Using the zebrafish as a pre-clinical animal tumour model for drug discovery and the evaluation of anti-leukemia agents

使用斑马鱼作为临床前动物肿瘤模型进行药物发现和抗白血病药物的评估

• 批准号: 413859-2012
• 负责人: Dellaire, Graham
• 金额: $ 9.71万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Collaborative Health Research Projects
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=530828
• 关键词: Using; zebrafish; pre; clinical; animal

T-cell acute lymphoblastic leukemia (T-ALL) is a high risk subtype of the most common leukemia affecting children. Although intensive chemotherapy treatments have improved survival in this disease, a significant number of patients do not respond to therapy or relapse. For these patients, a better understanding of the molecular pathways underlying the development of this disease holds the promise of personalized therapy with improved outcomes and fewer side effects. Two common pathways affected in T-ALL are NOTCH and PTEN/PI3K. Drugs targeting NOTCH signalling, called gamma secretase inhibitors (GSIs), have been effective against subtypes of T-ALL with NOTCH mutations. However, GSIs have had limited success in clinical trials due to side-effects including gut toxicity, and a significant proportion of leukemias are insensitive to GSIs. Recently drugs targeting the PTEN/PI3K pathway have shown promise for the treatment of T-ALL in both cell culture and mouse models of T-ALL. T-ALL cell lines are typically used for drug screening but they do not accurately represent the complexity of interactions between the leukemia cells and the human body. Transplanting human leukemia cells into mice may better represent human disease but is a costly and slow method of screening new anti-cancer compounds or to evaluate the drug sensitivity of an individual patient's cancer to a particular therapy. We have developed an innovative approach to transplant human cancer cells into zebrafish embryos, which can then be used for rapid pre-clinical drug testing for anti-leukemia agents. We propose a two-pronged approach testing new drugs developed by GlaxoSmithKline that block PI3K signaling

T细胞急性淋巴细胞白血病（T-ALL）是影响儿童的最常见白血病的高危亚型。虽然强化化疗治疗提高了这种疾病的生存率，但大量患者对治疗无反应或复发。对于这些患者，更好地了解这种疾病发展的分子途径，有望实现个性化治疗，改善疗效，减少副作用。T-ALL中受影响的两种常见途径是NOTCH和PTEN/PI 3 K。靶向NOTCH信号传导的药物，称为γ分泌酶抑制剂（GSI），对具有NOTCH突变的T-ALL亚型有效。然而，由于副作用，包括肠道毒性，GSI在临床试验中的成功有限，并且很大一部分白血病对GSI不敏感。最近，靶向PTEN/PI 3 K通路的药物在细胞培养和小鼠T-ALL模型中显示出治疗T-ALL的前景。T-ALL细胞系通常用于药物筛选，但它们不能准确地代表白血病细胞与人体之间相互作用的复杂性。将人类白血病细胞移植到小鼠体内可能更好地代表人类疾病，但这是一种昂贵且缓慢的筛选新抗癌化合物或评估个体患者癌症对特定疗法的药物敏感性的方法。我们开发了一种创新的方法，将人类癌细胞移植到斑马鱼胚胎中，然后可以用于抗白血病药物的快速临床前药物测试。我们提出了一种双管齐下的方法来测试葛兰素史克开发的阻断PI 3 K信号传导的新药