Innovative Delivery Strategy for CaSm Gene Therapy in Pancreatic Cancer

描述（申请人提供）：胰腺癌患者预后极差。即使完全手术切除和辅助放化疗，也只有20%的患者能存活5年。因此，需要更好的治疗方法。为此，申请人课题组此前已将CaSm确定为胰腺癌的潜在分子靶点。除了在胰腺癌中高表达外，在胰腺癌临床前模型中抑制CaSm表达的初步工作成功地减少了与细胞周期停滞相关的肿瘤进展。近年来，靶向转铁蛋白受体单链抗体片段的纳米颗粒脂质体复合物已被用于特异性靶向肿瘤的基因治疗。通过结合这些概念，我们假设CaSm作为一个“主开关”来破坏多个基因转录本的稳定性，从而导致胰腺癌中观察到的恶性表型，而这种表型将被一种新型转铁蛋白靶向纳米载体系统递送的CaSm siRNA有效靶向。这种新方法将克服基因治疗面临的重大障碍，如转染效率低、组织外显率差、药物递送到靶点的非特异性。该K08将使申请人能够确定参与casm介导的胰腺癌肿瘤发生的关键分子途径，并确保未来作为独立临床科学家进行成功的转化研究。本研究计划将提供：(1)强大的师徒关系；(2)在我们的研究领域向国内和国际观众展示；(3)建立富有成效的科研环境；(4)协助实现独立经费。设立了一个职业发展委员会，按季度评估进展情况。申请人通过先前的研究培训建立了基础科学基础，并完成了临床研究硕士课程（2009年5月），申请人准备开始下一阶段的独立研究项目，其中包括基因克隆和抑制技术方面的培训，生物信息学方法的设计和分析，包括微阵列分析，以及治疗性体内模型的设计和分析。这些研究工作将主要通过每周与共同导师举行会议来支持，以解决拟议研究中面临的概念和技术问题，并编写和编写手稿和赠款。最后，本项目将确立CaSm基因治疗在胰腺癌中的作用，为今后胰腺癌患者的临床试验奠定基础。这种新型转铁蛋白靶向纳米载体作为肿瘤特异性siRNA递送机制的评估，可能会增强针对胰腺癌的基因治疗策略，并可作为其他恶性肿瘤的模型。

DESCRIPTION (provided by applicant): The prognosis for patients with pancreatic cancer is exceedingly poor. Even with complete surgical resection and adjuvant chemoradiation, only 20% of patients survive five years. Thus, better therapeutic approaches are needed. To this end, the applicant's research group has previously identified CaSm as a potential molecular target for pancreatic cancer. Besides being highly expressed in pancreatic cancer, preliminary work inhibiting CaSm expression in preclinical models of pancreatic cancer successfully reduced tumor progression associated with cell cycle arrest. Recently, nanoparticle liposome-based complexes targeting the transferrin receptor single chain antibody fragment have been used to specifically target tumors in gene therapy. By combining these concepts, we hypothesize that CaSm functions as a "master switch" to destabilize multiple gene transcripts, contributing to the malignant phenotype observed in pancreatic cancer which will be effectively targeted by CaSm siRNA delivered by a novel transferrin-targeted nanovector system. This novel approach should overcome significant obstacles facing gene therapy such as low transfection efficiency, poor tissue penetrance, and non-specific delivery of drug to target. This K08 will enable the applicant to define the critical molecular pathways involved in CaSm-mediated oncogenesis in pancreatic cancer and to secure a future career as an independent clinician-scientist performing successful translational research. This research program will provide: (1) strong mentoring relationships; (2) exposure to national and international audiences in our field of study; (3) establishment of a productive research environment; and (4) assistance for achieving independent funding. A Career Development Committee has been created to assess progress on a quarterly basis. With the applicant's basic science foundation established through prior research training along with completion of a Masters of Science in Clinical Research program (May 2009), the applicant is prepared to embark on the next phase towards an independent research program that will include training in technical aspects of gene cloning and suppression, design and analysis of bioinformatic approaches including microarray analysis, and design and analysis of therapeutic in vivo models. These research efforts will primarily be supported through weekly meetings with co-mentors to address conceptual and technical issues faced within the proposed research, and generation and preparation of manuscripts and grants. Finally, this project will establish the role of CaSm gene therapy in pancreatic cancer and serve as the foundation of future clinical trials in patients with pancreatic cancer. Such evaluation of the novel transferrin-targeted nanovector as a tumor specific siRNA delivery mechanism may enhance gene therapy strategies designed for pancreatic cancer and serve as a model for other malignancies. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is devastating and remains the 4 leading cause of cancer related deaths in the US. Gene therapy is likely the next step for new treatment approaches in pancreatic cancer and our research group has identified a promising new molecular target, CaSm that may improve current treatment. Similarly, addressing the major problem of poor gene therapy delivery may lead to more successful treatments for pancreatic cancer which are badly needed and serve as a model for other cancers.