The SMYD3-ERK5 signaling module in pancreatic cancer

胰腺癌中的 SMYD3-ERK5 信号模块

• 批准号: 8950606
• 负责人: Pawel K. Mazur
• 金额: $ 14.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8950606
• 关键词: Ablation; Adenocarcinoma Cell; Apoptosis; Automobile Driving; Award; Biochemical; Cancer Biology; Cancer Etiology; Cancer cell line; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Data; Development; Disease; Drug Targeting; Drug resistance; Event; Family; Feedback; Genetic; Goals; Growth; Health; Human; In Vitro; Incidence; Investigation; KRAS2 gene; Knowledge; Lead; Lysine; MAP2K1 gene; MAPK3 gene; MAPK7 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Methylation; Methyltransferase; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Mutation; Nature; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Pre-Clinical Model; Proteins; Recurrence; Relapse; Research; Resistance; Resistance development; Role; SMYD3 gene; Science; Scientist; Signal Transduction; Stimulus; Systems Biology; Testing; Therapeutic; Toxic effect; Training; Validation; Work; base; cancer initiation; cancer type; career; cell motility; chemotherapy; field study; genetic approach; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; kinase inhibitor; member; mortality; mouse model; new therapeutic target; next generation; novel; pancreatic cancer cells; prevent; research study; response; skills; therapeutic target; therapy resistant; transcription factor; tumor; tumor progression; tumor xenograft

 DESCRIPTION (provided by applicant): My long-term career goal is to lead a productive academic research group, promoting science by conducting impactful cancer biology research and mentoring the next generation of dedicated scientists. I am particularly interested in the mechanisms of cancer development and resistance to therapy in Ras-driven tumors. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and it is almost universally driven by activation of oncogenic Ras. Unfortunately, PDAC mortality rates have remained almost equal to incidence rates over the past few decades. My main objective is to identify novel therapeutic targets in PDAC cells to guide the development of new efficacious drugs and treatment approaches in PDAC patients. A major goal of this K99/R00 proposal is to elucidate a novel signaling module implicated in PDAC: in this module, the SMYD3 lysine methyltransferase activates the MAP3K2 kinase, which in turn activates the MEK5 kinase, leading to activation of the downstream ERK5 kinase. A second important goal is to uncover molecular mechanisms promoting resistance to drugs targeting the Ras pathway. First, I will focus on defining the role of ERK5 in the initiation and progression of PDAC. The MEK5-ERK5 pathway has been implicated in cell survival and cell motility but its role in PDAC has never been investigated. Aim 1 will test the hypothesis that activation of the SMYD3-ERK5 signaling module, which I have recently observed in PDAC, facilitates early cancer progression by promoting pancreatic cell plasticity, proliferation, and impairing apoptosis in response to oncogenic Ras. I will use genetic and pharmacological approaches to test this hypothesis in mouse models of PDAC, patient derived tumor xenografts, and cancer cell lines. Clinical trials with inhibitors of kinases in the canonical Ras pathway have had disappointing results, in part because of the rapid emergence of resistant tumors. I have generated pre-clinical models to study tumors resistant to Ras pathway inhibitors and found amplification of SMYD3-ERK5 activity during tumor relapse. Aim 2 will utilize genetic and pharmacological approaches to characterize the functional role of the SMYD3- ERK5 signaling module in resistant tumors in vivo and in vitro. Finally, in Aim 3, I will perform an unbiased screen of transcriptional targets and interacting protein partners of ERK5 to elucidate its mechanisms of action in PDAC cells and identify novel key regulators of PDAC development and resistance to Ras pathway inhibitors. Candidate targets, including preliminarily identified YAP1 transcription factor, will be tested in a novel mouse model of human PDAC that I have developed for rapid investigation of putative regulators of disease development in vivo. A K99/R00 training award will allow me to carry out this transformative project, further developing my current skills in mouse genetics and cancer biology, while also allowing me to acquire knowledge in clinical aspects of pancreatic cancer and new expertise in biochemical signaling and systems biology.

 我的长期职业目标是领导一个富有成效的学术研究小组，通过进行有影响力的癌症生物学研究和指导下一代专门的科学家来促进科学。我特别感兴趣的是癌症发展的机制和Ras驱动的肿瘤对治疗的抵抗。胰腺导管腺癌（PDAC）是最致命的癌症之一，它几乎普遍由致癌Ras的激活驱动。不幸的是，在过去的几十年里，PDAC的死亡率几乎与发病率持平。我的主要目标是在PDAC细胞中识别新的治疗靶点，以指导PDAC患者新的有效药物和治疗方法的开发。该K99/R 00提案的主要目标是阐明PDAC中涉及的新信号传导模块：在该模块中，SMYD 3赖氨酸甲基转移酶激活MAP 3 K2激酶，MAP 3 K2激酶进而激活MEK 5激酶，导致下游ERK 5激酶的激活。第二个重要目标是揭示促进对Ras通路药物耐药性的分子机制。首先，我将重点阐述ERK 5在PDAC发生和发展中的作用。MEK 5-ERK 5通路与细胞存活和细胞运动有关，但其在PDAC中的作用从未被研究过。目的 1将测试这一假设，即SMYD 3-ERK 5信号传导模块的激活，我最近在PDAC中观察到，通过促进胰腺细胞可塑性，增殖和损害细胞凋亡来促进早期癌症进展，以响应致癌Ras。我会用基因 和药理学方法来在PDAC的小鼠模型、患者来源的肿瘤异种移植物和癌细胞系中测试该假设。经典Ras通路激酶抑制剂的临床试验结果令人失望，部分原因是耐药肿瘤的快速出现。我已经建立了临床前模型来研究对Ras通路抑制剂耐药的肿瘤，并发现在肿瘤复发期间SMYD 3-ERK 5活性的扩增。目的2将利用遗传学和药理学方法来表征SMYD 3-ERK 5信号模块在体内和体外耐药肿瘤中的功能作用。最后，在目标3中，我将对ERK 5的转录靶点和相互作用蛋白伴侣进行公正的筛选，以阐明其在PDAC细胞中的作用机制，并确定PDAC发育和对Ras途径抑制剂耐药性的新型关键调节因子。候选目标，包括初步确定的YAP 1转录因子，将在一种新的人类PDAC小鼠模型中进行测试，我已经开发了用于快速调查体内疾病发展的假定调节因子。K99/R 00培训奖将使我能够开展这一变革性项目，进一步发展我目前在小鼠遗传学和癌症生物学方面的技能，同时也使我能够获得胰腺癌临床方面的知识以及生化信号和系统生物学方面的新专业知识。