TARGETING THE CASM ONCOGENE AS A NOVEL THERAPY FOR PANCREATIC CANCER

针对 CASM 癌基因作为胰腺癌的新疗法

基本信息

批准号：
7497986
负责人：
DAVID J COLE
金额：
$ 27.88万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-18 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7497986
关键词：
Address Adenoviruses Affect Antisense RNA Apoptotic Biological Markers Bystander Effect Cancer Model Caring Cell Cycle Inhibition Cell Cycle Regulation Cell Proliferation Cells Clinical Collaborations Cytostatics Data Development Disruption Down-Regulation Ectopic Expression Gene Delivery Gene Targeting Genes Homologous Gene Human Immune response Immunocompetent In Vitro Laboratories Lead Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Messenger RNA Modeling Molecular Mus Neoplasm Metastasis Neoplastic Cell Transformation Ohio Oncogenes Paclitaxel Pancreatic Adenocarcinoma Pathogenesis Patients Phenotype Protein Overexpression Publications Research Research Personnel Role Standards of Weights and Measures Structure System Therapeutic Therapeutic Intervention Transcript Transduction Gene Translational Research Up-Regulation Xenograft procedure Yeasts base cancer cell cyclin B1 density design gain of function gemcitabine gene therapy improved in vivo innovation innovative technologies intraperitoneal mRNA Stability mRNA Transcript Degradation nanoparticle neoplastic cell novel novel therapeutics programs response survivorship tumor tumor growth tumorigenesis vector

项目摘要

DESCRIPTION (provided by applicant): Our translational research group is dedicated to the development of innovative pancreatic cancer (PC) therapeutics. We have identified and characterized a novel PC related oncogene (the Cancer-associated Sm-like oncogene(CaSm)) and shown that: 1) it contributes to the transformed state in human and murine PC cells, and 2) adenovirus expressing CaSm antisense RNA (Ad-DhCaSm) significantly reduces in vitro and in vivo tumor growth with prolonged survivorship via cyclin B1/CDK1 dependent cytostatic cell cycle inhibition. These results indicate that the CaSm oncogene is critical to PC cell cycle control and could be targeted for therapeutic intervention. One of the major barriers to an effective CaSm-based gene therapy approach is achieving adequate in vivo tumor delivery. In fact, insufficient and/or non-effective delivery of gene vectors is a global problem limiting cancer gene therapy. We have recently established an exciting collaboration with Dr. Jesse Au's laboratory (Ohio State) that has developed a novel paclitaxel tumor priming approach capable of enhancing the delivery large molecules throughout an intraperitoneal tumor. Furthermore, we now have preliminary studies suggesting that the down-regulation of CaSm may induce a bystander effect in vivo- which could alleviate the need for delivery of the CaSm anti-sense gene to 100% of PC cells in vivo. Utilizing the downregulation of CaSm as a novel therapeutic intervention and our recently characterized murine CaSm PC model, our specific aims are to: 1) Determine whether paclitaxel tumor priming improves delivery and efficacy for pancreatic cancer gene therapy, 2) Define the impact of tumor priming on, and the mechanisms by which, the reduction of CaSm over-expression mediates a bystander effect, and 3) Define the mechanism by which CaSm upregulation leads to PC oncogenesis. The focus of this proposal is to combine a novel tumor priming approach with a promising gene target in order to develop innovative PC therapeutics. Successful completion of the proposed studies will advance the research in treatment of pancreatic cancer and, on a broader scope, validate an innovative technology for delivering gene vectors or other nanoparticles to intraperitoneal tumors

描述（由申请人提供）：我们的转化研究小组致力于开发创新的胰腺癌（PC）疗法。我们已经鉴定并表征了一种新的 PC 相关癌基因（癌症相关 Sm 样癌基因 (CaSm)），并表明：1) 它有助于人和鼠 PC 细胞的转化状态，2) 表达 CaSm 反义 RNA 的腺病毒(Ad-DhCaSm) 通过细胞周期蛋白 B1/CDK1 依赖性细胞抑制细胞周期抑制，显着减少体外和体内肿瘤生长，延长存活期。这些结果表明 CaSm 癌基因对于 PC 细胞周期控制至关重要，可以作为治疗干预的目标。有效的基于 CaSm 的基因治疗方法的主要障碍之一是实现充分的体内肿瘤递送。事实上，基因载体的不充分和/或无效递送是限制癌症基因治疗的全球性问题。我们最近与 Jesse Au 博士的实验室（俄亥俄州）建立了令人兴奋的合作，该实验室开发了一种新型紫杉醇肿瘤启动方法，能够增强整个腹膜内肿瘤中大分子的输送。此外，我们现在的初步研究表明，CaSm 的下调可能会引起体内旁观者效应，这可以减轻将 CaSm 反义基因递送到体内 100% PC 细胞的需要。利用 CaSm 下调作为一种新型治疗干预措施以及我们最近表征的鼠 CaSm PC 模型，我们的具体目标是：1) 确定紫杉醇肿瘤引发是否改善胰腺癌基因治疗的递送和疗效，2) 定义肿瘤引发的影响以及 CaSm 过度表达减少介导旁观者效应的机制，以及 3) 定义 CaSm 上调导致 PC 肿瘤发生的机制。该提案的重点是将新型肿瘤引发方法与有前景的基因靶点相结合，以开发创新的 PC 疗法。拟议研究的成功完成将推进胰腺癌治疗的研究，并在更广泛的范围内验证将基因载体或其他纳米颗粒递送至腹膜内肿瘤的创新技术