Are ACF Surrogate Markers for Chemoprevention?

描述(申请人提供)：我们提出了一种多学科的方法，结合分子分析和资助的临床研究，评估变异隐窝病灶(ACF)和其他微小病变(&lt；5 mm)在远端和近端结肠癌发展中的重要性。我们认为远端结肠ACF是自限性病变，这些主要是增生性病变中很少有进展为肿瘤。虽然ACF具有致癌突变(如BRAF或KRAS)，但我们假设这些病变激活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)通路类似。我们将通过使用共聚焦成像技术和敏感的纳米流体蛋白质组学来研究ACF中癌基因激活和OIS之间的关系(特定目标1)。与远端结肠不同，我们在特定的目标2中提出，近端结肠的ACF(特别是那些BRAF激活的患者)进展的风险更高。我们将确定与远端结肠病变相比，BRAF激活的近端ACF是否表现出效率较低的OIS，可能是通过异常的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(特定目标3)来评估化学预防的区域差异。我们首先将重点放在阿托伐他汀上，这是一种化学预防性药物，已显示出希望，但最近已成为潜在增加近端结肠癌风险的一个问题。我们还将确定他汀类药物的使用对人类ACF(从完成的试验中获得)表达的分子标志物的影响。此外，我们将开发和评估一种新的BRAF激活的小鼠模型，该模型可能对近端癌症的化学预防研究特别有用。最后，在特定的目标4中，我们将检验ACF的频率和/或分子特征将为未来或同步的结肠癌风险提供指数标记物的假设。这些研究的成功完成有望为与ACF和其他近端和远端结肠微小病变的存在相关的癌症风险提供重要的洞察。我们研究的翻译意义在于，在结肠右侧进行筛查的范例可能会改变，从识别需要切除的大病变转变为包括ACF和其他微小病变作为癌症风险的生物标记物，甚至作为潜在的癌症前兆。这些信息可能会潜在地影响临床实践，特别注意(或切除)近端结肠的ACF和其他小病变，并根据所确定的分子特征，建议更频繁地监测结肠镜检查。 与公众健康相关：结肠粘膜暴露于广泛的致癌侮辱中，评估此类暴露造成的累积组织损害可能为评估个人的结肠癌风险提供重要信息。我们提出了一种结合分子分析和资助的临床研究的多学科方法来评估人类受试者和小鼠模型中的肿瘤前病变。我们的研究旨在确定与近端和远端结肠肿瘤前病变相关的风险，以确定临床上应该如何看待和治疗它们。

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.