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 急性淋巴细胞白血病迫切需要开发分子靶向疗法 白血病（全部）。缺乏针对这种疾病的靶向治疗是一个重要问题，因为 ALL 主要是一种儿科癌症，密集的一般细胞毒性化疗会产生严重且长期的副作用。 对儿童的长期不良影响。此外，患有 ALL 对细胞毒性药物没有反应的成人和儿童 由于治疗选择有限，化疗或复发的患者预后普遍较差。 众所周知的 ALL 驱动因素是错误表达的转录因子，例如 MYC，这些转录因子不容易被识别。 治疗靶向，不会对正常细胞产生不良副作用。初步数据建立在 在斑马鱼 MYC 诱导的 ALL 模型中进行的新型体内移植筛选表明，酪氨酸 磷酸酶 PRL3 与 MYC 合作促进白血病进展。体外和体内研究使用 人类细胞显示 PRL3 与 MYC 表达相关，并在 ALL 生存中发挥关键作用。 像 PRL3 这样的磷酸酶是最著名的肿瘤抑制因子，尽管有新的证据表明一些磷酸酶 磷酸酶具有致癌能力，目前临床上尚无磷酸酶抑制剂用于治疗 癌症患者，并且只有一名处于临床试验阶段。该应用程序的总体目标是明确定义 酪氨酸磷酸酶 PRL3 在 MYC 驱动的 ALL 中的致癌作用，并确定它是一种新型的 这种疾病的分子靶点。中心假设是 PRL3 是 MYC 的直接转录靶标，并且 与 MYC 协同作用，促进 ALL 细胞的促生存表型。这项研究的理由是 PRL3属于一个独特的磷酸酶家族，可以被选择性抑制；定义机制 PRL3 通过其促进 ALL 生存将为发展提供强有力的科学依据 PRL 和其他磷酸酶抑制剂用作癌症患者的靶向治疗。这个假设将是 通过追求三个具体目标进行测试：1) 定义 MYC 调节 PRL3 表达的机制 通过使用 enChIP 和生化方法来评估 MYC 与附近的新型增强子区域的相互作用 泌乳素3； 2) 利用无偏生物素确定 PRL3 控制的促生存机制 连接酶方法鉴定 ALL 细胞中的 PRL3 底物； 3）确定小分子抑制 PRL 家族通过完成三种药物的全面临床前测试，成为 ALL 的有效治疗策略 新型 PRL 抑制剂和 FDA 批准的一系列酪氨酸磷酸酶抑制剂。这项研究具有创新性 因为它偏离了现状，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，因为它有望纵向推进和扩展 了解磷酸酶在癌症进展中的作用。最终，这些知识具有 具有推动针对急性淋巴细胞白血病患者开发新型靶向治疗的潜力 白血病和其他 MYC 驱动的癌症。