Prognostic and Functional Significance of Adhesion Molecules in Pediatric AML

描述（由申请人提供）：急性髓性白血病（AML）的结局在个体患者之间差异很大。鉴于这种异质性，人们长期以来一直对确定治疗反应的预测因子感兴趣。然而，即使是整合了许多这些既定因素的复杂模型，目前的预测准确性也更接近于抛硬币而不是确定性，这表明需要描述新的关键生物学特征，以细化疾病风险分类，并允许更好地定制，风险分层治疗方法。我们最近的数据表明，极晚期抗原-4（VLA-4）整合素可能定义这样的标志物。具体而言，在216名儿童肿瘤组（COG）-AAML 03 P1试验的参与者中，我们发现VLA-4高表达独立预测复发风险（RR）较低和无病生存期（DFS）上级;这种效应在标准风险患者中尤其明显，即那些通常缺乏可识别的细胞遗传学/分子风险因素的多样化患者。到目前为止，所观察到的VLA-4表达与结局之间相关性的生物学基础尚不清楚。我们现在建议验证我们先前关于VLA-4在COG-AAML 0531研究中作为预后标志物的作用的研究结果，该研究是一项针对> 1，000名新诊断的AML儿童患者的III期试验，并确定其相对于其他已建立的标志物对预测模型准确性的定量贡献。我们还将测试我们的假设，即高VLA-4表达与粘附分子和细胞外基质（ECM）蛋白的特异性表达谱相关，正如我们的初步研究所表明的那样，以及对VLA-4配体的不同反应，最终导致化学抗性降低和结局改善，并为观察到的VLA-4预测能力提供生物学基础。具体而言，我们将：1）确定诊断性AML母细胞上的高VLA-4表达是否预测入组COG-AAML 0531的患有新诊断AML的儿科患者中降低的RR和上级DFS; 2）定义COG-AAML 0531试验组群中粘附分子和ECM蛋白的表达谱，并确定它们与VLA-4表达的关联以及诱导和巩固化疗后结果的预测作用;和3）比较和验证在基线和响应生理VLA-4配体时具有高和低VLA-4表达的靶向生物样本组中的基因表达特征。这些研究将进一步确定和验证VLA-4和其他粘附分子和ECM蛋白作为儿童AML治疗反应预测因子的作用。我们提出的研究可能会确定粘附分子的表达模式，有助于患者间的差异，在化疗反应，并提供个性化的，适应风险的治疗方法，目前的治疗策略的一个重大进步的基本原理。此外，除了这些蛋白的预后作用的描绘，我们的研究可能会发现新的治疗药物开发的目标，并提供了基本原理的机制研究，旨在了解其在白血病的功能作用。 公共卫生相关性：急性髓性白血病（AML）仍然是一种难以治疗的血癌，个体患者之间的结果存在很大差异。拟议的研究旨在通过深入研究粘附分子（特别是称为VLA-4的分子）作为AML中新型预后标志物的作用，提高我们预测每位患者对AML治疗的反应和预测结果的能力;这些研究的成功将使更好，更个性化的治疗算法成为可能，并最终导致AML患者的上级结局。该研究进一步旨在了解这些标记物提供预后信息的原因，这一理解可能会导致发现用于患者特异性治疗的新型药物靶点。

DESCRIPTION (provided by applicant): The outcome in acute myeloid leukemia (AML) varies widely between individual patients. Given this heterogeneity, there is long-standing interest in identifying predictors of therapeutic response. However, even complex models that integrate many of these established factors currently have a predictive accuracy that is closer to a coin flip than certainty, documenting the need for the delineation of novel, critical biological feature to refine disease-risk classification and allow better-tailored, risk-stratified treatment approaches. Our recent data suggest that the very late antigen-4 (VLA-4) integrin may define such a marker. Specifically, among 216 participants of the Children's Oncology Group (COG)-AAML03P1 trial, we found that high VLA-4 expression independently predicted a lower risk of relapse (RR) and superior disease-free survival (DFS); this effect was particularly pronounced in standard-risk patients, i.e. those diverse patients that often lack identifiable cytogenetic/molecular risk factors. So far, the biological basis for the observed association between VLA-4 expression and outcome is unknown. We now propose to validate our previous findings on the role of VLA-4 as prognostic marker in the COG-AAML0531 study, a phase 3 trial on >1,000 pediatric patients with newly diagnosed AML, and to define its quantitative contribution to the accuracy of prediction models relative to other, established markers. We will also test our hypothesis that high VLA-4 expression is associated with a specific expression profile of adhesion molecules and extracellular matrix (ECM) proteins, as suggested by our preliminary studies, as well as distinct responses to VLA-4 ligands that, ultimately, result in reduced chemoresistance and improved outcome and provide a biological basis for the observed predictive ability of VLA-4.] Specifically, we will: 1) Determine whether high VLA-4 expression on diagnostic AML blast cells predicts a reduced RR and superior DFS in pediatric patients with newly diagnosed AML enrolled in COG-AAML0531; 2) Define the expression profiles of adhesion molecules and ECM proteins in the COG-AAML0531 trial cohort and determine their association with VLA-4 expression and predictive role for outcome after induction and consolidation chemotherapy; and 3) Compare and validate the gene expression signatures in a targeted set of biospecimens with high and low VLA-4 expression at baseline and in response to physiological VLA-4 ligands. These studies will further define and validate the role of VLA-4 and other adhesion molecules and ECM proteins as predictors of therapeutic response in pediatric AML. Our proposed research may identify adhesion molecule expression patterns that contribute to the inter-patient variability in response to chemotherapy and provide the rationale for personalized, risk-adapted therapeutic approaches, a major advancement over current treatment strategies. Furthermore, beyond the delineation of the prognostic role of such proteins, our studies may discover novel targets for therapeutic drug development and provide the rationale for mechanistic studies aimed at understanding their functional role in leukemogenesis. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) remains a difficult-to-treat blood cancer with substantial variability in outcome between individual patients. The proposed research seeks to improve our ability to predict the response of each patient to AML treatment and forecast outcome through in-depth study of the role of adhesion molecules (in particular a molecule called VLA-4) as novel prognostic markers in AML; success in these studies will enable better, more personalized therapeutic algorithms and, ultimately, lead to superior outcomes of patients with AML. The research further aims to understand the reason(s) why these markers provide prognostic information, an understanding that could result in the discovery of novel drug targets for patient-specific therapies.