Molecular Basis of ME2-mediated Tumor Suppression in Pancreatic Cancer

ME2 介导的胰腺癌肿瘤抑制的分子基础

• 批准号: 10671029
• 负责人: Pankaj Kumar Singh
• 金额: $ 42.2万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671029
• 关键词: Acceleration; Agreement; Binding; Biological Assay; Biological Markers; Cancer Etiology; Cell Culture Techniques; Cells; Cessation of life; Clinical Treatment; Data; Data Set; Development; Diagnosis; Down-Regulation; Effectiveness; Event; FRAP1 gene; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; High-Throughput Nucleotide Sequencing; Human; Implant; Invaded; KRAS oncogenesis; KRASG12D; Knock-out; Lesion; Libraries; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; Organoids; Other Genetics; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Phase; Phosphatidylinositols; Phosphotransferases; Primary Neoplasm; Production; Prognosis; Protein Array; Reactive Oxygen Species; Research Personnel; Residual state; Resistance; Role; Series; Signal Pathway; Signal Transduction; Sirolimus; The Cancer Genome Atlas; Therapeutic; Treatment Efficacy; Tumor Burden; Tumor Suppression; Tumor Suppressor Proteins; Xenograft Model; cancer initiation; cell growth; chemotherapy; chromatin immunoprecipitation; clinically relevant; effective therapy; experimental study; gain of function mutation; high throughput screening; implantation; improved; inhibitor; innovation; kinase inhibitor; knock-down; malic enzyme; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel therapeutics; pancreatic PDX models; pancreatic cancer cells; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic tumorigenesis; patient derived xenograft model; patient prognosis; personalized medicine; personalized therapeutic; pharmacologic; promoter; response; three-dimensional modeling; transcriptome sequencing; treatment response; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

Project Summary: Early systemic dissemination, extraordinary local invasion, late diagnosis, and inadequate response to the existing chemotherapy contribute to poor prognosis for pancreatic cancer patients. There is an urgent need to identify novel therapies that would significantly improve survival in patients. While most pancreatic ductal adenocarcinomas have mutations in Kras, multiple other genetic alterations contribute to molecular oncogenesis and patient prognosis. These genetic lesions hold the key to novel personalized therapies for pancreatic cancer patients but remain poorly explored. Identifying novel personalized therapeutic combinations would be a significant advancement in combating PDAC. We and others identified a novel ME2 deletion as a passenger deletion with SMAD4 loss, which is prevalent in up to 30% of PDAC patients. By utilizing cell culture models, organoids, orthotopically-implanted mouse models, and patient-derived xenografts of pancreatic ductal adenocarcinoma with and without ME2-loss, we made the novel observation that ME2 has a direct negative impact on tumor growth and metastasis in pancreatic cancer. Here, we propose to investigate the molecular basis of ME2 loss-mediated oncogenesis in pancreatic cancer. By utilizing a series of unbiased high-throughput screening approaches, we have identified novel signaling alterations in pancreatic cancer cells due to ME2 loss. Hence, we will also investigate the effectiveness of blocking the signaling pathways induced by the ME2 loss that facilitate aggressiveness in pancreatic cancer. Such mechanisms potentially regulate tumor cell growth and invasiveness of low ME2-expressing tumor cells. Thus, our studies will facilitate the development of new and more effective treatments for pancreatic cancer. Our long-term goal is to determine the molecular basis of ME2 loss-mediated signaling that facilitates invasiveness and metastasis in pancreatic cancer. In the first aim, we will utilize genetically engineered mice models to investigate the impact of ME2 loss on pancreatic cancer initiation, progression, and metastasis. The second aim will investigate the molecular basis of ME2 loss-mediated aggressiveness in pancreatic cancer. Aim 3 will investigate the potential of personalized therapies for patients with ME2 loss by utilizing spontaneous models and patient-derived xenografts and evaluate biomarkers and molecular regulators of their efficacy. Collectively, the proposed studies employ an innovative and integrative approach to elucidate the molecular basis of ME2 loss-mediated tumor progression and may uncover additional personalized therapies and biomarkers of therapeutic efficacies for the treatment of aggressive pancreatic cancer.

项目摘要：早期全身传播，特殊的局部入侵，晚期诊断和不足 对现有化疗的反应导致胰腺癌患者的预后不良。有一个 迫切需要确定可以显着改善患者生存率的新型疗法。虽然最胰腺 导管腺癌在KRAS中具有突变，多种其他遗传改变有助于分子 肿瘤发生和患者预后。这些遗传病变是新颖的个性化疗法的关键 胰腺癌患者，但仍受到探索不佳。识别新颖的个性化治疗组合 在打击PDAC方面将是一个重大进步。 我们和其他人将新颖的ME2删除确定为带有SMAD4损失的乘客删除，这很普遍 多达30％的PDAC患者。通过利用细胞培养模型，器官，原位植入小鼠 模型和患者衍生的胰腺导管腺癌的异种移植物，有或没有ME2损坏，我们 使新的观察结果是，ME2对胰腺的肿瘤生长和转移有直接的负面影响 癌症。在这里，我们建议研究胰腺中ME2损失介导的肿瘤发生的分子基础 癌症。通过利用一系列公正的高通量筛选方法，我们已经确定了新颖的 ME2损失引起的胰腺癌细胞的信号改变。因此，我们还将研究有效性 通过ME2损失诱导的信号通路，促进胰腺癌的攻击性。 这种机制可能调节低表达ME2的肿瘤细胞的肿瘤细胞生长和侵袭性。 因此，我们的研究将有助于开发胰腺癌的新的，更有效的治疗方法。 我们的长期目标是确定ME2损耗介导的信号的分子基础，以促进 胰腺癌的侵入性和转移。在第一个目标中，我们将利用基因工程的小鼠 模型研究ME2损失对胰腺癌的启动，进展和转移的影响。这 第二个目标将研究ME2损失介导的胰腺癌侵袭性的分子基础。目的 3将通过使用自发来调查ME2损失患者的个性化疗法的潜力 模型和患者衍生的异种移植物，并评估其功效的生物标志物和分子调节剂。 总的来说，拟议的研究采用创新和综合方法来阐明分子 ME2损失介导的肿瘤进展的基础，可能会发现其他个性化疗法和 治疗侵袭性胰腺癌的治疗效率的生物标志物。