Development of EGFR-Targeted Oncolytic Adenovirus for Therapy of Oral Cancers

开发用于治疗口腔癌的靶向 EGFR 的溶瘤腺病毒

基本信息

批准号：
8094886
负责人：
Anton V. Borovjagin
金额：
$ 10.99万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8094886
关键词：
Adenoviruses Animal Cancer Model Animal Model Antibodies Antibody Therapy Antineoplastic Agents Apoptosis Area Biodistribution Biological Markers Bioluminescence Blood CXCR4 gene Capsid Capsid Proteins Cells Cetuximab Clinical Detection Development ERBB2 gene Early Diagnosis Engineering Epidermal Growth Factor Receptor Evaluation Fiber Firefly Luciferases Fluorescence Generations Genes Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Human IL24 gene Image Impairment In Vitro Label Life Ligands Liver Luciferases Lytic Malignant Neoplasms Metastatic/Recurrent Methods Modification Monitor Neoplasm Metastasis New Agents Normal tissue morphology Nude Mice Oncolytic Organ Patients Primary Neoplasm Principal Investigator Property Protein Secretion Proteins Radiation therapy Radiosurgery Recurrence Recurrent tumor Relative (related person)Reporter Reporting Research Resistance Safety Screening for cancer Site Specificity Stream Surgical margins Survival Rate Technology Testing Therapeutic Therapeutic Effect Time Toxic effect Treatment Efficacy Tumor Markers Validation Viral Virus Xenograft Model Xenograft procedure anti-cancer therapeutic arm base cancer cell cancer therapy clinical efficacy common treatment conditionally replicative adenovirus cytotoxic fluorescence imaging genetic technology improved killings male malignant mouth neoplasm mouse model mouth squamous cell carcinoma multimodality neoplastic cell oncolysis outcome forecast overexpression particle prevent programs promoter red fluorescent protein response secretory protein technology development therapeutic evaluation tool tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Oral squamous cell carcinoma (OSCC) is the fifth most frequently occurring cancer worldwide. Common treatments still include radiation therapy and surgery leading to disfiguring impairments, which warrant less invasive treatments such as targeted therapies. Conditionally Replicative Adenoviruses (CRAds) are promising anti-cancer agents owing to their clinical safety and high infectivity. The anti-tumor effect of CRAds is based on specific killing of cancer cells by a natural lytic mechanism (oncolysis), which is distinct from that of antibody therapy and potentially allows overcoming antibody therapy resistance of recurrent and metastatic OSCC. The most recent genetic technology allows incorporation of a small "affibody" molecule with engineered targeting specificity into the Ad capsid protein "fiber". We seek to pioneer implementation of this fiber modification technology in conjunction with a recently developed Epidermal Growth Factor Receptor (EGFR/ErbB1)-specific affibody for the development of a CRAd agent transductionally re-targeted to this cancer biomarker, overexpressed in most head and neck and oral cancers. Furthermore, the CRAd replication will be targeted to OSCC by CXCR4 Tumor Specific Promoter (TSP) with highly specific activation profile in oral cancers. On the other hand, a potentially limited intratumoral spread of the CRAd could be compensated by "arming" with a secretory protein MDA-7/IL24 gene, whose expression induces cell apoptosis in cancer-specific fashion via a bystander mechanism, fully compatible with oncolytic function of CRAd. In this application we also propose to perform an initial validation of the EGFR-targeted CXCR4-CRAd by testing its replication properties and oncolytic potential in the commonly used OSCC xenograft model in nude mice by a unique noninvasive multimodality imaging approach. Monitoring of tumor oncolysis via bioluminescence of OSCC tumor cells, stably expressing firefly luciferase and its correlation with intratumoral accumulation of red fluorescence, produced by the replicating CRAd with Infrared Fluorescent Protein 1.4 (IFP1.4)-labeled capsid, will provide an important tool for the initial assessment of the EGFR/OSCC dual targeting benefit. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to develop a new generation oncolytic adenovirus targeted to tumor marker EGFR/Erb1 for therapy and early detection of human head and neck and, particularly, oral cancers. The capsid of the new virus will be genetically tagged with a recently developed human EGFR-specific affibody for its transductional retargeting to EGFR. On the other hand, a new generation imaging reporter Infrared Fluorescent Protein 1.4 (IFP1.4) will be used to genetically label the viral particles to improve noninvasive real time imaging of viral replication and spread in tumors or biodistribution. We also propose to perform an initial targeting validation step of the new agent by imaging-based assessment of its replication in OSCC tumors and evaluation of its oncolytic efficacy in OSCC xenograft mouse model using a state-of-the-art multimodality imaging approach.

描述（由申请人提供）：口服鳞状细胞癌（OSCC）是全球第五次最常见的癌症。常见治疗方法仍然包括放射疗法和手术，导致损害损伤，这需要较少的侵入性治疗（例如靶向疗法）。由于其临床安全性和高感染力，有条件地复制的腺病毒（Crads）是有希望的抗癌药。 Crads的抗肿瘤作用是基于通过天然裂解机制（Oncolysosy）对癌细胞的特异性杀死，该机制与抗体疗法的抗肿瘤细胞不同，并有可能克服复发和转移性OSCC的抗体抗体耐药性。最新的遗传技术允许将一个小的“杂物”分子与工程靶向特异性纳入AD Capsid蛋白“纤维”中。我们试图与最近开发的表皮生长因子受体（EGFR/ERBB1）特异性杂物相结合，以开发这种纤维修饰技术，以开发在该癌症生物标志物上的CRAD剂的开发，在大多数头部和颈部和颈部和口腔癌症中都过表达。此外，CXCR4肿瘤特异性启动子（TSP）的CRAD复制将针对OSCC，并具有高度特异性的口服癌症。另一方面，可以通过与分泌蛋白MDA-7/IL24基因“武装”来补偿CRAD的潜在肿瘤内扩散，其表达通过旁观者的机制以癌症特异性的方式诱导细胞凋亡，与Crad Oncolotoltic功能完全兼容。在此应用程序中，我们还建议通过通过一种独特的非侵入性多模态成像方法测试裸鼠中常用的OSCC异种移植物模型中的复制属性和溶瘤势来对EGFR靶向的CXCR4-CRAD进行初始验证。通过OSCC肿瘤细胞的生物发光监测肿瘤肿瘤，稳定表达萤火虫荧光素酶及其与红色荧光内肿瘤内积累的相关性，由红外荧光蛋白1.4（IFP1.4）的重复CRAD产生，可为初始评估的工具提供eg/eg的重要工具。公共卫生相关性：拟议的研究的目的是开发针对肿瘤标记EGFR/ERB1的新一代癌性腺病毒，用于治疗和早期发现人头和颈部，尤其是口服癌症。新病毒的衣壳将以新近开发的人类EGFR特异性杂物为基因标记，因为其转导重新定位到EGFR。另一方面，新一代成像报告基因红外荧光蛋白1.4（IFP1.4）将用于遗传标记病毒颗粒，以改善病毒复制的非侵入性实时成像，并在肿瘤或生物分布中扩散。我们还建议通过使用先进的多模态成像方法对其在OSCC肿瘤中的复制进行基于成像的复制以及对其OSCC异种移植小鼠模型中其溶瘤疗效的评估来执行新代理的初始靶向验证步骤。