High-throughput screening identifies candidate drugs for the treatment of recurrent respiratory papillomatosis

Faris Alkhilaiwi , Siddartha Paul , Dan Zhou , Xiaohu Zhang , Feibai Wang , Nancy Palechor-Ceron , Kelli Wilson , Rajarshi Guha , Marc Ferrer , Nazaneen Grant , Craig Thomas , Richard Schlegel , Hang Yuan
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引用次数: 17

Abstract

Recurrent respiratory papillomatosis (RRP) is a benign neoplasm of the larynx caused mainly by human papillomavirus type 6 or 11 and its standard treatment involves repeated surgical debulking of the laryngeal tumors. However, significant morbidity and occasional mortality due to multiple recurrences occur. Conditional reprogramming (CR) was used to establish a HPV-6 positive culture from an RRP patient, named GUMC-403. High-throughput screening was performed at the National Center for Advanced Technology (NCATS) to identify potential drugs to treat this rare but morbid disease. GUMC-403 cells were screened against the NPC library of >2800 approved drugs and the MIPE library of >1900 investigational drugs to identify new uses for FDA-approved drugs or drugs that have undergone significant research and development. From the two libraries, we identified a total of 13 drugs that induced significant cytotoxicity in RRP cells at IC50 values that were clinically achievable. We validated the efficacy of the drugs in vitro using CR 2D and 3D models and further refined our list of drugs to panobinostat, dinaciclib and forskolin as potential therapies for RRP patients.

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高通量筛选确定治疗复发性呼吸道乳头状瘤病的候选药物
复发性呼吸道乳头状瘤病(RRP)是一种主要由6型或11型人乳头瘤病毒引起的喉部良性肿瘤,其标准治疗包括反复手术切除喉部肿瘤。然而,由于多次复发,会发生显著的发病率和偶尔的死亡率。采用条件重编程法(CR)对一名命名为GUMC-403的RRP患者进行HPV-6阳性培养。在国家先进技术中心(NCATS)进行了高通量筛选,以确定治疗这种罕见但病态疾病的潜在药物。GUMC-403 细胞与NPC库中2800种已批准的药物和MIPE库中1900种正在研究的药物进行筛选,以确定fda批准的药物或经过重大研究和开发的药物的新用途。从这两个文库中,我们共鉴定出13种药物在临床可达到的IC50值下对RRP细胞产生显著的细胞毒性。我们使用CR 2D和3D模型验证药物的体外疗效,并进一步将我们的药物清单细化为panobinostat, dinaciclib和forskolin作为RRP患者的潜在治疗药物。
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期刊介绍: The official Journal of the International Papillomavirus Society Papillomavirus Research (PVR), the Journal of HPV and other Small DNA Tumor Viruses publishes innovative papers related to all aspects of papillomaviruses and other small DNA tumor viruses. The official journal of the International Papillomavirus Society, PVR is an open access publication that aims to bring together virologists, immunologists, epidemiologists and clinicians working in the booming field of HPV and animal papillomaviruses, polyomaviruses and other small DNA tumor viruses and their associated diseases, in order to foster and facilitate interdisciplinary communication. The journal welcomes original research articles, reviews, short communications, opinion articles and regional update reports on papillomaviruses and other tumor viruses in the following sections: a. Biology of papillomaviruses and related viruses from life cycle to cancer b. Epidemiology etiology and natural history studies c. Natural and induced immunity including vaccine research d. Intervention studies and strategies including i. Clinical studies and trials ii. HPV treatments iii. HPV vaccination programs iv. Diagnostics and screening e. Infection and disease prevention, modeling studies f. Guidelines and public health recommendations g. HPV Studies in special populations Regional and local studies on these viruses.
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