Prognostic and Functional Significance of Adhesion Molecules in Pediatric AML

描述(由申请人提供)：急性髓系白血病(AML)的结果在不同患者之间差别很大。鉴于这种异质性，长期以来，人们对确定治疗反应的预测因素感兴趣。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，这证明需要描绘新的关键生物学特征，以完善疾病风险分类，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，很晚的抗原-4(VLA-4)整合素可能定义了这样的标记。具体地说，在儿童肿瘤学小组(COG)-AAML03P1试验的216名参与者中，我们发现高VLA-4表达独立地预测较低的复发风险(RR)和较高的无病生存率(DFS)；这一影响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/分子风险因素的不同患者。到目前为止，所观察到的VLA-4表达与预后之间的联系的生物学基础尚不清楚。我们现在建议在COG-AAML0531研究中验证我们之前关于VLA-4作为预后标记物的作用的发现，这是一项对1,000名新诊断的AML儿童患者进行的3期试验，并确定其相对于其他已建立的标记物对预测模型准确性的定量贡献。我们还将检验我们的假设，即VLA-4的高表达与我们初步研究所表明的黏附分子和细胞外基质(ECM)蛋白的特定表达谱以及对VLA-4配体的不同反应有关，最终导致化疗耐药性的降低和结果的改善，并为观察到的VLA-4的预测能力提供生物学基础。]具体地说，我们将：1)确定诊断AML原始细胞上VLA-4的高表达是否可以预测COG-AAML0531入选的新诊断AML患者的RR降低和DFS改善；2)确定COG-AAML0531试验队列中黏附分子和ECM蛋白的表达谱，并确定它们与VLA-4表达的关联以及对诱导和巩固化疗后预后的预测作用；以及3)比较和验证一组目标生物样本中VLA-4高表达和低表达的基因表达特征，这些细胞对生理性VLA-4配体有反应。这些研究将进一步定义和验证VLA-4和其他黏附分子和ECM蛋白作为儿童AML治疗反应预测因子的作用。我们建议的研究可能确定导致患者对化疗反应的差异性的黏附分子表达模式，并为个性化、风险适应的治疗方法提供理论基础，这是相对于当前治疗策略的一个重大进步。此外，除了描述这些蛋白质的预后作用外，我们的研究还可能发现治疗药物开发的新靶点，并为旨在了解它们在白血病发生中的功能作用的机制研究提供理论基础。 公共卫生相关性：急性髓系白血病(AML)仍然是一种难以治疗的血癌，不同患者的结果存在很大差异。这项拟议的研究旨在通过深入研究黏附分子(特别是一种名为VLA-4的分子)作为急性髓细胞白血病新的预后标志物的作用，提高我们预测每个患者对急性髓细胞白血病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，并最终导致急性髓细胞白血病患者获得更好的结果。这项研究进一步旨在了解(S)为什么这些标志物提供预后信息的原因，这一理解可能导致发现针对患者特定治疗的新药物靶点。

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.