TARGETING THE CASM ONCOGENE AS A NOVEL THERAPY FOR PANCREATIC CANCER

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）治疗方法。我们已经鉴定并鉴定了一种新的与PC相关的癌基因（癌症相关的sm样癌基因（CaSm）），并表明：1)它有助于人类和小鼠PC细胞的转化状态，2)表达CaSm反意义RNA的腺病毒（Ad-DhCaSm）通过细胞周期蛋白B1/CDK1依赖的细胞抑制剂细胞周期抑制显著降低体外和体内肿瘤生长，延长生存期。这些结果表明，CaSm癌基因对PC细胞周期的控制至关重要，可以作为治疗干预的靶点。有效的基于casm的基因治疗方法的主要障碍之一是实现足够的体内肿瘤递送。事实上，基因载体的递送不足和/或无效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（俄亥俄州立大学）建立了令人兴奋的合作，开发了一种新的紫杉醇肿瘤启动方法，能够增强腹膜内肿瘤大分子的传递。此外，我们现在有初步的研究表明，CaSm的下调可能会在体内诱导旁观者效应-这可以减轻CaSm反义基因在体内100%传递到PC细胞的需要。利用CaSm下调作为一种新的治疗干预手段和我们最近建立的小鼠CaSm PC模型，我们的具体目标是：1)确定紫杉醇肿瘤启动是否能改善胰腺癌基因治疗的递送和疗效；2)确定肿瘤启动对CaSm过表达减少介导旁观者效应的影响及其机制；3)确定CaSm上调导致PC癌发生的机制。本提案的重点是将一种新的肿瘤启动方法与有希望的基因靶点相结合，以开发创新的PC治疗方法。这些研究的成功完成将推动胰腺癌治疗的研究，并在更广泛的范围内验证将基因载体或其他纳米颗粒输送到腹膜内肿瘤的创新技术

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