Mechanisms of resistance to targeted therapy and chemotherapy in acute lymphoblastic leukemias

急性淋巴细胞白血病靶向治疗和化疗耐药机制

• 批准号: 423352691
• 负责人: Dr. Jesús Duque-Afonso
• 金额: --
• 依托单位: Klinik für Innere Medizin I - Hämatologie, Onkologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/423352691?language=en
• 关键词: Mechanisms; resistance; targeted; therapy; chemotherapy

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and one of the main causes of cancer death in children and young adults. Although the treatment of ALL has been improved in the last decades, there are still patients developing drug resistance and succumbing to the disease, especially in advanced age and with severe co-morbidities. Therefore, we propose to devise new therapeutic approaches, which are more effective while less toxic. We will establish combination therapies using preclinical in vitro and in vivo experimental models, which will be translated into clinical application in the near future.ALL is a heterogeneous disease and can be sub-classified by karyotype, cell type and immunophenotype. One distinctive immunophenotype is characterized by expression of the pre-B cell receptor (preBCR). Half of the preBCR+ ALL patients harbor the translocation t(1;19), which codes the chimeric fusion protein E2A/PBX1. Dasatinib is a new drug that is FDA approved for treatment of Ph+ CML and ALL. Recent studies have suggested that it might be effective in additional subtypes, including preBCR+ ALL. Previous studies from our group shows that preBCR+ ALL rapidly develop dasatinib resistance and disease relapse. However, genetic inactivation and pharmacological inhibition of preBCR-pathway related genes modulates dasatinib sensitivity and overcomes resistance. In order to identify novel candidate genes/pathways candidate genes, which are involved in proliferation/survival and targeted therapy resistance in preBCR+ ALL cells, we employed functional genomics studies and global transcriptome analysis. Bioinformatics analysis identified several genes/pathways on which preBCR+ ALL cells are dependent, mediate drug resistance and are susceptible of pharmacological inhibition. In this project, we hypothesize that: 1) our previous and novel identified genes in E2A-PBX1+/preBCR+ ALL play a key role in the molecular pathogenesis of a broader panel of lymphoid malignancies.2) pharmacological inhibition of previous and novel identified kinases increases sensitivity to targeted therapy as dasatinib in single and combination treatments.3) novel mechanism of chemotherapy resistance will be identified and characterized using same genetic and pharmacological approaches, establishing more rational combination therapies in ALL.Taken together, we aimed to identify novel therapeutic targets and understand mechanisms of resistance to targeted therapies and chemotherapy in ALL. Our studies will address the novel and important concept of drug resistance driven by alternative signaling pathways and transcriptional plasticity. They will result in an innovative and original way to overcome drug resistance and to identify novel therapeutic targets in lymphoid malignancies and, ultimately, impact the treatment, quality of life and prognosis of patients.

急性淋巴细胞白血病（ALL）是最常见的儿童癌症，也是儿童和年轻人癌症死亡的主要原因之一。尽管ALL的治疗在过去几十年中得到了改善，但仍有患者产生耐药性并死于该疾病，特别是在高龄和患有严重合并症的患者中。因此，我们建议设计新的治疗方法，这是更有效的，而毒性较小。我们将利用临床前的体外和体内实验模型建立联合治疗方案，并在不久的将来转化为临床应用。ALL是一种异质性疾病，可根据核型、细胞类型和免疫表型进行细分。一种独特的免疫表型的特征在于前B细胞受体（preBCR）的表达。一半的preBCR+ ALL患者携带易位t（1;19），其编码嵌合融合蛋白E2 A/PBX 1。达沙替尼是FDA批准用于治疗Ph+ CML和ALL的新药。最近的研究表明，它可能对其他亚型有效，包括preBCR+ ALL。我们小组以前的研究表明，preBCR+ ALL快速发展达沙替尼耐药和疾病复发。然而，前BCR途径相关基因的遗传失活和药理学抑制调节达沙替尼敏感性并克服耐药性。为了鉴定与preBCR+ ALL细胞增殖/存活和靶向治疗耐药相关的新的候选基因/途径候选基因，我们采用功能基因组学研究和全局转录组分析。生物信息学分析确定了preBCR+ ALL细胞依赖的几个基因/通路，介导了耐药性，并对药理学抑制敏感。在本项目中，我们假设：1） 我们先前和新鉴定的E2 A-PBX 1 +/preBCR+ ALL基因在更广泛的淋巴恶性肿瘤的分子发病机制中起关键作用。2） 药理学抑制先前和新鉴定的激酶增加了对靶向治疗的敏感性，如单药和联合治疗中的达沙替尼。3） 本研究的目的是寻找新的治疗靶点，了解ALL对靶向治疗和化疗的耐药机制。我们的研究将解决由替代信号通路和转录可塑性驱动的耐药性的新的和重要的概念。它们将以创新和原创的方式克服耐药性，并确定淋巴恶性肿瘤的新治疗靶点，并最终影响患者的治疗，生活质量和预后。