Enhanced CRAd for Pancreatic Cancer

增强型 CRAd 治疗胰腺癌

基本信息

批准号：
8067156
负责人：
MASATO YAMAMOTO
金额：
$ 28.76万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8067156
关键词：
Address Anatomic Models Animal Model Architecture Behavior Biological Biology Cancer Etiology Cancer Model Cell surface Cells Cessation of life Clinical Clinical Trials Data Development Dimensions Disease Early Diagnosis Engineering Environment Epithelial Exhibits Fiber Generations Hamsters Health Human Image Immune Immunocompetent Interferons Laboratories Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Mesenchymal Mesocricetus auratus Minnesota Modality Modeling Modification Molecular Molecular Biology Molecular Target Monitor Monoclonal Antibodies Mus North America Oncolytic Outcome Pathogenesis Patients Phase I Clinical Trials Phenotype Population Production Relapse Resistance Safety Slice Specificity Stem cells System Telomerase Testing Therapeutic Therapeutic Effect Therapeutic Uses Time Tissue Slice Technology Tissues Toxicology Transforming Growth Factors Transgenes Translating Translations Universities Unresectable Up-Regulation Viral Virus Xenograft Model base cancer cell cancer therapy chemotherapeutic agent clinically relevant conditionally replicative adenovirus cyclooxygenase 2 design gemcitabine human tissue improved in vivo in vivo Model insight mesothelin mouse model next generation novel novel therapeutic intervention novel therapeutics outcome forecast pancreatic neoplasm promoter receptor research clinical testing subcutaneous therapeutic gene transduction efficiency transgene expression tumor vector

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most aggressive malignancies. In order to change its devastating prognosis, a novel therapeutic approach must be developed. The conditionally replicative adenovirus (CRAd) is one such promising therapeutic modality for pancreatic cancer. CRAd clinical trials to date have established the safety of these agents and identified their current limitations, and our laboratory is developing safer and more potent CRAds for therapeutic use. In this proposal, we plan to develop of a new generation pancreatic cancer CRAds with superior therapeutic potency and disease selectivity by exploiting the specific molecular features of this disease itself. We have developed new generation vector modifications which can provide a different level of transduction efficiency, and recent advancements in pancreatic cancer molecular biology have identified several target-worthy molecular features. The CRAds engineered for better potency and target specificity will be outfitted with anti-tumor effectors modifying pancreatic cancer tumor environment. New vectors will be tested not only with mouse subcutaneous and orthotopic xenograft models but also with models showing close relevance to human clinical situations. A hamster syngeneic pancreatic cancer model which allows human adenoviral replication will provide deeper insight into CRAd biology. The CRAd function analysis based on tissue slice technology permits us to evaluate CRAds in patient materials. These assessments will be further strengthened by the non-invasive viral replication monitoring capability we have developed. The development and analysis of next-generation CRAds will precede a clinically meaningful and novel therapy for pancreatic cancer. PUBLIC HEALTH RELEVANCE: The poor prognosis for pancreatic cancer drives our effort to develop new therapeutic modalities. More potent and safer CRAds can be fashioned into a clinically effective therapeutics. Also, detailed analyses of CRAd functionality in clinically relevant models will provide the crucial information required to advance vector design. The outcome of this project will lead to a clinically usable therapeutics for pancreatic cancer.

描述（由申请人提供）：胰腺癌是最具侵略性的恶性肿瘤之一。为了改变其毁灭性的预后，必须开发一种新型的治疗方法。有条件复制的腺病毒（CRAD）是胰腺癌的一种有希望的治疗方式。迄今为止，CRAD临床试验已经确定了这些代理的安全性并确定了当前的局限性，我们的实验室正在开发更安全，更有效的crads用于治疗用途。在此提案中，我们计划通过利用该疾病本身的特定分子特征来开发具有优异治疗效力和疾病选择性的新一代胰腺癌。我们开发了新一代载体的修改，可以提供不同水平的转导效率，并且胰腺癌分子生物学的最新进展已经确定了几种值得靶标的分子特征。为了提高效力而设计的摇篮和目标特异性将配备抗肿瘤效应器，以修饰胰腺癌肿瘤环境。新向量不仅将通过小鼠皮下和原位异种移植模型进行测试，而且还将通过与人类临床情况密切相关的模型进行测试。允许人类腺病毒复制的仓鼠合成胰腺癌模型将为CRAD生物学提供更深入的见解。基于组织切片技术的CRAD功能分析使我们能够评估患者材料中的CRAD。通过我们开发的非侵入性病毒复制监测能力，将进一步加强这些评估。下一代围栏的开发和分析将在胰腺癌的临床上有意义且新颖的疗法之前。公共卫生相关性：胰腺癌的预后不佳驱动了我们开发新的治疗方式的努力。可以将更有效和更安全的围栏形成临床有效的治疗疗法。此外，对临床相关模型中CRAD功能的详细分析将提供推进向量设计所需的关键信息。该项目的结果将导致胰腺癌的临床可用疗法。