Targeting PTPN11 dependent Hematologic Malignancies

靶向 PTPN11 依赖性血液恶性肿瘤

• 批准号: 10057374
• 负责人: BILL H CHANG
• 金额: $ 35.23万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057374
• 关键词: Acute Myelocytic Leukemia; Adaptor Signaling Protein; Address; Animal Model; Biochemical; Biochemical Pathway; Biological Assay; Biological Models; Bone Marrow Cells; CRISPR/Cas technology; Cell Line; Cell Survival; Cell model; Cells; Chemicals; Chemoresistance; Clinical; Clinical Data; Combined Modality Therapy; Complex; Data; Dependence; Development; Disease; Drug Combinations; Evaluation; Foundations; Goals; Hematologic Neoplasms; Hematology; Hematopoietic; Immunodeficient Mouse; In Vitro; Juvenile Myelomonocytic Leukemia; Knowledge; Leukemic Cell; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MEKs; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Prognosis; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; RNA Interference; Role; Sampling; Signal Transduction; Solid Neoplasm; Tertiary Protein Structure; Testing; Therapeutic; Transgenic Organisms; Treatment Protocols; Validation; Xenograft procedure; acute myeloid leukemia cell; base; cell killing; clinical development; effective therapy; experience; improved; in vivo; inhibitor/antagonist; leukemia; mouse model; mutant; neoplastic cell; novel; pre-clinical; protein complex; protein phosphatase inhibitor-2; response; small molecule inhibitor; targeted treatment; therapeutic target

Activating mutations in Protein Tyrosine Phosphatase, non-receptor type 11 (PTPN11) are seen in approximately 5-10% percent of patients with acute myeloid leukemia (AML) that independently confers a poor prognosis, and is the leukemic driver in 35% of patients with the rare chemoresistant juvenile myelomonocytic leukemia (JMML). To date, targeting PTPN11 for clinical benefit has not been well established. Our preliminary data using high-throughput functional assays have identified that PTPN11 activity is dependent on an upstream tyrosine kinase, TNK2, and that leukemic cells with activating PTPN11 mutants are sensitive to TNK2 inhibition. The long-term goal of this proposal is to identify novel combinations of targeted therapies using PTPN11/TNK2 dependent leukemias as a model. The immediate goals are to comprehensively understand the molecular mechanisms of PTPN11 activation, and to define therapeutic regimens for treatment based on the central hypothesis that PTPN11-dependent leukemias are directly activated by TNK2. To accomplish these goals, several key AIMS will need to be addressed: 1) Develop a detailed understanding of the biochemical pathways interacting with activated PTPN11. We will use molecular and biochemical studies to dissect the interactions of proteins within PTPN11/TNK2 and downstream pathways through heterologous model systems, PTPN11 mutant AML cell lines, murine bone marrow cells with mutant PTPTN11, and primary mutant PTPN11 AML samples. Further, RNAi and CRISPR technology will be utilized to selectively inhibit expression of candidate proteins to identify critical interactions necessary for PTPN11/TNK2 activity within hematopoietic model systems. These studies will establish the molecular and biochemical foundation necessary for defining PTPN11/TNK2 activation, and help guide novel targeted approaches. 2) Test combination pathway inhibition to overcome escape from monotherapy. We will use our experience and expertise with small molecule inhibitors to identify synergistic combinations of inhibitors to TNK2, PTPN11, modulators of PTPN11/TNK2 activation, and downstream effectors in vitro using cell lines and primary patient samples. Molecular and biochemical studies will be performed on samples that overcome therapy to identify escape mechanisms. These studies will define the use of combination therapy for treatment of PTPN11-driven leukemias and provide critical pre-clinical data for further development of these combinations. 3) Test combination therapies in the animal model. We will test the above combinations in vivo using mouse models harboring PTPN11 mutations, as well as primary patient leukemia samples with PTPN11 mutations xenografted into immunodeficient mice. These studies will build the preclinical foundation for combination of targeted therapies for eventual use in patients with PTPN11-driven leukemias.

在蛋白质酪氨酸磷酸酶，非受体11（PTPN11）中激活突变在 大约5-10％ 预后，是35％的稀有化学毒性骨髓细胞的患者的白血病驱动力 白血病（JMML）。迄今为止，尚未确定针对PTPN11的临床利益。我们的 使用高通量功能测定的初步数据已经确定PTPN11活动取决于 上游酪氨酸激酶TNK2和活化PTPN11突变体的白血病细胞对 TNK2抑制。该提案的长期目标是确定目标的新型组合 使用PTPN11/TNK2依赖性白血病作为模型的疗法。直接目标是 全面了解PTPN11激活的分子机制，并定义 基于ptpn11依赖性白血病的中心假设，用于治疗的治疗方案 由TNK2直接激活。为了实现这些目标，需要解决一些关键目标：1） 对与活化的PTPN11相互作用的生化途径有详细的了解。我们将 使用分子和生化研究来剖析PTPN11/TNK2和 通过异源模型系统，PTPN11突变AML细胞系，鼠骨的下游途径 带有突变体PTPTN11的骨髓细胞和原代突变体PTPN11 AML样品。此外，RNAi和 CRISPR技术将用于选择性抑制候选蛋白的表达以识别 造血模型系统中PTPN11/TNK2活性所需的关键相互作用。这些研究 将建立定义PTPN11/TNK2激活所必需的分子和生化基础，并且 帮助指导新颖的目标方法。 2）测试组合途径抑制以克服从 单一疗法。我们将利用小分子抑制剂的经验和专业知识来识别协同作用 TNK2抑制剂，PTPN11，PTPN11/TNK2激活的调节剂和下游的组合 使用细胞系和主要患者样品在体外效应子。分子和生化研究将是 在克服治疗以鉴定逃生机制的样品上进行。这些研究将定义使用 用于治疗PTPN11驱动的白血病的组合疗法，并提供关键的临床前数据 这些组合的进一步发展。 3）动物模型中的测试组合疗法。我们将测试 上面使用携带PTPN11突变的小鼠模型以及主要患者的体内组合 用PTPN11突变的白血病样本异种移植到免疫缺陷小鼠中。这些研究将建立 临床前的基础，是针对PTPN11驱动患者最终使用的靶向疗法的组合 白血病。