Overcoming resistance in BCR-ABL-rearranged acute lymphoblastic leukemia

克服 BCR-ABL 重排急性淋巴细胞白血病的耐药性

• 批准号: 10204924
• 负责人: Mark A. Murakami
• 金额: $ 17.71万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204924
• 关键词: Acute Lymphocytic Leukemia; Acute Promyelocytic Leukemia; Acute leukemia; Adult; Adult Acute Lymphocytic Leukemia; Animal Model; Animals; Arsenic; B-Cell Acute Lymphoblastic Leukemia; BCR/ABL fusion gene; Bcr-Abl tyrosine kinase; Binding; Bioinformatics; Biological Assay; Biological Models; Biology; Blood; Catalytic Domain; Cells; Clinical Trials; Code; Collaborations; Combined Modality Therapy; Communities; Dana-Farber Cancer Institute; Development; Development Plans; Devices; Disease Reservoirs; Drug Targeting; Environment; Exposure to; Genetic; Genetic Transcription; Genomics; Goals; Heterogeneity; Human; In complete remission; Individual; Investigational Therapies; Laboratories; Leukemic Cell; Location; Measurement; Measures; Mediating; Mentors; Mentorship; Modeling; Mutation; Myristates; PML-RARalpha protein; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Physicians; Predisposition; Prognosis; Proteomics; Regimen; Relapse; Research; Research Personnel; Residual Neoplasm; Resistance; Scientist; Site; Specimen; Testing; Therapeutic; Training; Translations; Tretinoin; Tyrosine Kinase Inhibitor; Untranslated RNA; base; bcr-abl Fusion Proteins; bench to bedside; career; career development; curative treatments; drug sensitivity; early detection biomarkers; in vivo; in vivo Model; in vivo evaluation; inhibitor/antagonist; kinase inhibitor; leukemia; leukemia/lymphoma; molecular subtypes; neoplastic cell; new technology; next generation; novel; novel therapeutics; patient derived xenograft model; preclinical trial; predictive marker; prevent; programs; prospective; relapse patients; repository; resistance mechanism; resistance mutation; response; single-cell RNA sequencing; skills; targeted agent; teacher; therapy resistant; transcriptome; tumor; virtual

Project Summary/Abstract The BCR-ABL fusion defines the most common molecular subtype of acute lymphoblastic leukemia (BCR-ABL+ ALL) in adults but historically conferred a poor prognosis. Incorporation of tyrosine kinase inhibitors (TKIs) that bind the ABL catalytic domain into frontline regimens can induce complete remissions in >90% of patients, but nearly all will relapse, typically with resistance mutations that disfavor drug binding. This suggests that relapses remain addicted to ABL kinase activity. In contrast, novel type IV inhibitors bind the ABL myristate site and allosterically modulate BCR-ABL function. We hypothesize that the combination of catalytic and allosteric TKIs can prevent the emergence of cross-resistant clones and cure a subset of treatment-naïve BCR-ABL+ ALLs. We have established a diverse panel of 16 patient-derived xenograft (PDX) models of BCR-ABL+ ALL in which we can perform controlled and adequately powered pre-clinical trials to assess heterogeneity of response to in vivo combined blockade, develop predictive biomarkers, and establish models of acquired in vivo resistance. We have also developed an approach for characterizing therapeutic sensitivity in individual tumor cells that is amenable to minimal residual disease (MRD) specimens. Specifically, we use a microcantilever-based platform known as the suspended microchannel resonator (SMR) to assay drug sensitivity by measuring changes in the buoyant mass of individual cells exposed to targeted inhibitors ex vivo with femtogram-range sensitivity. These cells are then collected downstream of the SMR for single-cell RNA-Seq (scRNA-seq) to define transcriptional programs and cell states that modulate differential response to therapeutics. To test our hypothesis that combined ABL blockade has curative potential, and to meet the pressing need for rapid and robust approaches to characterize sensitivity within individual tumor specimens at MRD, we propose the following Specific Aims: (1) Test whether combined catalytic and allosteric BCR-ABL inhibition can cure some BCR-ABL+ ALL PDX models. Any models that relapse on combination therapy will be interrogated for mutational, transcriptional (both coding and non-coding RNA), and proteomic correlates of acquired in vivo resistance. (2) Define approaches to overcome therapeutic resistance directly within MRD in vivo. We will use the SMR to identify resistant subclones within MRD and apply scRNA-seq to define transcriptional programs and cell states mediating resistance for which bulk tumor assays would be insensitive. Defining patients who could be cured with combined ABL blockade would be transformative, just as combined PML-RAR targeting with arsenic and ATRA has proven to be in promyelocytic leukemias. The applicant Dr. Mark Murakami has outlined a 5-year career development plan to become an independent investigator in translational leukemia biology. He has assembled a distinguished group of mentors, advisors, and collaborators whose expertise spans the continuum of bench to bedside translation. The Dana-Farber Cancer Institute is the ideal environment for completion of his scientific and career goals given its outstanding research community and record of training independent physician-scientists.

项目摘要/摘要 BCR-ABL融合定义了急性淋巴细胞白血病的最常见分子亚型（BCR-ABL+ 所有）在成年人中，但在历史上赋予了预后不佳。掺入酪氨酸激酶抑制剂（TKI） 将ABL催化域结合到前线方案中可以诱发> 90％的患者，但 几乎所有的都将中继，通常会带有抗药性突变。这表明继电器 仍然沉迷于ABL激酶活性。相比之下，新型IV型抑制剂结合了ABL肉豆蔻酸酯部位，并 变构调节BCR-ABL函数。我们假设催化和变构TKI的组合 可以防止抗耐药克隆的出现，并治愈未经治疗的BCR-ABL+ ALLS的子集。我们 已经建立了一个由16个患者衍生的Xenographotic（PDX）模型组成的BCR-ABL+的面板。 可以执行受控和足够动力的临床前试验，以评估对体内反应的异质性 结合封锁，开发预测性生物标志物，并建立在体内抗性中获得的模型。我们 还开发了一种表征单个肿瘤细胞中治疗敏感性的方法 适合最小残留疾病（MRD）标本。具体来说，我们使用基于微型武器的平台 被称为悬浮的微通道谐振器（SMR），以测量测量药物敏感性 浮力的单个细胞的浮力质量暴露于靶向抑制剂具有femtogram-图范围敏感性的离体。这些 然后，将单细胞RNA-seq（SCRNA-Seq）的SMR下游收集细胞以定义转录 调节对治疗差异反应的程序和细胞状态。测试我们的假设 合并的ABL封锁具有治愈的潜力，并满足了快速和强大方法的紧迫需求 为了表征MRD单个肿瘤规范中的灵敏度，我们提出以下特定目的： （1）测试合并催化和变构BCR-ABL抑制是否可以治愈一些BCR-ABL+所有PDX 型号。任何中继结合疗法的模型都将被审问以进行突变，转录（都 编码和非编码RNA），以及在体内耐药性中获得的蛋白质组学相关性。 （2）定义方法 在体内直接克服直接在MRD内的热电阻。我们将使用SMR识别抗性子克隆 在MRD中并应用SCRNA-SEQ来定义转录程序和细胞状态介导阻力 哪种大肿瘤分析将不敏感。定义可以通过ABL封锁治愈的患者 将是变革性的，就像合并的PML-arr靶向与砷和ATRA的靶向 Promyelocytic Leukemias。申请人马克·穆拉卡米（Mark Murakami）博士概述了一项为期5年的职业发展计划 成为翻译白血病生物学的独立研究者。他聚集了一个独特的群体 指导者，顾问和合作者的专业知识涵盖了长凳与床边翻译的连续性。 达纳 - 法伯癌症研究所是完成其科学和职业目标的理想环境 其杰出的研究社区和培训独立身体科学家的记录。