Innovative Delivery Strategy for CaSm Gene Therapy in Pancreatic Cancer

胰腺癌 CaSm 基因治疗的创新递送策略

• 批准号: 8136300
• 负责人: Ernest Ramsay Camp
• 金额: $ 17.34万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136300
• 关键词: Address; Adjuvant; Basic Science; Bioinformatics; Cancer Etiology; Cancer cell line; Cell Cycle Arrest; Cessation of life; Clinical; Clinical Research; Clinical Trials; Complex; Development; Drug Delivery Systems; Effectiveness; Environment; Evaluation; Excision; Exposure to; Foundations; Funding; Future; Gene Targeting; Generations; Genes; Goals; Grant; Human; Immunoglobulin Fragments; International; Lead; Liposomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Manuscripts; Master of Science; Mediating; Mediator of activation protein; Mentors; Microarray Analysis; Modeling; Molecular; Molecular Target; Oncogenic; Operative Surgical Procedures; Pathway interactions; Patients; Penetrance; Phase; Pre-Clinical Model; Preparation; Proteins; Research; Research Training; Role; Scientist; Secure; Small Interfering RNA; Surrogate Markers; System; Testing; Therapeutic; Therapeutic Effect; Tissues; Training; Transcript; Transfection; Transferrin; Transferrin Receptor; Translational Research; Work; base; career; career development; clinically relevant; design; field study; gene cloning; gene therapy; improved; in vivo; in vivo Model; innovation; innovative technologies; loss of function; malignant phenotype; meetings; nanoparticle; nanovector; new therapeutic target; novel; novel strategies; outcome forecast; pancreatic cancer cells; preclinical study; programs; public health relevance; response; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：胰腺癌患者的预后非常差。即使进行完整的手术切除和辅助化学放疗，只有20％的患者存活了五年。因此，需要更好的治疗方法。为此，申请人的研究小组先前已将CASM确定为胰腺癌的潜在分子靶标。除了在胰腺癌中高度表达外，在胰腺癌的临床前模型中抑制CASM表达的初步工作成功地降低了与细胞周期停滞相关的肿瘤进展。最近，靶向转铁蛋白受体单链抗体片段的纳米颗粒脂质体络合物已用于特异性地靶向基因治疗中的肿瘤。通过结合这些概念，我们假设CASM充当“主开关”，可破坏多个基因转录本，这有助于在胰腺癌中观察到的恶性表型，这将由Casm siRNA有效地靶向由新型的转铁蛋白靶向的Nanovector System提供。这种新型方法应克服面临基因疗法的重大障碍，例如低转染效率，不良的组织渗透率以及非特异性药物向靶标提供的障碍。该K08将使申请人能够定义胰腺癌中CASM介导的肿瘤发生涉及的关键分子途径，并确保作为独立临床医生的未来职业，从而成功地进行转化研究。该研究计划将提供：（1）牢固的指导关系； （2）在我们的研究领域接触国家和国际观众； （3）建立生产研究环境； （4）协助获得独立资金。已经成立了一个职业发展委员会，以季度评估进度。通过申请人的基础科学基金会通过先前的研究培训建立，并完成了临床研究计划的科学硕士学位（2009年5月），申请人准备迈向下一阶段，朝着独立的研究计划迈进，其中包括在基因克隆和抑制，设计和设计和分析的生物学方法分析的技术方面培训，包括微阵列分析，包括微级别分析和设计和设计的theape of terape of terape insape insepic ins vivo in vivo ins vivo中。这些研究工作将主要通过与联合会的每周会议来支持，以解决拟议的研究中所面临的概念和技术问题，以及手稿和赠款的产生和准备。最后，该项目将确定CASM基因疗法在胰腺癌中的作用，并成为胰腺癌患者未来临床试验的基础。对新型转铁蛋白靶向纳米植物作为肿瘤特异性siRNA递送机制的评估可以增强为胰腺癌设计的基因治疗策略，并作为其他恶性肿瘤的模型。 公共卫生相关性：胰腺癌是毁灭性的，仍然是美国与癌症有关的四个主要原因。基因治疗可能是胰腺癌新治疗方法的下一步，我们的研究小组确定了一个有希望的新分子靶标CASM，可以改善当前治疗。同样，解决不良基因疗法递送的主要问题可能会导致对胰腺癌的更成功治疗，这是急需的，并作为其他癌症的模型。