The phosphatase PRL3 as a MYC target and pro-survival oncogene in Acute Lymphoblastic Leukemia

磷酸酶 PRL3 作为急性淋巴细胞白血病的 MYC 靶点和促生存癌基因

• 批准号: 9904131
• 负责人: Jessica S. Blackburn
• 金额: $ 35万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-06 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904131
• 关键词: Acute Lymphocytic Leukemia; Adult; Adverse effects; Apoptosis; Binding Sites; Biochemical; Biotin; Cancer Patient; Cells; Cessation of life; Child; Clinic; Clinical Trials; Cytotoxic Chemotherapy; DNA-Binding Proteins; Data; Defect; Development; Developmental Delay Disorders; Diagnosis; Disease; Disease Progression; Drug Targeting; Enhancers; FDA approved; Family; Gene Chips; General Population; Genes; Genetic Transcription; Growth; Human; Human Cell Line; In Vitro; Kinetics; Knowledge; Leukemic Cell; Life; Ligase; Link; MYC gene; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Methods; Mission; Modeling; Molecular Target; Normal Cell; Nucleic Acid Regulatory Sequences; Oncogenes; Oncogenic; Organ; Outcomes Research; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Play; Preclinical Testing; Protein Array; Protein Tyrosine Phosphatase; Public Health; Regimen; Relapse; Research; Role; Sampling; Second Primary Cancers; Signal Pathway; Single Nucleotide Polymorphism; TP53 gene; Testing; Therapeutic; Transcriptional Regulation; Transplantation; Tumor Suppressor Proteins; Xenograft procedure; Zebrafish; acute lymphoblastic leukemia cell; antileukemic activity; base; cancer type; chemotherapy; in vivo; inhibitor/antagonist; innovation; knock-down; leukemia; member; molecular targeted therapies; novel; outcome forecast; pediatric patients; phosphatase inhibitor; preclinical trial; side effect; small molecule; targeted cancer therapy; targeted treatment; therapeutic target; transcription factor; translational impact; tumor progression

PROJECT SUMMARY There is a great need for the development of molecularly targeted therapies in Acute Lymphoblastic Leukemia (ALL). The lack of targeted therapies for this disease is an important problem because ALL is primarily a pediatric cancer, and intensive rounds of general cytotoxic chemotherapy have severe and long-term adverse effects in children. Additionally, adults and children whose ALL does not respond to cytotoxic chemotherapy, or who develop relapse, have a universally poor prognosis due to limited treatment options. The well-known drivers of ALL are mis-expressed transcription factors, such as MYC, which are not easily therapeutically targeted without undesirable side-effects on normal cells. Preliminary data, which built on a novel in vivo transplantation screen in a MYC-induced ALL model in zebrafish, demonstrated that the tyrosine phosphatase PRL3 collaborated with MYC to enhance leukemia progression. In vitro and in vivo studies using human cells showed that PRL3 is linked with MYC expression, and plays a critical role in ALL survival. Phosphatases like PRL3 are most well-known as tumor suppressors, and despite emerging evidence that some phosphatases have oncogenic abilities, there are currently no phosphatase inhibitors used in the clinic for cancer patients, and only one in clinical trial. The overall objective of this application is to clearly define the oncogenic role of the tyrosine phosphatase PRL3 in MYC-driven ALL and to establish that it is a novel molecular target in this disease. The central hypothesis is that PRL3 is a direct transcriptional target of MYC, and synergizes with MYC to promote a pro-survival phenotype in ALL cells. The rationale for this research is that PRL3 belongs to a unique family of phosphatases that can be selectively inhibited; defining the mechanisms through which PRL3 promotes ALL survival will provide a strong scientific rationale for the development of PRL and other phosphatase inhibitors for use as targeted therapy for cancer patients. This hypothesis will be tested by pursuing three specific aims: 1) Define a mechanism through which MYC regulates PRL3 expression by using enChIP and biochemical approaches to assess MYC interaction with a novel enhancer region near PRL3; 2) determine the pro-survival mechanisms that are controlled by PRL3 by utilizing an unbiased biotin ligase approach to identify PRL3 substrates in ALL cells; and 3) establish that small molecule inhibition of the PRL family is a potent therapeutic strategy in ALL by completing comprehensive pre-clinical testing of three new PRL inhibitors and a panel of FDA-approved tyrosine phosphatase inhibitors. This research is innovative because it departs from the status quo to use new methods to define an oncogenic role for a phosphatase in cancer. The proposed research is also significant because it is expected to vertically advance and expand understanding of the role that phosphatases play in cancer progression. Ultimately, this knowledge has the potential to drive the development of a new class of targeted therapy for patients with acute lymphoblastic leukemia and other MYC-driven cancers.

项目摘要 急需在急性淋巴细胞白血病中开发分子靶向疗法 （全部）。缺乏针对该疾病的靶向疗法是一个重要的问题，因为所有问题主要是 小儿癌和一般细胞毒性化学疗法的强化回合患有严重和长期不良 对儿童的影响。此外，成年人和儿童对细胞毒性化疗没有反应，或 由于治疗方案有限而导致的复发，预后普遍差。众所周知 所有的驱动因素是误表达的转录因素，例如MYC，在治疗上不容易 针对正常细胞没有不良副作用的靶向。初步数据，该数据建立在体内小说的基础上 MYC诱导的斑马鱼中的所有模型中的移植屏幕表明酪氨酸磷酸酶 PRL3与MYC合作，以增强白血病进展。使用人类细胞的体外和体内研究 表明PRL3与MYC的表达相关，并且在所有生存中起着至关重要的作用。磷酸酶 PRL3是肿瘤抑制剂最著名的，尽管有一些证据表明某些磷酸酶 具有致癌能力，目前在癌症患者的诊所中没有使用磷酸酶抑制剂， 只有一个在临床试验中。该应用的总体目的是清楚地定义 MYC驱动的全部酪氨酸磷酸酶PRL3，并确定它是一个新颖的分子靶 疾病。中心假设是PRL3是MYC的直接转录目标，并与 MYC在所有细胞中促进促生物的表型。这项研究的理由是PRL3属于 可以选择性抑制的独特磷酸酶家族；定义通过 PRL3促进所有生存将为PRL和其他其他的发展提供强大的科学原理 磷酸酶抑制剂作为癌症患者的靶向治疗。该假设将通过 追求三个特定目标：1）定义一种机制，MYC通过使用该机制调节PRL3表达 Enchip和生化方法评估MYC与PRL3附近的新型增强剂区域的相互作用； 2） 通过使用无偏的生物素连接酶来确定由PRL3控制的促生物生存机制 识别所有细胞中PRL3底物的方法； 3）确定对PRL的小分子抑制 家庭通过完成三个新的全面临床前测试，是一种有效的治疗策略 PRL抑制剂和一组FDA批准的酪氨酸磷酸酶抑制剂。这项研究是创新的 因为它从现状背离了使用新方法来定义磷酸酶的致癌作用 癌症。拟议的研究也很重要，因为它有望垂直进步和扩展 了解磷酸酶在癌症进展中的作用。最终，这些知识具有 推动急性淋巴细胞患者开发新的靶向治疗的新型靶向疗法的潜力 白血病和其他由MYC驱动的癌症。