Novel Chimeric RNA Aptamer Technology to Treat Head and Neck Cancer

治疗头颈癌的新型嵌合 RNA 适体技术

• 批准号: 7740331
• 负责人: Paloma Hoban Giangrande
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740331
• 关键词: Applications Grants; Aptamer Technology; Binding; Biological Models; Cancer Model; Cancer cell line; Cause of Death; Cells; Chimera organism; Complex; Development; Disease; Down-Regulation; ERBB2 gene; Epithelial; Epithelial Cells; Gene Targeting; Genes; Growth; HPV-High Risk; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immunocompetent; In Vitro; Laboratories; Lead; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Methodology; Methods; Mouth Diseases; Mus; Normal tissue morphology; Oral mucous membrane structure; Oropharyngeal; Public Health; Qualifying; RNA; Reagent; Receptor Cell; Role; Safety; Small Interfering RNA; Specificity; Testing; Tonsil; Transcript; Tumorigenicity; Viral Oncogene; Work; aptamer; cancer cell; cell transformation; chimeric gene; design; improved; in vivo; malignant mouth neoplasm; malignant oropharynx neoplasm; malignant tonsil neoplasm; mouse model; mutant; novel; public health relevance; receptor; tumorigenic

DESCRIPTION (provided by applicant): Head and neck cancer (HNC) continues to be a major cause of death and disfigurement, and therapies for HNC have not improved significantly in the last several decades. There is now convincing evidence that a subset of HNC, particularly those from the oropharyngeal (tonsillar) region, are caused by human papillomavirus (HPV). Over 50% of oropharyngeal cancers contain and express the E6/E7 genes from HPV, mostly HPV-16, a subtype that is frequently involved in the development of cervical cancer. Our studies have demonstrated that HPV-16 E6/E7 can immortalize and transform human and mouse tonsillar epithelial cells. While it has been demonstrated that inhibition of HPV genes in cancer cell lines can effectively suppress transformation in vitro, current strategies of inhibition are relatively non-specific and inefficient for in vivo delivery. We have developed a unique mouse model of HNC in which HPV-16 E6/E7 mouse tonsillar epithelial cells (MTECs) are transformed to tumorigenicity by expression of mutant Ras or ErbB2. This unique HNC model systemwill allow the assessment of methods to inhibit HPV genes to suppress tumorigenic growth in a syngeneic immunocompetent host. Our group has previously shown that chimeric all RNA aptamer-siRNAs can be utilized in vivo for specific binding, internalization, and delivery of siRNAs into target cells. Here, we propose to develop RNA aptamers that specifically localize and internalize into HPV transformed MTECs. Aptamer-siRNA chimeras that target HPV genes will then be tested for their ability to specifically inhibit growth of HPV transformed tonsillar epithelial cells in vitro and in vivo. Overall, our proposed proof-of-concept studies could lead to the development of more specific and effective methods to treat HPV associated oropharyngeal cancer and other oral diseases. PUBLIC HEALTH RELEVANCE: The development of novel methodologies to specifically and efficiently inhibit HPV genes in transformed tonsillar epithelial cells could lead to advanced treatment methods for head and neck cancer. The findings from this work could be applicable to the treatment of other oral diseases, as well.

描述（由申请人提供）：头颈癌（HNC）仍然是导致死亡和毁容的主要原因，在过去的几十年里，HNC的治疗方法没有显著改善。现在有令人信服的证据表明，HNC的一部分，特别是来自口咽（扁桃体）区域的HNC，是由人乳头瘤病毒（HPV）引起的。超过50%的口咽癌含有并表达来自HPV的E6/E7基因，主要是HPV-16，这是一种经常参与宫颈癌发展的亚型。我们的研究表明，HPV-16 E6/E7可以永生化和转化人和小鼠扁桃体上皮细胞。虽然已经证明在癌细胞系中抑制HPV基因可以有效地在体外抑制转化，但目前的抑制策略相对来说是非特异性的，并且对于体内递送效率低。我们开发了一种独特的小鼠HNC模型，其中HPV-16 E6/E7小鼠扁桃体上皮细胞（MTECs）通过表达突变Ras或ErbB2转化为致瘤性。这种独特的HNC模型系统将允许评估抑制HPV基因的方法，以抑制同基因免疫活性宿主的致瘤性生长。我们的团队之前已经证明嵌合的所有RNA适配体- sirna可以在体内用于特异性结合、内化和将sirna递送到靶细胞中。在这里，我们建议开发RNA适体，特异性地定位和内化到HPV转化的mtec中。针对HPV基因的适配体- sirna嵌合体将在体内和体外测试其特异性抑制HPV转化扁桃体上皮细胞生长的能力。总的来说，我们提出的概念验证研究可能导致开发更具体和有效的方法来治疗HPV相关口咽癌和其他口腔疾病。