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.

项目概要/摘要 BCR-ABL 融合定义了急性淋巴细胞白血病最常见的分子亚型（BCR-ABL+ ALL）在成人中，但历史上结合酪氨酸激酶抑制剂（TKI）导致预后不良。 将 ABL 催化结构域结合到一线治疗方案中可以诱导 >90% 的患者完全缓解，但是 几乎所有疾病都会复发，通常会出现不利于药物结合的耐药突变。这表明会复发。 仍然对 ABL 激酶活性上瘾，相比之下，新型 IV 型抑制剂结合 ABL 肉豆蔻酸位点并 我们勇敢地将催化和变构 TKI 结合起来。 可以防止交叉耐药克隆的出现并治愈一部分未接受过治疗的 BCR-ABL+ ALL。 建立了由 16 个患者来源的 BCR-ABL+ ALL 异种移植 (PDX) 模型组成的多样化组，其中我们 可以进行受控且充分有力的临床前试验，以评估体内反应的异质性 联合封锁，开发预测生物标志物，并建立获得性体内耐药性模型。 还开发了一种表征个体肿瘤细胞治疗敏感性的方法，即 具体来说，我们使用基于微悬臂梁的平台。 称为悬浮微通道谐振器 (SMR)，通过测量微通道谐振器的变化来测定药物敏感性 离体暴露于靶向抑制剂的单个细胞的浮力质量，具有飞克范围的灵敏度。 然后在 SMR 下游收集细胞进行单细胞 RNA 测序 (scRNA-seq)，以定义转录 调节对治疗的差异反应的程序和细胞状态来检验我们的假设。 联合 ABL 封锁具有治疗潜力，并能满足对快速、稳健方法的迫切需求 为了表征 MRD 中单个肿瘤标本的敏感性，我们提出以下具体目标： (1) 测试联合催化和变构 BCR-ABL 抑制是否可以治愈某些 BCR-ABL+ ALL PDX 任何在联合治疗中复发的模型都将被检查是否存在突变、转录（两者）。 (2) 定义方法 直接克服体内 MRD 的治疗耐药性 我们将使用 SMR 来识别耐药亚克隆。 在 MRD 内，并将 scRNA-seq 应用于介导耐药性的转录定义程序和细胞状态 哪些肿瘤检测不敏感，无法确定联合 ABL 阻断可以治愈的患者。 将是变革性的，正如事实证明，将 PML-RAR 与砷和 ATRA 联合靶向 申请人 Mark Murakami 博士概述了一个 5 年职业发展计划 成为转化白血病生物学的独立研究者，他组建了一个杰出的团队。 由导师、顾问和合作者组成，他们的专业知识涵盖从实验室到临床翻译的连续过程。 丹娜—法伯癌症研究所是他完成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医师科学家的记录。