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的分子靶向治疗是一个巨大的需求， 白血病（ALL）。缺乏针对这种疾病的靶向治疗是一个重要的问题，因为ALL是 主要是一种儿科癌症，密集轮的一般细胞毒性化疗具有严重和长期的- 长期对儿童的不良影响。此外，成人和儿童的ALL不响应细胞毒性 化疗或复发的患者由于有限的治疗选择而具有普遍不良的预后。 ALL的众所周知的驱动因子是错误表达的转录因子，如MYC，其不容易被表达。 在治疗上靶向，而对正常细胞没有不期望的副作用。初步数据建立在 在斑马鱼MYC诱导的ALL模型中进行的新的体内移植筛选表明，酪氨酸 磷酸酶PRL 3与MYC协同促进白血病进展。体外和体内研究，使用 人类细胞显示PRL 3与MYC表达相关，并在ALL存活中起关键作用。 像PRL 3这样的磷酸酶作为肿瘤抑制剂是最为人所知的，尽管有新的证据表明， 由于磷酸酶具有致癌能力，目前临床上没有磷酸酶抑制剂用于治疗癌症。 癌症患者，只有一个在临床试验中。本申请的总体目标是明确定义 酪氨酸磷酸酶PRL 3在MYC驱动的ALL中的致癌作用，并确定它是一种新的 分子靶点核心假设是PRL 3是MYC的直接转录靶点， 与MYC协同促进ALL细胞中的促存活表型。这项研究的基本原理是， PRL 3属于一个独特的磷酸酶家族，可以被选择性抑制; PRL 3促进ALL生存的机制将为以下研究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。这一假设将是 通过追求三个具体目标进行测试：1）定义MYC调节PRL 3表达的机制 通过使用enChIP和生物化学方法来评估MYC与一个新的增强子区域的相互作用， PRL 3; 2）通过利用无偏生物素确定由PRL 3控制的促存活机制 连接酶方法鉴定ALL细胞中PRL 3底物;和3）建立小分子抑制 PRL家族是ALL的一种有效治疗策略，通过完成三种药物的全面临床前试验， 新的PRL抑制剂和一组FDA批准的酪氨酸磷酸酶抑制剂。这项研究具有创新性 因为使用新的方法来确定磷酸酶在肿瘤中的致癌作用与现状不同， 癌拟议中的研究也具有重大意义，因为它有望纵向推进和扩大 了解磷酸酶在癌症进展中的作用。最终，这些知识 有可能推动急性淋巴细胞白血病患者新型靶向治疗的发展 白血病和其他MYC驱动的癌症。