Targeting altered phosphatase-dependent signaling to overcome the inefficacy of targeted therapy in myeloproliferative neoplasms

靶向改变的磷酸酶依赖性信号传导以克服靶向治疗在骨髓增殖性肿瘤中的无效性

• 批准号: 10560575
• 负责人: GARY W REUTHER
• 金额: $ 47.8万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560575
• 关键词: Acute Myelocytic Leukemia; Affect; Automobile Driving; Biochemical; Biological; Biology; Blood; Blood coagulation; Bone marrow failure; Cancer Center; Cause of Death; Cell Line; Cell Survival; Cells; Climacteric; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Disease; Disease remission; Drug resistance; Environment; Exposure to; FDA approved; Genetic; Glues; Goals; Hematological Disease; Hematopoietic Neoplasms; Induced Mutation; Inferior; JAK2 gene; Knowledge; Laboratories; Lead; MAP Kinase Gene; Maintenance; Mediating; Modeling; Molecular; Molecular Biology; Mutation; Myeloproliferative disease; Neoplasms; Outcome; PTPN11 gene; Pathway Analysis; Patients; Persons; Pharmaceutical Preparations; Philadelphia Chromosome; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotyrosine; Play; Protein Tyrosine Kinase; Proteins; Proteomics; Qualifying; RNA Interference; Regulation; Remission Induction; Research; Resistance; Resistance development; Role; Signal Transduction; Stem cell transplant; Symptoms; Testing; Therapeutic; associated symptom; cell growth; curative treatments; drug development; effective therapy; experience; experimental study; genetic manipulation; improved; inhibitor; inhibitor therapy; innovation; interferon therapy; leukemia; loss of function; mouse model; neoplasm therapy; neoplastic cell; novel; novel strategies; novel therapeutic intervention; phosphoproteomics; prevent; response; small molecule inhibitor; success; synergism; targeted treatment; therapeutic target; therapeutically effective; thrombotic complications; transcriptome sequencing; tumor progression

Project Summary/Abstract Classical myeloproliferative neoplasms (MPNs) are blood disorders that affect about 300,000 people in the U.S. Blood clotting complications and bone marrow failure can cause death, as can the development of an incurable leukemia. Curative therapy by stem cell transplant is rarely possible. Aberrant regulation of a protein called JAK2 drives these disorders, and while JAK2 inhibitors improve MPN patient symptoms they do not induce remission, with inherent drug resistance being a major clinical bottleneck. Our recent studies suggest a protein called SHP2 plays a unique role in the response of MPN cells to the FDA-approved JAK inhibitor ruxolitinib. Therapeutically targeting SHP2 is now possible following the recent development of drugs that function as molecular glue to keep SHP2 stuck in an inactive state. The upfront survival of MPN cells in the face of ruxolitinib treatment is a form of drug resistance called persistence. Our current studies show that ruxolitinib persistent cells are more sensitive to SHP2 inhibition than cells that have never been exposed to ruxolitinib. In the latter cells ruxolitinib inhibits JAK2-dependent signals including STAT and ERK proteins. However, ERK rapidly becomes re-activated even while ruxolitinib is still present. We have observed that SHP2 inhibition blocks this re-activation of ERK. Since ERK can promote cell growth/survival, it is possible that altered SHP2 regulation during ruxolitinib treatment leads to cell survival. Interestingly, the activation states of proteins that mediate JAK2 signaling respond differently to SHP2 inhibition in persistent cells, suggesting cell signaling during ruxolitinib persistence is in a re-wired state. This may explain our observations that SHP2 inhibition can prevent a ruxolitinib persistent state. Thus, SHP2 may provide a vulnerability that can be exploited to improve MPN therapy, which is further supported by our observations that SHP2 inhibition can antagonize disease in an MPN mouse model and can improve the inhibitory effect of ruxolitinib on cells from MPN patients. The major objective of this application is to determine the extent to which SHP2 inhibition overcomes barriers of current anti-JAK2 MPN therapy. The central hypothesis is that targeting SHP2 will thwart the development of JAK2 inhibitor persistence, which is observed in MPN patients. We will utilize cellular, genetic, and biological approaches, including mouse models and cells from MPN patients in our studies. Experiments in aim 1 will determine mechanistic details by which SHP2 inhibition sensitizes MPN cells to JAK2 inhibition; in aim 2 will assess the role of SHP2 in drug persistence; and in aim 3 will determine the molecular basis/consequences of altered SHP2 signaling in response to ruxolitinib, which has potential to help develop new therapeutic approaches based on our novel observations. Our studies are innovative because the unique role of SHP2 in response to JAK2 inhibitor treatment is completely unknown and utilizing SHP2 as a therapeutic target in these MPNs has never been tested. Our studies could contribute to the development of effective therapies for the 300,000 people in the U.S. who suffer with an MPN.

项目概要/摘要 经典骨髓增生性肿瘤 (MPN) 是一种血液疾病，影响着大约 300,000 人 在美国，凝血并发症和骨髓衰竭可能导致死亡，出现一种疾病也可能导致死亡。 无法治愈的白血病。通过干细胞移植进行治愈性治疗几乎是不可能的。监管异常 JAK2 蛋白质会导致这些疾病，虽然 JAK2 抑制剂可以改善 MPN 患者的症状 不能诱导缓解，固有耐药性是主要的临床瓶颈。我们最近的研究 表明一种名为 SHP2 的蛋白质在 MPN 细胞对 FDA 批准的 JAK 的反应中发挥着独特的作用 抑制剂鲁索替尼。随着最近药物的开发，针对 SHP2 的治疗现已成为可能 它起到分子胶水的作用，使 SHP2 保持在非活性状态。 MPN 细胞的前期存活 鲁索替尼治疗面临的是一种称为持久性的耐药性。我们目前的研究表明 鲁索替尼持久性细胞比从未接触过的细胞对 SHP2 抑制更敏感 鲁索替尼。在后者细胞中，鲁索替尼抑制 JAK2 依赖性信号，包括 STAT 和 ERK 蛋白。 然而，即使鲁索替尼仍然存在，ERK 也会迅速重新激活。我们观察到 SHP2 抑制可阻止 ERK 的重新激活。由于 ERK 可以促进细胞生长/存活，因此有可能 在 ruxolitinib 治疗期间改变 SHP2 调节可导致细胞存活。有趣的是，激活 介导 JAK2 信号传导的蛋白质状态对持久性细胞中的 SHP2 抑制反应不同， 表明鲁索替尼持续存在期间的细胞信号传导处于重新连接状态。这或许可以解释我们的 观察发现 SHP2 抑制可以防止鲁索替尼持续状态。因此，SHP2 可以提供 可用于改善 MPN 治疗的脆弱性，我们的观察进一步支持了这一点 表明 SHP2 抑制可以拮抗 MPN 小鼠模型中的疾病，并可以提高 SHP2 的抑制效果 鲁索替尼（ruxolitinib）作用于 MPN 患者的细胞。该应用程序的主要目标是确定 SHP2 抑制克服了当前抗 JAK2 MPN 治疗的障碍。中心假设是 针对 SHP2 将阻碍 JAK2 抑制剂持久性的发展，这一点在 MPN 患者中观察到。 我们将利用细胞、遗传和生物学方法，包括来自 MPN 的小鼠模型和细胞 我们研究中的患者。目标 1 中的实验将确定 SHP2 抑制的机制细节 使 MPN 细胞对 JAK2 抑制敏感；目标 2 将评估 SHP2 在药物持久性中的作用；并瞄准 3 将确定响应鲁索替尼而改变的 SHP2 信号传导的分子基础/后果，这 有潜力根据我们的新观察帮助开发新的治疗方法。我们的研究是 创新是因为 SHP2 在 JAK2 抑制剂治疗中的独特作用尚不清楚 利用 SHP2 作为这些 MPN 的治疗靶点从未经过测试。我们的研究可以做出贡献 致力于为美国 300,000 名 MPN 患者开发有效的疗法。