Innovative Delivery Strategy for CaSm Gene Therapy in Pancreatic Cancer

描述(申请人提供)：胰腺癌患者的预后非常差。即使完全手术切除并辅以放化疗，也只有20%的患者能存活五年。因此，需要更好的治疗方法。为此，申请人的研究小组此前已将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，以转铁蛋白受体单链抗体片段为靶点的纳米脂质体复合体已被用于基因治疗中的肿瘤靶向。通过结合这些概念，我们假设CASM的功能是破坏多个基因转录本的稳定，导致在胰腺癌中观察到的恶性表型，这将有效地靶向CASM siRNA通过一个新的转铁蛋白靶向的纳米载体系统。这一新方法将克服基因治疗面临的重大障碍，如低转染率、组织穿透性差、药物非特异性递送到靶点。这份K08将使申请者能够确定CASM介导的胰腺癌发生过程中涉及的关键分子途径，并确保未来作为一名独立的临床医生兼科学家进行成功的转化研究。这项研究计划将提供：(1)强大的指导关系；(2)在我们的研究领域接触到国内和国际受众；(3)建立一个富有成效的研究环境；以及(4)帮助获得独立的资金。已经设立了一个职业发展委员会，以每季度评估进展情况。申请人的基础科学基础通过先前的研究培训以及临床研究理学硕士课程(2009年5月)的完成而建立，申请人准备开始下一阶段的独立研究计划，其中将包括基因克隆和抑制的技术方面的培训，包括微阵列分析在内的生物信息学方法的设计和分析，以及体内治疗性模型的设计和分析。这些研究工作将主要通过与共同导师的每周会议来支持，以解决拟议研究中面临的概念和技术问题，并生成和准备手稿和赠款。最后，该项目将确定CASM基因治疗在胰腺癌中的作用，并为未来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加强为胰腺癌设计的基因治疗策略，并为其他恶性肿瘤提供模型。 公共卫生相关性：胰腺癌是毁灭性的，仍然是美国癌症相关死亡的四大原因。基因治疗可能是胰腺癌新治疗方法的下一步，我们的研究小组已经确定了一种有希望的新分子靶点，CASM，它可能会改善目前的治疗。同样，解决基因治疗效果不佳的主要问题可能会导致胰腺癌的更成功治疗，而胰腺癌是亟需的，并可作为其他癌症的典范。

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.