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: 10527104
• 负责人: Jessica S. Blackburn
• 金额: $ 34.3万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10527104
• 关键词: Acute Lymphocytic Leukemia; Adult; Adverse effects; Apoptosis; Binding Sites; Biochemical; Biotin; Cancer Patient; Cells; Cessation of life; Child; Clinic; Clinical Trials; Collaborations; 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; Prognosis; 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; Zebrafish; acute lymphoblastic leukemia cell; antileukemic activity; cancer type; chemotherapy; in vivo; inhibitor; innovation; knock-down; leukemia; member; molecular targeted therapies; novel; patient derived xenograft model; pediatric patients; phosphatase inhibitor; preclinical trial; side effect; small molecule; synergism; targeted cancer therapy; targeted treatment; therapeutic target; transcription factor; translational impact; tumor progression

ORIGINAL 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.

原始项目摘要 在急性淋巴细胞中的分子靶向疗法非常需要发展 白血病（全部）。缺乏针对这种疾病的靶向疗法是一个重要的问题，因为一切都是 主要是儿科癌，大量的一般细胞毒性化学疗法具有严重和长期 儿童的术语不良影响。此外，成年人和儿童对细胞毒性不反应 由于治疗选择有限，化学疗法或发生复发的人的预后普遍差。 所有的众所周知的驱动因素是表达错误的转录因素，例如MYC，不容易 治疗靶向正常细胞没有不良副作用。初步数据，建立在 在MYC诱导的斑马鱼中的所有模型中，小说中的体内移植屏幕证明了酪氨酸 磷酸酶PRL3与MYC合作，以增强白血病进展。使用体外和体内研究 人类细胞表明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。 像PRL3这样的磷酸酶是最著名的肿瘤抑制剂，尽管有一些证据表明有些有些 磷酸酶具有致癌能力，目前诊所中没有使用磷酸酶抑制剂。 癌症患者，只有一个在临床试验中。该应用程序的总体目的是清楚地定义 酪氨酸磷酸酶PRL3在MYC驱动的全部中的致癌作用，并确定它是一种新颖的 该疾病中的分子靶标。中心假设是PRL3是MYC的直接转录目标，并且 与MYC协同作用，以促进所有细胞中的促生存表型。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。定义机制 PRL3促进所有生存将为发展提供强大的科学原理 PRL和其他磷酸酶抑制剂作为癌症患者的靶向治疗。这个假设将是 通过追求三个特定目标测试：1）定义一种机制，MYC调节PRL3表达 通过使用Enchip和生化方法评估MYC与附近的新型增强剂区域的相互作用 prl3; 2）确定通过使用公正的生物素来控制PRL3控制的促生物学机制 连接酶的方法鉴定所有细胞中的PRL3底物； 3）确定对小分子的抑制 PRL家族是通过完成三个的全面临床前测试，是一种有效的治疗策略 新的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。