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

PKCz；

• 批准号: 8627593
• 负责人: Amanda M Butler
• 金额: $ 2.22万
• 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 2014-06-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627593
• 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; protein kinase C zeta; 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.

描述（由申请人提供）：胰腺癌 (PC) 是美国第四大癌症死亡原因，平均生存时间不到 6 个月，总体 5 年生存率不到 5%。最近，具有“干细胞”、“起始”或“祖细胞”特性的独特癌细胞群已被鉴定和表征，它们在肿瘤的发展、维持、肿瘤转移和治疗耐药性中发挥着重要和关键的作用，这些因素已知会促进PC的杀伤力极高。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？在人类胰腺肿瘤的亚群中过度表达，并且在体外PC细胞的转化生长以及体内肿瘤发生和转移中发挥关键作用。在这里，我们在“低粘附”3D 培养中生成了 Panc-1 PCSC。该群体的“干细胞性”的功能特征在于这些细胞能够克隆扩增、向趋化因子 SDF-1 迁移、在软琼脂中生长的能力增强以及 SC 标记表达增加。初步数据表明 PKC 的作用？在 PCSC 中。此外，PCSC 的生长可以通过 PKC 的分子靶向抑制剂金硫苹果酸 (ATM) 来抑制。该项目的具体目标是 1）阐明 PKC 的作用？ PCSC 转化生长、肿瘤发生和肿瘤转移； 2) 评估单独使用 ATM 以及与常规化疗药物联合使用 ATM 抑制 PCSC 表型的能力。这些目标将通过增殖、存活和干细胞标记物表达测定以及皮下和原位肿瘤模型来实现。