Cancer dual-targeting of an infectivity-enhance CRAd

增强感染性的 CRAd 的癌症双重靶向

• 批准号: 7687926
• 负责人: J. Michael Mathis
• 金额: $ 41.25万
• 依托单位: VECTORLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687926
• 关键词: 5' Untranslated Regions; A549; Adenovirus Vector; Adenoviruses; Advanced Malignant Neoplasm; Affinity; Animal Model; Biodistribution; Biological; Biological Models; Biology; Breast; CAR receptor; CXCR4 gene; Cancer Control; Cell Line; Cells; Clinical; Clinical Trials; Cyclic GMP; Cytolysis; Development; Disease; Elements; Fiber; Fibroblast Growth Factor 2; Figs - dietary; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Translation; Glioma; Goals; Head and Neck Squamous Cell Carcinoma; Hereditary Disease; Human; Immunologics; In Vitro; Indium; Infection; Intervention; Knowledge; Lead; Lesion; Liver; Malignant Neoplasms; Mammary Gland Parenchyma; Marketing; Mediating; Messenger RNA; Methods; Modeling; Modification; Molecular; Mus; Neoplastic Cell Transformation; Normal Cell; Normal tissue morphology; ONYX-015; Oncolytic; Operative Surgical Procedures; Organ; Ovarian; Patients; Phase; Phase I Clinical Trials; RGD (sequence); Radiation; Refractory; Regulation; Relative (related person); Resistance; Series; Serotyping; Slice; Solid Neoplasm; Specificity; System; Technology; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Index; Tissues; Toxic effect; Toxicology; Transcriptional Regulation; Transduction Gene; Translation Initiation; Translational Regulation; Treatment Protocols; Tumor Tissue; Untranslated Regions; Viral; Viral Genome; Virus; alternative treatment; base; cancer cell; cancer therapy; cell killing; cell type; cellular transduction; chemotherapy; conditionally replicative adenovirus; design; efficacy testing; gene therapy; improved; in vivo; killings; malignant breast neoplasm; neoplastic; neoplastic cell; novel; oncolysis; pre-clinical; promoter; public health relevance; research and development; research study; standard care; three dimensional structure; transduction efficiency; treatment strategy; tumor; vector

DESCRIPTION (provided by applicant): Studies of the molecular mechanisms underlying neoplastic transformation and progression have resulted in the understanding that cancer is a genetic disease, deriving from the accumulation of a series of acquired genetic lesions. Despite advances in chemotherapy, radiation delivery, and surgical treatment regimens, survival from many advanced cancers remains poor, and it is apparent that alternative treatment approaches are necessary. Gene therapy/virotherapy is a promising strategy for the treatment of cancer. Although attempted in the past and abandoned because of toxicity and inefficacy, the virotherapy approach has reemerged with great promise, in large part due to better understanding of virus biology and the ability to genetically modify viruses. With this knowledge, we can now design viruses to better replicate in and specifically kill tumor cells. Using conditionally replicative adenoviruses (CRAds) represent a method to achieve efficient tumor cell oncolysis and mitigate tumor cell infection limitations. Ideally, cancer-specific replication of CRAds would result in viral-mediated oncolysis of infected tumor tissues and release of the virus progeny, capable of further propagating in surrounding tumor cells but not in those of normal tissues, which would be refractory to CRAd replication. In our Phase I study, we exploited a novel cancer-specific control of mRNA translation initiation in order to achieve enhanced replicative specificity of a CRAd virotherapy agent. In contrast, control of mRNA translation has not been exploited for the design of tumor specific replicating viruses to date. The technical and scientific merit and feasibility of this approach that combines both transcriptional and translational regulation strategies for the key goal of CRAd replicative specificity has now been established. Our Phase I in vitro and in vivo studies demonstrated strong proof-of-principle that this CRAd agent, utilizing a heterologous mRNA translational control element, retains anti-tumor potency. The objective of this Phase II application is to continue the R&D efforts initiated in Phase I by optimizing the CRAd virotherapy agent with enhanced tumor infectivity. Relative resistance of tumor tissues to adenovirus serotype 5 (Ad5) infections has been noted in a number of in vivo gene therapy trials. Deficiency of the primary Ad receptor CAR, is understood to be the biologic basis of this phenomenon. The inclusion of a high affinity Arg-Gly-Asp (RGD) motif into the HI loop of the Ad5 fiber knob has been shown to overcome low CAR expression on tumor cells, thereby enhancing transduction. In Specific Aim 1, cancer cell transduction of the CRAd virotherapy agent will be enhanced by inserting an RGD motif. In Specific Aim 2, in vivo experiments will be conducted to evaluate the biological efficacy and establish specific treatment protocols in animal models of loco-regional and disseminated disease. Finally, in Specific Aim 3, biodistribution and toxicology studies required for IND submission to the FDA will be performed. Successful completion of this Phase II application will lead directly to clinical investigation of the modified CRAd agent (CXCR4-5'-UTR-RGD CRAd) in patients with disseminated disease. PUBLIC HEALTH RELEVANCE: Despite many advances in standard treatment regimens, survival from many advanced cancers remains poor, and it is apparent that new alternative treatment approaches are necessary. Using viruses designed to divide in and specifically kill tumor cells has become a promising approach to better understanding of virus biology and the ability to genetically modify viruses. The objective of this application is to further develop a conditionally replicative adenovirus (CRAd) that has been designed to infect, divide and lyse efficiently in tumor cells but not in normal cells; successful completion.

描述（由申请人提供）：对肿瘤转化和进展的分子机制的研究，导致了这样一种理解，即癌症是一种遗传疾病，源自一系列获得的遗传病变的积累。尽管化学疗法，放疗和手术治疗方案取得了进步，但许多晚期癌症的生存仍然很差，而且很明显，有必要采用替代治疗方法。基因治疗/病毒疗法是治疗癌症的有前途的策略。尽管过去曾尝试过由于毒性和效率低下而被放弃，但病毒疗法的方法已经重现了很大的希望，这在很大程度上是由于对病毒生物学的了解更好，并且能够改善了病毒。有了这些知识，我们现在可以设计病毒以更好地复制并特别杀死肿瘤细胞。使用条件复制性腺病毒（CRADS）代表了一种实现有效的肿瘤细胞闭塞并减轻肿瘤细胞感染限制的方法。理想情况下，crads的癌症特异性复制将导致病毒介导的感染肿瘤组织的闭塞和病毒后代的释放，能够在周围的肿瘤细胞中进一步传播，而不能在正常组织的肿瘤细胞中传播，这将是对Crad复制的难治性。在我们的第一阶段研究中，我们利用了对mRNA翻译起始的新型癌症特异性控制，以达到CRAD病毒疗法剂的复制特异性。相比之下，尚未利用对肿瘤特异性复制病毒设计的控制。现在已经建立了这种方法的技术和科学优点和可行性，该方法结合了转录和翻译调节策略，以实现Crad复制特异性的关键目标。我们的I阶段体外和体内研究表明，这种Crad剂利用异源mRNA翻译控制元件，保留了抗肿瘤效力。该II期应用的目的是通过优化具有增强的肿瘤感染性的CRAD病毒疗法剂来继续在I期发起的研发工作。在许多体内基因治疗试验中，已经注意到肿瘤组织对腺病毒血清型5（AD5）感染的相对耐药性。原发性AD受体车的缺乏被认为是这种现象的生物学基础。已证明将高亲和力Arg-Gly-Asp（RGD）序列纳入AD5纤维旋钮的HI环中可以克服肿瘤细胞上的低CAR表达，从而增强转导。在特定的目标1中，通过插入RGD基序，将增强CRAD病毒疗法剂的癌细胞转导。在特定的目标2中，将进行体内实验，以评估生物学疗效并建立特定的治疗方案。最后，在特定的目标3中，将进行IND提交FDA所需的生物分布和毒理学研究。成功完成此II期应用的完成将直接导致对传播疾病患者的改性CRAD剂（CXCR4-5'-utr-RGD Crad）的临床研究。公共卫生相关性：尽管标准治疗方案取得了许多进步，但许多先进的癌症的生存仍然很差，显然是需要新的替代治疗方法。使用设计用于分裂并特别杀死肿瘤细胞的病毒已成为更好地理解病毒生物学和基因修饰病毒的能力的一种有希望的方法。该应用的目的是进一步开发有条件地复制性腺病毒（CRAD），该腺病毒（CRAD）旨在在肿瘤细胞中有效地感染，分裂和裂解，但在正常细胞中却没有有效。成功完成。