Are ACF Surrogate Markers for Chemoprevention?

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，以评估异常隐窝病灶（ACF）和其他微小病变（<5 mm）在远端和近端结肠癌症发展中的重要性。我们认为远端结肠ACF是自限性病变，这些主要增生性病变进展为肿瘤的可能性很小。虽然ACF具有致癌突变（例如BRAF或KRAS），我们假设这些病变动员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。我们将通过使用共聚焦成像技术和敏感的纳米流体蛋白质组学来研究ACF（特定目标1）内癌基因激活和OIS之间的关系来解决这个问题。与远端结肠相反，我们在特定目标2中提出，近端结肠中的ACF（特别是具有活化BRAF的ACF）的进展风险更高。我们将确定BRAF激活的近端ACF是否表现出较低的OIS效率，可能是通过异常的DNA甲基化，以及更频繁的微卫星不稳定性，相对于远端结肠病变。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，这是一种化学预防剂，已显示出前景，但最近已成为一个潜在的增加近端结肠癌风险的关注。我们还将确定他汀类药物使用对人类ACF中表达的分子标志物的影响（从已完成的试验中获得）。此外，我们将开发和评估一种新的BRAF激活的小鼠模型，可能特别适用于近端癌症化学预防研究。最后，在具体目标4中，我们将检验ACF的频率和/或分子特征将为未来或同步结肠癌风险提供指标标志物的假设。这些研究的成功完成，预计将提供重要的洞察与ACF和其他微小病变的近端和远端结肠的存在相关的癌症风险。我们研究的转化意义在于，在结肠右侧进行筛查的范例可能会从识别大病灶以进行切除转变为将ACF和其他小病灶作为癌症风险的生物标志物，甚至作为潜在的癌症前体。这些信息可能会影响临床实践，额外关注（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，建议更频繁地进行监测结肠镜检查。

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.