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

• 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
• 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

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）：口腔鳞状细胞癌（OSCC）是全球第五大常见癌症。常见的治疗方法仍然包括放射治疗和手术，导致毁容损伤，这需要微创治疗，如靶向治疗。连续复制型腺病毒（CRAds）具有临床安全性和高感染性，是一种很有前途的抗肿瘤药物。CRAds的抗肿瘤作用是基于通过天然溶解机制（溶瘤）特异性杀死癌细胞，这与抗体治疗不同，并可能克服复发性和转移性OSCC的抗体治疗抗性。最新的遗传技术允许将具有工程化靶向特异性的小的“抗体”分子掺入到Ad衣壳蛋白“纤维”中。我们寻求将这种纤维修饰技术与最近开发的表皮生长因子受体（EGFR/ErbB 1）特异性抗体结合，以开发CRAd试剂，该CRAd试剂在转导上重新靶向这种癌症生物标志物，在大多数头颈癌和口腔癌中过表达。此外，CRAd复制将通过CXCR 4肿瘤特异性启动子（TSP）靶向OSCC，其在口腔癌中具有高度特异性的激活谱。另一方面，CRAd的潜在有限的肿瘤内扩散可以通过用分泌蛋白MDA-7/IL 24基因“武装”来补偿，其表达通过旁观者机制以癌症特异性方式诱导细胞凋亡，与CRAd的溶瘤功能完全相容。在本申请中，我们还建议通过独特的非侵入性多模态成像方法在常用的裸鼠OSCC异种移植模型中测试EGFR靶向CXCR 4-CRAd的复制特性和溶瘤潜力，对EGFR靶向CXCR 4-CRAd进行初步验证。通过OSCC肿瘤细胞的生物发光监测肿瘤溶解，稳定表达萤火虫荧光素酶及其与红色荧光的肿瘤内积累的相关性，由具有红外荧光蛋白1.4（IFP1.4）标记衣壳的复制CRAd产生，将为EGFR/OSCC双靶向益处的初步评估提供重要工具。 公共卫生关系：该研究的目标是开发新一代靶向肿瘤标志物EGFR/Erb 1的溶瘤腺病毒，用于治疗和早期检测人类头颈部，特别是口腔癌。新病毒的衣壳将用最近开发的人类EGFR特异性亲和体进行基因标记，以使其转导重靶向EGFR。另一方面，新一代成像报告分子红外荧光蛋白1.4（IFP1.4）将用于基因标记病毒颗粒，以改善病毒在肿瘤中复制和传播或生物分布的非侵入性真实的时间成像。我们还建议通过基于成像的评估其在OSCC肿瘤中的复制以及使用最先进的多模态成像方法评估其在OSCC异种移植小鼠模型中的溶瘤功效来执行新药剂的初始靶向验证步骤。