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: 8702091
• 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/8702091
• 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; chemoradiation; 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）：胰腺癌患者的预后极差。即使完全手术切除和辅助放化疗，只有20%的患者存活五年。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。除了在胰腺癌中高度表达外，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。最近，靶向转铁蛋白受体单链抗体片段的纳米脂质体复合物已被用于在基因治疗中特异性靶向肿瘤。通过结合这些概念，我们假设CaSm作为“主开关”发挥作用，使多个基因转录物不稳定，导致胰腺癌中观察到的恶性表型，其将被新型转铁蛋白靶向纳米载体系统递送的CaSm siRNA有效靶向。这种新的方法将克服基因治疗面临的重大障碍，如低转染效率，差的组织转染率，和非特异性递送药物的目标。该K 08将使申请人能够定义胰腺癌中CaSm介导的肿瘤发生中涉及的关键分子途径，并确保未来作为独立的临床医生-科学家进行成功的转化研究。该研究计划将提供：（1）强有力的指导关系;（2）在我们的研究领域接触国内和国际观众;（3）建立一个富有成效的研究环境;和（4）实现独立的资金援助。已设立职业发展委员会，每季度评估进展情况。申请人的基础科学基础是通过先前的研究培训建立的，沿着完成临床研究硕士课程（2009年5月），申请人准备开始下一阶段的独立研究计划，该计划将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的会议来支持，以解决拟议研究中面临的概念和技术问题，以及手稿和赠款的生成和准备。最后，本项目将建立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递送机制的评价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，仍然是美国癌症相关死亡的4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个有前途的新分子靶点，CaSm，可能会改善目前的治疗。同样，解决基因治疗效果差的主要问题可能会导致胰腺癌的更成功的治疗，这是迫切需要的，并作为其他癌症的模型。

项目成果

Slug expression enhances tumor formation in a noninvasive rectal cancer model.

• DOI: 10.1016/j.jss.2011.02.012
• 发表时间: 2011-09
• 期刊: The Journal of surgical research
• 作者: Camp ER;Findlay VJ;Vaena SG;Walsh J;Lewin DN;Turner DP;Watson DK
• 通讯作者: Watson DK

CCR 20th Anniversary Commentary: RAS as a Biomarker for EGFR--Targeted Therapy for Colorectal Cancer-From Concept to Practice.

• DOI: 10.1158/1078-0432.ccr-14-2900
• 发表时间: 2015-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Camp ER;Ellis LM
• 通讯作者: Ellis LM

Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: insights from cancer biology with therapeutic implications for colorectal cancer.

• DOI: 10.1038/cgt.2014.15
• 发表时间: 2014-05
• 期刊: Cancer gene therapy
• 影响因子: 6.4

SNAI2 modulates colorectal cancer 5-fluorouracil sensitivity through miR145 repression.

• DOI: 10.1158/1535-7163.mct-14-0207
• 发表时间: 2014-11
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Findlay VJ;Wang C;Nogueira LM;Hurst K;Quirk D;Ethier SP;Staveley O'Carroll KF;Watson DK;Camp ER
• 通讯作者: Camp ER