PKCz; a novel therapeutic target for pancreatic cancer 'stem cells'

PKCz；

• 批准号: 8316532
• 负责人: Amanda M Butler
• 金额: $ 4.09万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316532
• 关键词: Agar; Anchorage-Independent Growth; Aurothiomalate; Binding; Biological Assay; CXCR4 gene; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Line; Cells; Cessation of life; Characteristics; Cisplatin; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Data; Detection; Development; Effectiveness; Exhibits; FDA approved; Genetic; Goals; Growth; Human; In Vitro; Invaded; Isoenzymes; Laboratories; Maintenance; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mean Survival Times; Mediating; Modeling; Molecular Target; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pharmaceutical Preparations; Phenotype; Play; Population; Property; RNA Interference; Resistance; Role; Signal Transduction; Stem cells; Stromal Cell-Derived Factor 1; Survival Rate; Testing; Therapeutic; Tumorigenicity; Work; atypical protein kinase C; cancer cell; cancer stem cell; cell growth; chemokine; chemotherapy; design; in vivo; inhibitor/antagonist; neoplastic cell; new therapeutic target; pancreatic cancer cells; pancreatic neoplasm; progenitor; resistance factors; small molecule; stem; stem cell population; stem cell therapy; subcutaneous; therapeutic target; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the US with a mean survival time of less than 6 months and an overall 5-year survival rate of less than 5 percent. Recently a distinct population of cancer cells with 'stem cel', 'initiating', or 'progenitor' properties has been identified and characterized to play a significan and critical role in tumor development, maintenance, tumor metastases and therapy resistance, factors known to promote the high lethality of PC. My long term goal is to identify therapeutic strategies that target pancreatic cancer 'stem cells' (PCSCs). The atypical protein kinase C (aPKC) isozyme, PKC?, is over- expressed in a subset of human pancreatic tumors and plays a critical role in the transformed growth of PC cells in vitro, and in their tumorigenesis and metastasis in vivo. Here, we generated Panc-1 PCSCs in "low adherent" 3D culture. The 'stem cell-ness' of this population was functionally characterized by the ability of these cells to clonaly expand, migrate toward the chemokine, SDF-1, enhanced ability to grow in soft agar, and increased expression of SC markers. Preliminary data suggests a role for PKC? in PCSCs. Furthermore, PCSC growth can be inhibited with a molecularly targeted inhibitor of PKC?, aurothiomalate (ATM). The specific aims of this project are to 1) elucidate the role of PKC? in PCSC transformed growth, tumorigenesis, and tumor metastasis; and 2) evaluate the ability to inhibit the PCSC phenotype with ATM alone and in combination with conventional chemotherapeutics. These aims will be carried out using proliferation, survival, and stem cell marker expression assays along with subcutaneous and orthotopic tumor models. PUBLIC HEALTH RELEVANCE: Since ATM is an FDA-approved drug, and already in clinical trials for the treatment of lung and ovarian cancer, the proposed studies have the potential to rapidly impact the therapy of pancreatic cancer patients, who currently have few effective options for treatment. PUBLIC HEALTH RELEVANCE: Cancer is amongst the leading causes of worldwide death, and pancreatic cancer is a particularly lethal form due to its late detection and resistance to current chemotherapy. Cancer 'stem cells' mediate tumor initiation, metastasis, chemotherapy resistance, and tumor relapse. Therefore, identification and characterization of therapeutic target(s) specific to pancreatic cancer 'stem cells' has the potential to revolutionize chemotherapy for pancreatic cancer patients.

描述（由申请人提供）：胰腺癌（PC）是美国癌症死亡的第四个主要原因，平均生存时间少于6个月，总5年生存率低于5％。最近，已经确定并表征了具有“茎Cel”，“启动”或“祖细胞”特性的不同癌细胞群体在肿瘤发育，维持，肿瘤转移和耐药性中起着显着和关键作用，这些因素已知可促进PC的高杀伤性。我的长期目标是确定针对胰腺癌“干细胞”（PCSC）的治疗策略。非典型蛋白激酶C（APKC）同工酶，PKC？，在人类胰腺肿瘤的一部分中过度表达，并且在体外PC细胞的转化以及其体内的肿瘤发生和转移中起着至关重要的作用。在这里，我们在“低粘附” 3D文化中生成了PANC-1 PCSC。该人群的“干细胞性”在功能上的特征是这些细胞的克隆膨胀，朝向趋化因子，SDF-1迁移，增强在软琼脂中生长的能力以及SC标记的表达增加。初步数据表明PKC的作用？在PCSC中。此外，PCSC生长可以用PKC？aurothiomalate（ATM）的分子靶向抑制剂抑制。该项目的具体目的是1）阐明PKC的作用？在PCSC中，变化了生长，肿瘤发生和肿瘤转移。 2）评估单独使用ATM并与常规化学治疗剂结合使用PCSC表型的能力。这些目标将使用增殖，存活和干细胞标记表达测定法以及皮下和原位肿瘤模型进行。公共卫生相关性：由于ATM是一种经FDA批准的药物，并且已经在治疗肺癌和卵巢癌的临床试验中，因此拟议的研究有可能快速影响胰腺癌患者的治疗，他们目前几乎没有有效治疗方案。 公共卫生相关性：癌症是全球死亡的主要原因之一，胰腺癌是一种特别致命的形式，由于其迟到和对当前化学疗法的抵抗力。癌症“干细胞”介导肿瘤的启动，转移，化学疗法耐药性和肿瘤复发。因此，胰腺癌“干细胞”特异性治疗靶标的鉴定和表征有可能彻底改变胰腺癌患者的化学疗法。