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.

项目总结：早期全身播散，异常局部侵袭，晚期诊断， 对现有化疗的反应导致胰腺癌患者预后不良。有一个 迫切需要确定新的治疗方法，将显着提高患者的生存。虽然大多数胰腺 导管腺癌有Kras突变，多种其他遗传改变有助于分子 肿瘤发生和患者预后。这些遗传性病变是新型个性化治疗的关键， 胰腺癌患者，但仍然很少探索。识别新型个性化治疗组合 将是对抗PDAC的重大进步。 我们和其他人发现了一种新的ME2缺失，作为一种乘客缺失与SMAD 4丢失，这是普遍存在的 高达30%的PDAC患者。通过利用细胞培养模型，类器官，原位植入小鼠， 模型，和患者来源的胰腺导管腺癌的异种移植物，有和没有ME2损失，我们 提出了新的观察结果，即ME2对胰腺癌的肿瘤生长和转移具有直接的负面影响， 癌在此，我们建议研究胰腺癌中ME2缺失介导的肿瘤发生的分子基础。 癌通过利用一系列无偏的高通量筛选方法，我们已经确定了新的 胰腺癌细胞中由于ME2丢失而引起的信号改变。因此，我们亦会研究 阻断由ME2丢失诱导的信号通路，促进胰腺癌的侵袭性。 这些机制可能调节肿瘤细胞生长和低ME2表达肿瘤细胞的侵袭性。 因此，我们的研究将有助于开发新的和更有效的胰腺癌治疗方法。 我们的长期目标是确定ME2丢失介导的信号传导的分子基础， 胰腺癌的侵袭和转移。在第一个目标中，我们将利用基因工程小鼠 研究ME2缺失对胰腺癌发生、进展和转移的影响。的 第二个目标是研究胰腺癌中ME2缺失介导的侵袭性的分子基础。目的 3将研究ME2丢失患者的个性化治疗潜力， 模型和患者来源的异种移植物，并评估其功效的生物标志物和分子调节剂。 总的来说，拟议的研究采用了一种创新和综合的方法来阐明分子 ME2丢失介导的肿瘤进展的基础，并可能揭示其他个性化治疗， 用于治疗侵袭性胰腺癌的治疗功效的生物标志物。