Efficacy of Histone Deacetylase Inhibitor Vorinostat in Myeloproliferative Neopla

组蛋白脱乙酰酶抑制剂伏立诺他在骨髓增生性肿瘤中的疗效

• 批准号: 8049817
• 负责人: Golam Mohi
• 金额: $ 23.81万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-05 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049817
• 关键词: Acute Myelocytic Leukemia; Animal Model; Antineoplastic Agents; Apoptosis; Blood; Bone Marrow Transplantation; Cell Cycle Progression; Cell Line; Cell Lineage; Cells; Clinical Data; Clinical Trials; Critical Pathways; Data; Disease; Drug resistance; Erythrocytes; Erythroid; Erythropoietin; Genetic Transcription; Hematocrit procedure; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hemoglobin; Hemorrhagic Thrombocythemia; Histone Deacetylase Inhibitor; Histones; Human; JAK2 gene; Journals; Knock-in Mouse; Leukocytosis; Malignant Neoplasms; Manuscripts; Modeling; Molecular; Mutation; Myelogenous; Myeloproliferative disease; Myelosuppressive Therapy; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Phosphotransferases; Point Mutation; Polycythemia Vera; Pre-Clinical Model; Primary Myelofibrosis; Production; Protein Tyrosine Kinase; Publications; Risk; Serum; Splenomegaly; Supportive care; Toxic effect; Transfusion; Venous blood sampling; Vorinostat; cell transformation; chromatin modification; efficacy testing; human MPL protein; inhibitor/antagonist; mouse model; mutant; pre-clinical; progenitor; thrombocytosis; tumor

DESCRIPTION (provided by applicant): The myeloproliferative neoplasmss (MPNs) polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a group of hematologic malignancies characterized by excessive production of myeloid lineage cells. A somatic point mutation (V617F) in the JAK2 tyrosine kinase has been detected in most patients with PV and 50-60% patients with ET and PMF. Additional mutations in the thrombopoietin receptor MPL (MPLW515L, MPLW515K) have been found in 5-10% cases of ET and PMF. At present, there is no curative therapy for these MPNs. Recently, a number of JAK2 inhibitors have been developed and undergoing Phase I clinical trials. Although there is considerable enthusiasm for JAK2 inhibitor for these disorders, there are also a number of important concerns. There is evidence that JAK2V617F- negative acute myeloid leukemia occurs frequently in patients with a JAK2V617F-positive MPN, raising the possibility that JAK2 inhibitor therapy might increase the risk of leukemic transformation. Moreover, drug resistance is likely to emerge in some patients treated with JAK2 inhibitors. Therefore, identifying additional therapies targeting JAK2V617F or MPLW515L or critical pathways downstream of JAK2V617F/MPLW515L would be beneficial for the treatment of MPNs. In preliminary studies, we have observed that histone deacetylase (HDAC) inhibitor vorinostat selectively inhibits JAK2V617F expression and induces apoptosis in hematopoietic cells expressing JAK2V617F or MPLW515L. We have generated a knock-in mouse model of JAK2V617F-evoked MPN. We will this knock-in mouse model of JAK2V617F and retroviral bone marrow transplant model of MPLW515L to test the efficacy of HDAC inhibitor vorinostat in treating MPNs. The molecular mechanism of anti-cancer activity of vorinostat in MPN will also be determined. The results of these studies will lay the groundwork for Phase I and II clinical trials involving HDAC inhibitor vorinostat in the treatment of MPNs. PUBLIC HEALTH RELEVANCE: The proposed studies will evaluate the efficacy of histone deacetylase (HDAC) inhibitor vorinostat in pre- clinical models of MPNs, and identify the bio-marker for vorinostat therapy in MPNs. The data generated from these studies will lay the groundwork for Phase I and II clinical trials of vorinostat in MPNs.

描述（由申请方提供）：骨髓增生性肿瘤（MPN）、真性红细胞增多症（PV）、原发性血小板增多症（ET）和原发性骨髓纤维化（PMF）是一组以髓系细胞过度生成为特征的恶性血液病。在大多数PV患者和50-60%的ET和PMF患者中检测到JAK 2酪氨酸激酶的体细胞点突变（V617 F）。在5-10%的ET和PMF病例中发现了血小板生成素受体MPL（MPLW 515 L，MPLW 515 K）的其他突变。目前，对于这些MPN没有治愈性疗法。最近，已经开发了许多JAK 2抑制剂并正在进行I期临床试验。虽然JAK 2抑制剂对这些疾病有相当大的热情，但也有一些重要的问题。有证据表明JAK 2 V617 F阴性急性髓性白血病经常发生在JAK 2 V617 F阳性MPN患者中，这增加了JAK 2抑制剂治疗可能增加白血病转化风险的可能性。此外，耐药性可能出现在一些JAK 2抑制剂治疗的患者中。因此，鉴定靶向JAK 2 V617 F或MPLW 515 L或JAK 2 V617 F/MPLW 515 L下游的关键途径的另外的疗法将有益于治疗MPN。在初步研究中，我们观察到组蛋白脱乙酰酶（HDAC）抑制剂伏立诺他选择性地抑制JAK 2 V617 F表达并诱导表达JAK 2 V617 F或MPLW 515 L的造血细胞凋亡。我们已经产生了JAK 2 V617 F诱发的MPN的敲入小鼠模型。我们将这种JAK 2 V617 F的基因敲入小鼠模型和MPLW 515 L的逆转录病毒骨髓移植模型用于测试HDAC抑制剂伏立诺他在治疗MPN中的功效。伏立诺他在MPN中的抗癌活性的分子机制也将被确定。这些研究的结果将为涉及HDAC抑制剂伏立诺他治疗MPN的I期和II期临床试验奠定基础。 公共卫生相关性：所提出的研究将评估组蛋白脱乙酰酶（HDAC）抑制剂伏立诺他在MPN的临床前模型中的功效，并鉴定用于伏立诺他治疗MPN的生物标志物。这些研究产生的数据将为伏立诺他在MPN中的I期和II期临床试验奠定基础。