Efficacy of Allosteric SHP2 Inhibitor in RAS Mutant-Driven Myeloid Neoplasms

变构 SHP2 抑制剂在 RAS 突变驱动的骨髓肿瘤中的疗效

• 批准号: 9815636
• 负责人: Golam Mohi
• 金额: $ 14.05万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815636
• 关键词: Acute T Cell Leukemia; Animal Model; Applications Grants; Bone Marrow; Cell Line; Cell Lineage; Cell Proliferation; Cell model; Cells; Chronic; Chronic Myelomonocytic Leukemia; Clinical; Clinical Trials; Constitutional Symptom; Data; Development; Disease remission; Drug Combinations; Exhibits; Fibrosis; Frequencies; Gene Expression Profiling; Genes; Genetic; Goals; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; Human; JAK1 gene; JAK2 gene; Juvenile Myelomonocytic Leukemia; KRAS2 gene; Knock-in Mouse; MEKs; MPL gene; Mediating; Molecular; Mus; Mutant Strains Mice; Mutation; Myelofibrosis; Myelogenous; Myeloproliferative disease; Oncogenic; Outcome; PTPN11 gene; Pathogenesis; Pathway interactions; Patients; Penetrance; Pharmacology; Phase; Phenotype; Play; Polycythemia Vera; Pre-Clinical Model; Production; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; RAS inhibition; Ras/Raf; Role; Signal Transduction; Somatic Mutation; Splenomegaly; Stem cells; Testing; Therapeutic; Time; Work; base; calreticulin; chemotherapy; design; efficacy testing; expectation; improved; inhibitor/antagonist; knock-down; mouse model; mutant; new therapeutic target; novel therapeutic intervention; novel therapeutics; small hairpin RNA; therapeutic target; transcriptome sequencing; treatment strategy

Title: Efficacy of Allosteric SHP2 Inhibitor in RAS Mutant-Driven Myeloid Neoplasms Project Summary/Abstract Myeloid neoplasms are a group of stem cell-derived hematologic malignancies characterized by abnormal production of myeloid lineage cells. Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are aggressive myeloproliferative neoplasms (MPN) that have poor clinical outcome. Current chemotherapies are not adequate to treat CMML and JMML. Somatic mutations in RAS are found in ~40% of CMML and ~30% of JMML cases. Direct inhibition of oncogenic RAS has not been successful. Therefore, targeting of RAS regulator or effector could be a useful strategy in treating MPN driven by RAS mutants. Aberrant activation of the MEK/ERK pathway is commonly observed in RAS mutant expressing cells. Although MEK inhibitor treatment can reduce cell proliferation, it only partially improves MPN phenotype in KRAS mutant mice. Furthermore, MEK inhibitor treatment failed to reduce the RAS mutant hematopoietic progenitors in the bone marrow, and T-lineage acute lymphoblastic leukemia (T-ALL) emerged in some mice despite ongoing treatment. So, there is a need to identify new therapeutic target(s) and develop novel targeted therapies for oncogenic RAS-driven MPN (CMML and JMML). SHP2 regulates the RAS/RAF/MEK/ERK pathway. Genetic deletion or pharmacologic inhibition of SHP2 abrogates the activation of the RAS/RAF/MEK/ERK pathway. So, we hypothesize that inhibition of SHP2 might be useful in treating RAS mutant-driven MPN (CMML and JMML). To test our hypothesis, we propose two specific aims. Specific Aim 1 will determine the efficacy of allosteric SHP2 inhibitor SHP099 against RAS mutant hematopoietic cells/progenitors and KRasG12D knockin mouse model of MPN. Specific Aim 2 will determine the mechanism of inhibition of RAS mutant-driven MPN by SHP099 treatment. Our proposed studies will determine if targeting of SHP2 is effective against oncogenic RAS-driven MPN. Moreover, results from these studies will lay the groundwork for clinical trials of allosteric SHP2 inhibitor for treatment of CMML and JMML.

标题：变构SHP2抑制剂在RAS驱动的髓样肿瘤中的功效 项目摘要/摘要 髓样肿瘤是一组干细胞衍生的血液学恶性肿瘤，其特征是髓样谱系细胞异常产生。慢性脊髓细胞性白血病（CMML）和少年脊髓细胞白血病（JMML）是侵袭性的骨髓增生性肿瘤（MPN），临床结果较差。当前的化学疗法不足以治疗CMML和JMML。在约40％的CMML和〜30％的JMML病例中发现了RAS中的体细胞突变。直接抑制致癌性RA并未成功。因此，靶向RAS调节剂或效应子可能是治疗由RAS突变体驱动的MPN的有用策略。 MEK/ERK途径的异常激活通常在表达细胞的Ras突变体中观察到。尽管MEK抑制剂治疗可以减少细胞增殖，但仅部分改善了KRAS突变小鼠的MPN表型。此外，MEK抑制剂治疗未能降低骨髓中的RAS突变体造血祖细胞，尽管持续治疗，但在某些小鼠中出现了T-Linege急性淋巴细胞白血病（T-ALL）。因此，有必要鉴定新的治疗靶标，并开发出新的针对致癌性RAS驱动的MPN（CMML和JMML）的靶向疗法。 SHP2调节RAS/RAF/MEK/ERK途径。 SHP2的遗传缺失或药理抑制作用消除了RAS/RAF/MEK/ERK途径的激活。因此，我们假设抑制SHP2可能有助于治疗RAS突变驱动的MPN（CMML和JMML）。为了检验我们的假设，我们提出了两个具体目标。具体目标1将确定变构SHP2抑制剂SHP099对RAS突变体造血细胞/祖细胞和MPN的KRASG12D敲击小鼠模型的疗效。具体目标2将确定SHP099处理对RAS突变驱动的MPN抑制的机理。我们提出的研究将确定SHP2的靶向是否有效抵抗致癌RAS驱动的MPN。此外，这些研究的结果将为变构SHP2抑制剂的临床试验奠定基础，以治疗CMML和JMML。