationship between oncogene activation and OIS within ACF (Specific Aim 1). In contrast to the distal colon, we propose in Specific Aim 2 that ACF in the proximal colon (particularly those with activated BRAF) are at higher risk for progression. We will determine whether BRAF-activated proximal ACF show less efficient OIS, possibly through aberrant DNA methylation, and more frequent microsatellite instability, relative to distal colon lesions. In addition to assessing regional differences in colon cancer progression, we will also evaluate regional differences in chemoprevention using a mouse model of proximal colon cancer driven by KRAS activation (Specific Aim 3). We will focus initially on atorvastatin, a chemoprevention agent that has shown promise but has recently become a concern for potentially increasing proximal colon cancer risk. We will also determine the impact of statin usage on molecular markers expressed in human ACF (obtained from a completed trial). In addition, we will develop and evaluate a novel BRAF activated mouse model that may be particularly useful for proximal cancer chemoprevention studies. Finally, in Specific Aim 4, we will test the hypothesis that the frequency and/or molecular features of ACF will provide an index marker for future or synchronous colon cancer risk. Successful completion of these studies is anticipated to provide important insight into the cancer risk associated with the presence of ACF and other diminutive lesions in the proximal and distal colon. The Translational Significance of our studies is that the paradigm for screening on the right side of the colon may change from identifying large lesions for removal to the inclusion of ACF and other diminutive lesions as biomarkers for cancer risk, or even as potential cancer precursors. This information could potentially shape clinical practice, with additional attention to (or removal of) ACF and other small lesions in the proximal colon and depending on the molecular features identified, a recommendation of more frequent surveillance colonoscopies. PUBLIC HEALTH RELEVANCE: The colonic mucosa is exposed to a wide range of carcinogenic insults and assessing the cumulative tissue damage resulting from such exposures could provide important information for assessing an individual's colon cancer risk. We propose a multi-disciplinary approach combining molecular analysis with funded clinical studies to evaluate pre-neoplastic lesions in human subjects and in mouse models. Our studies are intended to determine the risk associated with these pre-neoplastic lesions in the proximal and distal colon to determine how they should be viewed and treated clinically.

描述（由申请人提供）：我们提出了一种多学科方法，将分子分析与资助的临床研究相结合，以评估异常隐窝灶（ACF）和其他微小病变（<5毫米）在远端和近端结肠癌症发展中的重要性。 We propose that distal colon ACF are self-limiting lesions and that few if any of these mainly hyperplastic lesions progress to neoplasia.尽管 ACF 具有致癌突变（例如 BRAF 或 KRAS），但我们假设这些病变调动的信号通路与其他细胞和组织类型中描述的癌基因诱导衰老 (OIS) 通路相当。我们将通过使用共焦成像技术和敏感的纳米流体蛋白质组学来研究 ACF 内癌基因激活和 OIS 之间的关系来解决这个问题（具体目标 1）。与远端结肠相比，我们在具体目标 2 中提出，近端结肠中的 ACF（特别是那些具有激活的 BRAF 的患者）具有更高的进展风险。我们将确定相对于远端结肠病变，BRAF 激活的近端 ACF 是否表现出较低效率的 OIS（可能是通过异常 DNA 甲基化）和更频繁的微卫星不稳定性。除了评估结肠癌进展的区域差异外，我们还将使用 KRAS 激活驱动的近端结肠癌小鼠模型评估化学预防的区域差异（具体目标 3）。我们将首先关注阿托伐他汀，这是一种化学预防药物，已显示出前景，但最近因可能增加近端结肠癌风险而受到关注。我们还将确定他汀类药物的使用对人类 ACF 中表达的分子标记（从已完成的试验中获得）的影响。此外，我们将开发和评估一种新型 BRAF 激活小鼠模型，该模型可能对近端癌症化学预防研究特别有用。最后，在具体目标 4 中，我们将检验以下假设：ACF 的频率和/或分子特征将为未来或同期结肠癌风险提供指数标记。这些研究的成功完成预计将为近端和远端结肠中 ACF 和其他微小病变的存在相关的癌症风险提供重要的见解。我们研究的转化意义在于，右侧结肠筛查的范式可能会发生变化，从识别需要切除的大病变到将 ACF 和其他微小病变纳入癌症风险的生物标志物，甚至作为潜在的癌症前兆。这些信息可能会影响临床实践，特别关注（或去除）ACF 和近端结肠中的其他小病变，并根据确定的分子特征，建议更频繁地进行结肠镜监测监测。 公共健康相关性：结肠粘膜暴露于多种致癌损伤，评估此类暴露造成的累积组织损伤可以为评估个体患结肠癌的风险提供重要信息。我们提出了一种将分子分析与资助的临床研究相结合的多学科方法，以评估人类受试者和小鼠模型的肿瘤前病变。我们的研究旨在确定与近端和远端结肠中这些肿瘤前病变相关的风险，以确定临床上应如何看待和治疗它们。