The Role of post-translational activation of Myc in pancreatic cancer

Myc 翻译后激活在胰腺癌中的作用

• 批准号: 8912231
• 负责人: ROSALIE C SEARS
• 金额: $ 39.27万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912231
• 关键词: Adhesions; Automobile Driving; Cancer Etiology; Cancer Patient; Cancer cell line; Cells; Cessation of life; DNA Binding; Data; Desmoplastic; Development; Disease; Disease Progression; Duct (organ) structure; Ductal; Event; Evolution; Gene Targeting; Genetic Transcription; Goals; Heterogeneity; Human; Immune; In Vitro; KRAS2 gene; Lesion; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Metaplasia; Metastatic to; Molecular; Mus; Mutation; Nature; Normal Cell; Oncogene Proteins; Oncogenic; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Peripheral; Phosphorylation; Phosphorylation Site; Physiological; Play; Preclinical Testing; Process; Reaction; Regulation; Resistance; Role; ST13 gene; Sampling; Serine; Serine Phosphorylation Site; Signal Transduction; Staging; Survival Rate; Testing; Therapeutic; Threonine; Translational Activation; Treatment Efficacy; Work; angiogenesis; c-myc Genes; cancer cell; cell transformation; chemotherapy; genetic evolution; human disease; in vivo; insight; migration; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; pancreatic cancer cells; pancreatic neoplasm; programs; promoter; public health relevance; therapy resistant; tumor; tumor growth; tumor microenvironment; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): The 5-year survival rate for pancreatic cancer patients is only 6%, the lowest of all major cancers, indicating a critical need for increased mechanistic understanding of pancreatic cancer development in order to identify new therapeutic targets. The c-Myc (Myc) oncoprotein is overexpressed in a variety of cancers, including pancreatic ductal adenocarcinoma (PDA), and generally correlates with poor prognosis. Through its global regulation of gene transcription, Myc helps regulate multiple oncogenic processes, including cancer cell intrinsic proliferation, survival, and adhesion/migration, as well as extrinsic tumor microenvironment remodeling including angiogenesis and immune cell reprogramming. The expression and activity of Myc is tightly regulated in normal cells. We have identified Serine 62 (S62) as a critical phosphorylation site, which increases the stability and DNA binding activity of Myc. S62 is phosphorylated downstream of RAS signaling; and activating mutations in KRAS are near universal driver mutations in PDA. The role of Myc in pancreatic cancer, however, is currently poorly understood. We have observed elevated levels of S62 phosphorylated Myc (pS62-Myc) in pancreatic cancer cell lines and primary pancreatic tumor samples. Furthermore, analysis of early precursor lesions (PanIN) peripheral to tumors also shows elevated pS62-Myc as compared to adjacent normal ducts. We have generated a novel mouse model, LSL-KRASG12D;ROSA-LSL-MycWT;Pdx1- or p48-Cre (KMC) mice, which shows that deregulated expression of Myc at physiologic levels is able to cooperate with mutant KRAS to accelerate acinar to ductal metaplasia (ADM), PanIN progression, and conversion to metastatic PDA. Importantly, our preliminary data indicate that KMC tumors develop common mutations seen in the evolution of the human disease, initiate a pronounced stromal reaction, show resistance to standard chemotherapy, and can progress to an aggressive, poorly differentiated PDA with a high metastatic rate. Further, we have established two therapeutics in the lab that target Myc post-translationally, both of which have shown promising activity against pancreatic cancer in vitro and in vivo. The overall hypothesis of this proposal is that KRAS-mediated phosphorylation of Myc at Serine 62 is an important driver of pancreatic cancer cell transformation, that this mechanism of activating Myc significantly contributes to the evolution of metastatic PDA, and that targeting post-translational activation of Myc has therapeutic efficacy in pancreatic cancer. The following aims are proposed: Aim 1: Elucidate the role of Myc and KRAS-mediated Serine 62 phosphorylation in the development of pancreatic cancer; Aim 2: Characterize KRAS/Myc-driven pancreatic tumor evolution, stromal expansion, heterogeneity, and therapeutic resistance; Aim 3: Establish the therapeutic efficacy of targeting post-translational activation of Myc for the treatment of pancreatic cancer. This work will reveal if phosphorylation of Myc downstream of KRAS plays a critical role in pancreatic cancer development and progression, and whether targeting this post-translational activation of Myc could have therapeutic value in the treatment of this devastating disease.

 描述（申请人提供）：胰腺癌患者的5年生存率仅为6%，是所有主要癌症中最低的，这表明迫切需要增加对胰腺癌发展机制的了解，以确定新的治疗靶点。 c-Myc (Myc) 癌蛋白在多种癌症中过度表达，包括胰腺导管腺癌 (PDA)，并且通常与不良预后相关。通过对基因转录的全局调节，Myc 有助于调节多种致癌过程，包括癌细胞内在增殖、存活和粘附/迁移，以及外在肿瘤微环境重塑，包括血管生成和免疫细胞重编程。 Myc 的表达和活性在正常细胞中受到严格调控。我们已经确定丝氨酸 62 (S62) 是一个关键的磷酸化位点，它增加了 Myc 的稳定性和 DNA 结合活性。 S62 在 RAS 信号传导下游被磷酸化； KRAS 的激活突变接近 PDA 的普遍驱动突变。然而，目前对 Myc 在胰腺癌中的作用知之甚少。我们观察到胰腺癌细胞系和原发性胰腺肿瘤样本中 S62 磷酸化 Myc (pS62-Myc) 水平升高。此外，对肿瘤周围早期前体病变 (PanIN) 的分析也显示，与邻近的正常导管相比，pS62-Myc 升高。我们建立了一种新型小鼠模型，LSL-KRASG12D；ROSA-LSL-MycWT；Pdx1-或p48-Cre (KMC)小鼠，该模型表明生理水平上Myc表达失调能够与突变型KRAS配合，加速腺泡向导管化生(ADM)、PanIN进展以及向转移性PDA的转化。重要的是，我们的初步数据表明，KMC 肿瘤会产生人类疾病进化中常见的突变，引发明显的基质反应，对标准化疗表现出耐药性，并可能进展为具有高转移率的侵袭性、低分化 PDA。此外，我们在实验室中建立了两种针对翻译后 Myc 的疗法，这两种疗法在体外和体内都显示出有希望的抗胰腺癌活性。该提案的总体假设是，KRAS 介导的 Myc 在丝氨酸 62 处的磷酸化是胰腺癌细胞转化的重要驱动因素，这种激活 Myc 的机制显着促进转移性 PDA 的进化，并且靶向翻译后激活 Myc 对胰腺癌具有治疗功效。提出以下目标： 目标 1：阐明 Myc 和 KRAS 介导的丝氨酸 62 磷酸化在胰腺癌发生中的作用；目标 2：表征 KRAS/Myc 驱动的胰腺肿瘤进化、基质扩张、异质性和治疗耐药性；目标 3：建立靶向翻译后激活的治疗功效 Myc 用于治疗胰腺癌。这项工作将揭示 KRAS 下游 Myc 的磷酸化是否在胰腺癌的发生和进展中发挥关键作用，以及针对 Myc 的这种翻译后激活是否可以在治疗这种破坏性疾病中具有治疗价值。