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

标题：别构SHP 2抑制剂在RAS突变驱动的髓样肿瘤中的疗效 项目总结/摘要 髓系肿瘤是一组干细胞来源的血液恶性肿瘤，其特征在于髓系细胞的异常产生。慢性粒单核细胞白血病（CMML）和青少年粒单核细胞白血病（JMML）是侵袭性骨髓增生性肿瘤（MPN），临床预后差。目前的化疗不足以治疗CMML和JMML。RAS的体细胞突变在约40%的CMML和约30%的JMML病例中发现。直接抑制致癌RAS尚未成功。因此，靶向RAS调节子或效应子可能是治疗RAS突变驱动的MPN的有用策略。在RAS突变表达细胞中通常观察到MEK/ERK途径的异常激活。虽然MEK抑制剂治疗可以减少细胞增殖，但它仅部分改善KRAS突变小鼠中的MPN表型。此外，MEK抑制剂治疗未能减少骨髓中的RAS突变造血祖细胞，尽管正在进行治疗，但在一些小鼠中出现了T系急性淋巴细胞白血病（T-ALL）。因此，有必要确定新的治疗靶点并开发针对致癌RAS驱动的MPN（CMML和JMML）的新型靶向治疗。SHP 2调节RAS/RAF/MEK/ERK通路。SHP 2的遗传缺失或药理学抑制消除了RAS/RAF/MEK/ERK途径的激活。因此，我们假设抑制SHP 2可能有助于治疗RAS突变驱动的MPN（CMML和JMML）。为了验证我们的假设，我们提出了两个具体目标。具体目标1将确定变构SHP 2抑制剂SHP 099对RAS突变造血细胞/祖细胞和MPN的KRasG 12 D敲入小鼠模型的功效。具体目标2将确定SHP 099处理抑制RAS突变驱动的MPN的机制。我们提出的研究将确定靶向SHP 2是否对致癌RAS驱动的MPN有效。此外，这些研究结果将为变构SHP 2抑制剂治疗CMML和JMML的临床试验奠定基础。

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.