Pharmacogenomics of Ara-C in AML

Ara-C 在 AML 中的药物基因组学

• 批准号: 8858835
• 负责人: Jatinder K. Lamba
• 金额: $ 32.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858835
• 关键词: Accounting; Acute Myelocytic Leukemia; Ara-C; Biological; Blast Cell; Cell Line; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Classification; Clinical; Clinical Trials; Cohort Studies; Cytarabine; DNA Methylation; Diagnostic; Disease-Free Survival; Drug Kinetics; Drug usage; Epigenetic Process; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Health; In Vitro; Leukemic Cell; Malignant Childhood Neoplasm; Mediating; Metabolic Pathway; Methylation; Modeling; Outcome; Patients; Pattern; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Prognostic Factor; Research; Residual Neoplasm; Resistance development; Risk; Role; Saint Jude Children' s Research Hospital; Small Interfering RNA; Statistical Methods; Statistical Models; Stratification Factors; System; Therapeutic; Toxic effect; Treatment outcome; Variant; candidate validation; chemotherapeutic agent; chemotherapy; clinically significant; cohort; epigenetic marker; epigenetic variation; improved; interest; novel; nucleoside analog; outcome forecast; overexpression; prognostic; response; treatment response

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is the second most common form of childhood leukemia and has the worst prognosis of all major childhood cancers. The nucleoside analog, Cytarabine (ara-C), is the most effective and widely used chemotherapeutic agent used to treat AML. However, wide inter-patient variation in its treatment response, development of resistance, and severe toxicity remain major hurdles to effective ara-C chemotherapy. Inter-patient variation in expression and/or activity of ara-C pharmacokinetic (PK) and pharmacodynamic (PD) genes is likely to contribute to the variability observed in ara-C treatment outcomes. During the last funding period of this application, we evaluated 12 PK genes in ara-C metabolic pathway and identified genetic polymorphisms that could explain a substantial portion of the variability in ara-C clinical response and could be of similar prognosti relevance as currently used risk stratification factors in AML patients. We found that genetic variation in PK genes may explain 11% of variation in prognosis (event-free survival, EFS) after accounting for 6 well established prognostic factors that cumulatively explain 18% of variation in EFS. To more fully understand the mechanisms contributing to variability in ara-C treatment outcomes, we now propose to study genes involved in ara-C pharmacodynamic response, which unfortunately have not been well studied so far. We have developed a novel statistical method, PROMISE (Projection Onto the Most Interesting Statistical Evidence), which dramatically increases our power to make important pharmacogenomic discoveries by identifying genetic features with a biologically meaningful pattern of associations with multiple pharmacologic and clinical endpoints. As a first step, we will use PROMISE to identify diagnostic leukemic blast gene expression signatures associated with in vitro leukemic blast sensitivity to ara-C as well as multiple clinical outcomes in AML patients (Aim 1). Following functional validation of candidate ara-C PD genes, we will identify and validate the clinical and prognostic significance of polymorphisms in ara-C PD genes in AML patients from multiple independent cohorts (Aim 2). Since epigenetic mechanisms such as DNA methylation have been suggested to influence gene expression in AML, we shall also evaluate DNA methylation for its role in regulating expression of ara-C PK and PD genes, and in influencing clinical outcomes in AML patients treated with ara-C (Aim 3). Finally, we will identify, and validate in independent cohorts of AML patients, the pharmacogenetic and pharmacoepigenetic markers that supplement currently known prognostic factors in an integrated system of risk assignment for purposes of determining treatment intensity. Understanding the interplay of genetic and epigenetic factors in mediating ara-C response and their integration into current prognostic features would present an opportunity to increase our accuracy in forecasting therapeutic outcomes in AML and allow more tailored, risk-stratified treatment approaches - a major advancement over current strategy.

描述（由申请人提供）：急性髓样白血病（AML）是童年白血病的第二大最常见形式，并且在所有主要儿童癌症中都具有最差的预后。核苷类似物Cytarabine（ARA-C）是用于治疗AML的最有效，最广泛使用的化学治疗剂。然而，其治疗反应，耐药性和严重毒性的广泛差异仍然是有效ARA-C化学疗法的主要障碍。 ARA-C药代动力学（PK）和药效（PD）基因表达和/或活性的患者间变化可能有助于在ARA-C治疗结果中观察到的可变性。在本应用的最后一项资金期间，我们评估了ARA-C代谢途径中的12个PK基因，并确定了遗传多态性，这些遗传多态性可以解释ARA-C临床反应中可变性的很大一部分，并且可能与AML患者中当前使用的风险分层因子具有相似的预后相关性。我们发现，PK基因的遗传变异可能解释了预后的11％（无事件生存，EFS），这是在考虑了6种良好确定的预后因素后，累计解释了EFS的差异的18％。为了更充分地了解导致ARA-C治疗结果可变性的机制，我们现在建议研究参与ARA-C药效反应的基因，不幸的是，到目前为止尚未对此进行很好的研究。我们已经开发了一种新颖的统计方法，即希望（投影到最有趣的统计证据），该方法通过鉴定具有与多个药理和临床终点的生物学有意义的关联模式来鉴定遗传特征，从而大大提高了我们的力量，从而使我们的能力提高了重要的药物基因组学发现。作为第一步，我们将使用承诺来鉴定与体外白血病爆炸对ARA-C的敏感性以及AML患者的多个临床结果相关的诊断性白血病基因表达特征（AIM 1）。在对候选ARA-C PD基因的功能验证后，我们将识别并验证来自多个独立队列的AML患者中ARA-C PD基因中多态性的临床和预后意义（AIM 2）。由于已经提出了表观遗传机制（例如DNA甲基化）影响AML中的基因表达，因此我们还应评估DNA甲基化在调节ARA-C PK和PD基因表达中的作用，以及用ARA-C治疗的AML患者在AML患者中的影响（AIM 3）。最后，我们将在AML患者的独立人群中识别并验证药物遗传学和药物概性标记，这些标志物是为确定治疗强度的目的，在风险分配的综合系统中补充了当前已知的预后因素。了解遗传和表观遗传因素在介导ARA-C反应中的相互作用及其在当前预后特征中的整合将提供一个机会，以提高我们在AML中预测治疗结果的准确性，并允许更量身定制，风险分解的治疗方法 - 一项主要进步而不是当前策略。