Targeting cancer stem cells in JAK2V617F induced neoplasm

靶向 JAK2V617F 诱导肿瘤中的癌症干细胞

• 批准号: 10576376
• 负责人: Shaoguang Li
• 金额: $ 52.56万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576376
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Affect; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Asthma; Bone Marrow Transplantation; CD34 gene; Cell Survival; Cells; Cellular Assay; Chemical Agents; Clinical; Colon; Development; Disease; Disease remission; Effectiveness; Engraftment; Esophagus; FDA approved; Foundations; Genes; Growth; Human; Immunocompromised Host; In Vitro; Individual; Inflammatory; Inflammatory Response; JAK2 gene; Knockout Mice; Leukemic Cell; Leukotriene Receptor; Leukotrienes; Link; Lipids; Liver; Lung; Malignant - descriptor; Malignant Neoplasms; Molecular; Mus; Myeloid Cells; Myeloproliferative disease; Names; Neoplasms; New Agents; Non obese; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Polycythemia Vera; Preventive treatment; Recurrent disease; Regulation; Relapse; Reporting; Residual state; Role; Severe Combined Immunodeficiency; Skin; Solid; Solid Neoplasm; Symptoms; Testing; Therapeutic Agents; Time; Transcript; anticancer research; beta catenin; cancer stem cell; clinical remission; clinically significant; curative treatments; diabetic; gene function; genetic approach; human disease; in vitro testing; in vivo evaluation; inhibitor; montelukast; novel; novel strategies; novel therapeutic intervention; novel therapeutics; peripheral blood; prevent; receptor binding; stem cells; symptomatic improvement; tumorigenesis

Project Summary/Abstract We aim to develop a new therapeutic strategy for one major form of JAK2V617F-induced myeloproliferative neoplasms (MPNs), polycythemia vera (PV), with a focus on targeting PV-initiating cells (cancer stem cells in PV). A curative therapy for PV is still lacking. The proposed studies are based on our preliminary finding that the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) plays a key role in survival regulation of PV-initiating cells. The Alox5 pathway is known for producing inflammatory (asthma-causing) leukotrienes, and an FDA-approved human anti-asthma drug called Singulair (Montelukast) blocks leukotriene receptor binding to reduce the inflammatory response. We have found that Singulair inhibits the growth of JAK2-V617F-expressing cells in vitro and in mice. Thus, Singulair could be an effective new agent for treating PV. We hypothesize that leukotrienes produced in the Alox5-pathway play an essential role in survival regulation of MPN-initiating cells in PV, and Singulair antagonizes the action of leukotrienes to act as a potential new therapeutic agent for PV. Testing this hypothesis is of clinical significance and would benefit: 1) PV patients who have not progressed to acute myeloid leukemia (AML); 2) PV patients who are in clinical remission of AML with residual JAK2V617F-expressing cells and may relapse with time; 3) PV patients who had bone marrow transplantation for treating AML progressed from PV but still have residual JAK2V617F-expressing cells; and 4) the individuals who have detectable JAK2V617F transcripts in myeloid cells but have not developed clinical symptoms of PV. Because the Alox5 pathway is known to produce leukotrienes, one plausible mechanistic explanation of action of Singulair is that it eradicates PV by blocking receptor binding of leukotriens to PV-initiating cells. We also need to know the underlying molecular mechanisms by which Singulair inhibits PV-initiating cells and PV development. In fact, our preliminary studies show that JAK2V617F regulates the Alox5 pathway involving two Alox5 downstream genes, beta-catenin (as a stimulator) and Blk (as a suppressor), and it will be important to investigate whether Singuliar regulates these two genes in PV-initiating cells. Finally, it is critical to determine whether Singulair inhibits the growth of human PV-initiating cells. The specific aims are: 1) To determine whether the survival of PV-initiating cells is dependent on leukotrienes and whether a blockade of leukotrienes by Singulair reduces their effects on PV-initiating cells; 2) To determine the molecular mechanisms by which Singulair inhibits PV-initiating cells and PV development; and 3) To determine whether Singulair blocks the Alox5 pathway in human PV-initiating cells and reduces engraftment of human PV-initiating cells in immunocompromised mice. Broadly, Singulair is a potential therapeutic agent for solid tumors as Alox5 is associated with tumorigenesis in the colon, lung, pancreas, liver, esophagus, skin, etc.

项目摘要/摘要 我们旨在为一种主要形式的JAK2V617F诱导的一种新的治疗策略制定新的治疗策略 骨髓增生性肿瘤（MPN），多性毛细血管Vera（PV），重点是靶向PV发射细胞 （PV中的癌症干细胞）。仍然缺乏用于PV的治疗疗法。拟议的研究是基于我们的 初步发现蛛网酸5-脂氧合酶（5-lo）基因（Alox5）在生存中起关键作用 调节PV发射细胞。 ALOX5途径以产生炎症（引起哮喘）而闻名 白细胞和FDA批准的人类抗哮喘药物称为Singulair（Montelukast）阻滞 白三烯受体结合以减少炎症反应。我们发现Singulair抑制了 在体外和小鼠中表达JAK2-V617F的细胞的生长。因此，Singulair可能是一个有效的新代理商 用于治疗PV。我们假设在Alox5-Pathway中产生的白细胞发挥了必不可少的 在PV中MPN发射细胞的生存调节中的作用，Singulair拮抗 白细胞充当PV的潜在新治疗剂。检验该假设是临床的 意义并受益：1）尚未发展为急性髓样白血病（AML）的PV患者； 2）用残留的JAK2V617F细胞临床缓解AML的PV患者，可能 随着时间的流逝而复发； 3）用于治疗AML的骨髓移植的光伏患者从 PV但仍然具有残留的JAK2V617F表达细胞； 4）有可检测的个人 JAK2V617F髓样细胞中的转录本尚未出现PV的临床症状。因为Alox5 众所周知，途径会产生白细胞，一种合理的机械解释，是单卢拉的作用的一种说明 它通过阻止白细胞与PV发射细胞的受体结合来消除PV。我们还需要知道 Singulair抑制PV发射细胞和PV发育的基本分子机制。在 事实，我们的初步研究表明，JAK2V617F调节涉及两个Alox5的Alox5途径 下游基因，β-catenin（作为刺激剂）和BLK（作为抑制器），对 研究Singuliar是否调节PV发射细胞中的这两个基因。最后，至关重要 确定Singulair是否抑制了人类PV发射细胞的生长。具体目的是：1） 确定PV发射细胞的存活是否取决于白细胞以及是否封锁 Singulair的白细胞减少了它们对PV发射细胞的影响。 2）确定分子 Singulair抑制PV发射细胞和PV发育的机制； 3）确定 Singulair是否阻止了人类PV发射细胞中的Alox5途径并减少人类的植入 免疫功能低下的小鼠中的PV启动细胞。从广义上讲，Singulair是固体的潜在治疗剂 肿瘤作为ALOX5与结肠，肺，胰腺，肝脏，食道，皮肤等的肿瘤发生有关。