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Gazal S, Gazal S, Kaur P, Bhan A, Olagnier D. Breaking Barriers: Animal viruses as oncolytic and immunotherapeutic agents for human cancers. Virology 2024; 600:110238. [PMID: 39293238 DOI: 10.1016/j.virol.2024.110238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/29/2024] [Accepted: 09/09/2024] [Indexed: 09/20/2024]
Abstract
Oncolytic viruses, defined as viruses capable of lysing cancer cells, emerged as a groundbreaking class of therapeutic entities poised to revolutionize cancer treatment. Their mode of action encompasses both direct tumor cell lysis and the indirect enhancement of anti-tumor immune responses. Notably, four leading contenders in this domain, Rigvir® in Latvia, T-VEC in the United States, H101 in China and Teserpaturev (DELYTACT®) in Japan, have earned approval for treating metastatic melanoma (Rigvir and T-VEC), nasopharyngeal carcinoma and malignant glioma, respectively. Despite these notable advancements, the integration of oncolytic viruses into cancer therapy encounters several challenges. Foremost among these hurdles is the considerable variability observed in clinical responses to oncolytic virus interventions. Moreover, the adaptive immune system may inadvertently target the oncolytic viruses themselves, diverting immune resources away from tumor antigens and undermining therapeutic efficacy. Another significant limitation arises from the presence of preexisting immunity against oncolytic viruses in certain patient populations, hampering treatment outcomes. To circumvent this obstacle, researchers are investigating the utilization of animal viruses, for which humans lack preexisting immunity, as a compelling alternative to human-derived counterparts. In our comprehensive review, we delve into the intricate nuances of oncolytic virotherapy, elucidating the multifaceted mechanisms through which these viruses exert their anti-cancer effects. Furthermore, we provide a thorough examination of animal-derived oncolytic viruses, highlighting their respective strengths and limitations. Lastly, we explore the promising potential of leveraging animal viruses as potent oncolytic agents, offering new avenues for enhancing the efficacy and reach of human cancer therapeutics.
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Affiliation(s)
- Sabahat Gazal
- Division of Veterinary Microbiology and Immunology, Faculty of Veterinary Science and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu, R.S. Pura, Jammu, Jammu & Kashmir, India; Department of Biomedicine, Aarhus University, Denmark
| | - Sundus Gazal
- Division of Veterinary Microbiology and Immunology, Faculty of Veterinary Science and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu, R.S. Pura, Jammu, Jammu & Kashmir, India.
| | - Paviter Kaur
- Division of Veterinary Microbiology, College of Veterinary Sciences, Guru Angad Dev Veterinary and Animal Science University, Ludhiana, Punjab, India
| | - Anvesha Bhan
- Division of Veterinary Microbiology and Immunology, Faculty of Veterinary Science and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu, R.S. Pura, Jammu, Jammu & Kashmir, India
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Peng Y, Bai J, Li W, Su Z, Cheng X. Advancements in p53-Based Anti-Tumor Gene Therapy Research. Molecules 2024; 29:5315. [PMID: 39598704 PMCID: PMC11596491 DOI: 10.3390/molecules29225315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
The p53 gene is one of the genes most closely associated with human tumors and has become a popular target for tumor drug design. Currently, p53-based gene therapy techniques have been developed, but these therapies face challenges such as immaturity, high safety hazards, limited efficacy, and low patient acceptance. However, researchers are no less enthusiastic about the treatment because of its theoretical potential to treat cancer. In this paper, the advances in p53-based gene therapy and related nucleic acid delivery technologies were reviewed and prospected in order to support further development in this field.
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Affiliation(s)
- Yuanwan Peng
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.P.); (J.B.); (W.L.)
| | - Jinping Bai
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.P.); (J.B.); (W.L.)
| | - Wang Li
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.P.); (J.B.); (W.L.)
| | - Zhengding Su
- School of Pharmaceutical Sciences and Institute of Materia Medica, Xinjiang University, Urumqi 830017, China
| | - Xiyao Cheng
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.P.); (J.B.); (W.L.)
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Chen SY, Wang CT, Huang TH, Tsai JL, Wang HT, Yen YT, Tseng YL, Wu CL, Chang JM, Shiau AL. Advancing Lung Cancer Treatment with Combined c-Met Promoter-Driven Oncolytic Adenovirus and Rapamycin. Cells 2024; 13:1597. [PMID: 39329778 PMCID: PMC11430802 DOI: 10.3390/cells13181597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 09/28/2024] Open
Abstract
Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells' vulnerabilities, potentially marking a significant advancement in managing this deadly disease.
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Affiliation(s)
- Shih-Yao Chen
- Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan;
| | - Chung-Teng Wang
- Tong Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (C.-T.W.); (C.-L.W.)
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Tang-Hsiu Huang
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
| | - Jeng-Liang Tsai
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Hao-Tien Wang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Yi-Ting Yen
- Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (Y.-T.Y.); (Y.-L.T.)
| | - Yau-Lin Tseng
- Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (Y.-T.Y.); (Y.-L.T.)
| | - Chao-Liang Wu
- Tong Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (C.-T.W.); (C.-L.W.)
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan
| | - Jia-Ming Chang
- Thoracic Division, Department of Surgery, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan
- Institute of Molecular Biology, National Chung Cheng University, Chiayi 62102, Taiwan
| | - Ai-Li Shiau
- Tong Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (C.-T.W.); (C.-L.W.)
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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Song B, Yang P, Zhang S. Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy. Cancer Commun (Lond) 2024; 44:297-360. [PMID: 38311377 PMCID: PMC10958678 DOI: 10.1002/cac2.12520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 01/03/2024] [Accepted: 01/11/2024] [Indexed: 02/10/2024] Open
Abstract
Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well as immunotherapy have benefited cancer patients considerably. Tumor protein p53 (TP53), a crucial tumor suppressor gene encoding p53, regulates numerous downstream genes and cellular phenotypes in response to various stressors. The affected genes are involved in diverse processes, including cell cycle arrest, DNA repair, cellular senescence, metabolic homeostasis, apoptosis, and autophagy. However, accumulating recent studies have continued to reveal novel and unexpected functions of p53 in governing the fate of tumors, for example, functions in ferroptosis, immunity, the tumor microenvironment and microbiome metabolism. Among the possibilities, the evolutionary plasticity of p53 is the most controversial, partially due to the dizzying array of biological functions that have been attributed to different regulatory mechanisms of p53 signaling. Nearly 40 years after its discovery, this key tumor suppressor remains somewhat enigmatic. The intricate and diverse functions of p53 in regulating cell fate during cancer treatment are only the tip of the iceberg with respect to its equally complicated structural biology, which has been painstakingly revealed. Additionally, TP53 mutation is one of the most significant genetic alterations in cancer, contributing to rapid cancer cell growth and tumor progression. Here, we summarized recent advances that implicate altered p53 in modulating the response to various cancer therapies, including chemotherapy, radiotherapy, and immunotherapy. Furthermore, we also discussed potential strategies for targeting p53 as a therapeutic option for cancer.
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Affiliation(s)
- Bin Song
- Laboratory of Radiation MedicineWest China Second University HospitalSichuan UniversityChengduSichuanP. R. China
| | - Ping Yang
- Laboratory of Radiation MedicineWest China Second University HospitalSichuan UniversityChengduSichuanP. R. China
| | - Shuyu Zhang
- Laboratory of Radiation MedicineWest China Second University HospitalSichuan UniversityChengduSichuanP. R. China
- The Second Affiliated Hospital of Chengdu Medical CollegeChina National Nuclear Corporation 416 HospitalChengduSichuanP. R. China
- Laboratory of Radiation MedicineNHC Key Laboratory of Nuclear Technology Medical TransformationWest China School of Basic Medical Sciences & Forensic MedicineSichuan UniversityChengduSichuanP. R. China
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Hu M, Liao X, Tao Y, Chen Y. Advances in oncolytic herpes simplex virus and adenovirus therapy for recurrent glioma. Front Immunol 2023; 14:1285113. [PMID: 38022620 PMCID: PMC10652401 DOI: 10.3389/fimmu.2023.1285113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Recurrent glioma treatment is challenging due to molecular heterogeneity and treatment resistance commonly observed in these tumors. Researchers are actively pursuing new therapeutic strategies. Oncolytic viruses have emerged as a promising option. Oncolytic viruses selectively replicate within tumor cells, destroying them and stimulating the immune system for an enhanced anticancer response. Among Oncolytic viruses investigated for recurrent gliomas, oncolytic herpes simplex virus and oncolytic adenovirus show notable potential. Genetic modifications play a crucial role in optimizing their therapeutic efficacy. Different generations of replicative conditioned oncolytic human adenovirus and oncolytic HSV have been developed, incorporating specific modifications to enhance tumor selectivity, replication efficiency, and immune activation. This review article summarizes these genetic modifications, offering insights into the underlying mechanisms of Oncolytic viruses' therapy. It also aims to identify strategies for further enhancing the therapeutic benefits of Oncolytic viruses. However, it is important to acknowledge that additional research and clinical trials are necessary to establish the safety, efficacy, and optimal utilization of Oncolytic viruses in treating recurrent glioblastoma.
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Affiliation(s)
- Mingming Hu
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - XuLiang Liao
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Tao
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yaohui Chen
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
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Zhu X, Fan C, Xiong Z, Chen M, Li Z, Tao T, Liu X. Development and application of oncolytic viruses as the nemesis of tumor cells. Front Microbiol 2023; 14:1188526. [PMID: 37440883 PMCID: PMC10335770 DOI: 10.3389/fmicb.2023.1188526] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/18/2023] [Indexed: 07/15/2023] Open
Abstract
Viruses and tumors are two pathologies that negatively impact human health, but what occurs when a virus encounters a tumor? A global consensus among cancer patients suggests that surgical resection, chemotherapy, radiotherapy, and other methods are the primary means to combat cancer. However, with the innovation and development of biomedical technology, tumor biotherapy (immunotherapy, molecular targeted therapy, gene therapy, oncolytic virus therapy, etc.) has emerged as an alternative treatment for malignant tumors. Oncolytic viruses possess numerous anti-tumor properties, such as directly lysing tumor cells, activating anti-tumor immune responses, and improving the tumor microenvironment. Compared to traditional immunotherapy, oncolytic virus therapy offers advantages including high killing efficiency, precise targeting, and minimal side effects. Although oncolytic virus (OV) therapy was introduced as a novel approach to tumor treatment in the 19th century, its efficacy was suboptimal, limiting its widespread application. However, since the U.S. Food and Drug Administration (FDA) approved the first OV therapy drug, T-VEC, in 2015, interest in OV has grown significantly. In recent years, oncolytic virus therapy has shown increasingly promising application prospects and has become a major research focus in the field of cancer treatment. This article reviews the development, classification, and research progress of oncolytic viruses, as well as their mechanisms of action, therapeutic methods, and routes of administration.
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Affiliation(s)
- Xiao Zhu
- Zhejiang Provincial People's Hospital Affiliated to Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
- Department of Biological and Chemical Sciences, New York Institute of Technology—Manhattan Campus, New York, NY, United States
| | - Chenyang Fan
- Department of Clinical Medicine, Medicine and Technology, School of Zunyi Medical University, Zunyi, China
| | - Zhuolong Xiong
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Mingwei Chen
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital(Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Tao Tao
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Xiuqing Liu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Wallis B, Bowman KR, Lu P, Lim CS. The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer. Biomolecules 2023; 13:159. [PMID: 36671544 PMCID: PMC9855757 DOI: 10.3390/biom13010159] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/13/2023] Open
Abstract
It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, despite accounting for only 2.5% of all female malignancies. The overall 5-year survival rate for ovarian cancer is around 47%; however, this drops to an abysmal 29% for the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC). HGSOC has upwards of 96% of cases expressing mutations in p53. Therefore, wild-type (WT) p53 and p53-based therapies have been explored as treatment options via a plethora of drug delivery vehicles including nanoparticles, viruses, polymers, and liposomes. However, previous p53 therapeutics have faced many challenges, which have resulted in their limited translational success to date. This review highlights a selection of these historical p53-targeted therapeutics for ovarian cancer, why they failed, and what the future could hold for a new generation of this class of therapies.
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Affiliation(s)
| | | | | | - Carol S. Lim
- Department of Molecular Pharmaceutics, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA
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Brown DW, Beatty PH, Lewis JD. Molecular Targeting of the Most Functionally Complex Gene in Precision Oncology: p53. Cancers (Basel) 2022; 14:5176. [PMID: 36358595 PMCID: PMC9654076 DOI: 10.3390/cancers14215176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/29/2023] Open
Abstract
While chemotherapy is a key treatment strategy for many solid tumors, it is rarely curative, and most tumor cells eventually become resistant. Because of this, there is an unmet need to develop systemic treatments that capitalize on the unique mutational landscape of each patient's tumor. The most frequently mutated protein in cancer, p53, has a role in nearly all cancer subtypes and tumorigenesis stages and therefore is one of the most promising molecular targets for cancer treatment. Unfortunately, drugs targeting p53 have seen little clinical success despite promising preclinical data. Most of these drug compounds target specific aspects of p53 inactivation, such as through inhibiting negative regulation by the mouse double minute (MDM) family of proteins. These treatment strategies fail to address cancer cells' adaptation mechanisms and ignore the impact that p53 loss has on the entire p53 network. However, recent gene therapy successes show that targeting the p53 network and cellular dysfunction caused by p53 inactivation is now possible and may soon translate into successful clinical responses. In this review, we discuss p53 signaling complexities in cancer that have hindered the development and use of p53-targeted drugs. We also describe several current therapeutics reporting promising preclinical and clinical results.
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Affiliation(s)
- Douglas W. Brown
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Entos Pharmaceuticals, Unit 4550, 10230 Jasper Avenue, Edmonton, AB T5J 4P6, Canada
| | - Perrin H. Beatty
- Entos Pharmaceuticals, Unit 4550, 10230 Jasper Avenue, Edmonton, AB T5J 4P6, Canada
| | - John D. Lewis
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Entos Pharmaceuticals, Unit 4550, 10230 Jasper Avenue, Edmonton, AB T5J 4P6, Canada
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Mahmoud AB, Ajina R, Aref S, Darwish M, Alsayb M, Taher M, AlSharif SA, Hashem AM, Alkayyal AA. Advances in immunotherapy for glioblastoma multiforme. Front Immunol 2022; 13:944452. [PMID: 36311781 PMCID: PMC9597698 DOI: 10.3389/fimmu.2022.944452] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system and has a very poor prognosis. The current standard of care for patients with GBM involves surgical resection, radiotherapy, and chemotherapy. Unfortunately, conventional therapies have not resulted in significant improvements in the survival outcomes of patients with GBM; therefore, the overall mortality rate remains high. Immunotherapy is a type of cancer treatment that helps the immune system to fight cancer and has shown success in different types of aggressive cancers. Recently, healthcare providers have been actively investigating various immunotherapeutic approaches to treat GBM. We reviewed the most promising immunotherapy candidates for glioblastoma that have achieved encouraging results in clinical trials, focusing on immune checkpoint inhibitors, oncolytic viruses, nonreplicating viral vectors, and chimeric antigen receptor (CAR) immunotherapies.
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Affiliation(s)
- Ahmad Bakur Mahmoud
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
| | - Reham Ajina
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Sarah Aref
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Manar Darwish
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - May Alsayb
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Mustafa Taher
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Shaker A. AlSharif
- King Fahad Hospital, Ministry of Health, Almadinah Almunwarah, Saudi Arabia
| | - Anwar M. Hashem
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center; King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Almohanad A. Alkayyal
- Department of Medical Laboratory Technology, University of Tabuk, Tabuk, Saudi Arabia
- Immunology Research Program, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
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Feola S, Russo S, Ylösmäki E, Cerullo V. Oncolytic ImmunoViroTherapy: A long history of crosstalk between viruses and immune system for cancer treatment. Pharmacol Ther 2021; 236:108103. [PMID: 34954301 DOI: 10.1016/j.pharmthera.2021.108103] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/09/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022]
Abstract
Cancer Immunotherapy relies on harnessing a patient's immune system to fine-tune specific anti-tumor responses and ultimately eradicate cancer. Among diverse therapeutic approaches, oncolytic viruses (OVs) have emerged as a novel form of cancer immunotherapy. OVs are a naturally occurring or genetically modified class of viruses able to selectively kill cancer cells, leaving healthy cells unharmed; in the last two decades, the role of OVs has been redefined to act beyond their oncolytic activity. Indeed, the immunogenic cancer cell death mediated by OVs induces the release of tumor antigens that in turn induces anti-tumor immunity, allowing OVs to act as in situ therapeutic cancer vaccines. Additionally, OVs can be engineered for intratumoral delivery of immunostimulatory molecules such as tumor antigens or cytokines to further enhance anti-tumor response. Moreover, OVs can be used in combination with other cancer immunotherapeutic approaches such as Immune Checkpoint Inhibitors and CAR-T cells. The current review first defines the three main mechanisms of action (MOA) of OVs currently used in cancer therapy that are: i) Oncolysis, ii) OV-induced cancer-specific immune activation, and iii) Exploiting pre-existing anti-viral immunity to enhance cancer therapy. Secondly, we focus on how OVs can induce and/or improve anti-cancer immunity in a specific or unspecific fashion, highlighting the importance of these approaches. Finally, the last part of the review analyses OVs combined with other cancer immunotherapies, revising present and future clinical applications.
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Affiliation(s)
- S Feola
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland
| | - S Russo
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland
| | - E Ylösmäki
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland
| | - V Cerullo
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland; TRIMM, Translational Immunology Research Program, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, S. Pansini 5, 80131 Naples, Italy.
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12
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Watanabe M, Nishikawaji Y, Kawakami H, Kosai KI. Adenovirus Biology, Recombinant Adenovirus, and Adenovirus Usage in Gene Therapy. Viruses 2021; 13:v13122502. [PMID: 34960772 PMCID: PMC8706629 DOI: 10.3390/v13122502] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/08/2021] [Accepted: 12/10/2021] [Indexed: 12/13/2022] Open
Abstract
Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse "CRAs that can specifically target tumors with multiple factors" (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine.
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Affiliation(s)
- Maki Watanabe
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Yuya Nishikawaji
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hirotaka Kawakami
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Ken-Ichiro Kosai
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
- South Kyushu Center for Innovative Medical Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
- Center for Innovative Therapy Research and Application, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
- Center for Clinical and Translational Research, Kagoshima University Hospital, Kagoshima 890-8544, Japan
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13
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Nguyen TTT, Shingyoji M, Hanazono M, Zhong B, Morinaga T, Tada Y, Shimada H, Hiroshima K, Tagawa M. An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression. Cell Death Dis 2021; 12:663. [PMID: 34230456 PMCID: PMC8260618 DOI: 10.1038/s41419-021-03934-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/20/2022]
Abstract
A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.
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Affiliation(s)
- Thao Thi Thanh Nguyen
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan
- Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Division of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, 2374 National Highway 1, District 12, Ho Chi Minh, Vietnam
| | - Masato Shingyoji
- Division of Respirology, Chiba Cancer Center, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan
| | - Michiko Hanazono
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Boya Zhong
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan
- Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takao Morinaga
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan
| | - Yuji Tada
- Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku©, Chiba, 260-8670, Japan
- Department of Respiratory Medicine, International University of Health and Welfare Atami Hospital, 13-1 Higasikaigan, Atami, 413-0012, Japan
| | - Hideaki Shimada
- Department of Surgery, Graduate School of Medicine, Toho University, 6-11-1 Oomori-nishi, Oota-ku, 143-8541, Tokyo, Japan
| | - Kenzo Hiroshima
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, 477-96 Ohwadashinden, Yachiyo, 276-8524, Japan
| | - Masatoshi Tagawa
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan.
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
- Funabashi Orthopedic Hospital, 1-833 Hazama, Funabashi, 274-0822, Japan.
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14
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Mozhei O, G. Teschemacher A, Kasparov S. Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma. Cancers (Basel) 2020; 12:E3724. [PMID: 33322507 PMCID: PMC7764372 DOI: 10.3390/cancers12123724] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 01/02/2023] Open
Abstract
In this review, we scrutinize the idea of using viral vectors either as cytotoxic agents or gene delivery tools for treatment of glioblastoma multiforme (GBM) in light of the experience that our laboratory has accumulated over ~20 years when using similar vectors in experimental neuroscience. We review molecular strategies and current clinical trials and argue that approaches which are based on targeting a specific biochemical pathway or a characteristic mutation are inherently prone to failure because of the high genomic instability and clonal selection characteristics of GBM. For the same reasons, attempts to develop a viral system which selectively transduces only GBM cells are also unlikely to be universally successful. One of the common gene therapy approaches is to use cytotoxic viruses which replicate and cause preferential lysis of the GBM cells. This strategy, in addition to its reliance on the specific biochemical makeup of the GBM cells, bears a risk of necrotic cell death accompanied by release of large quantities of pro-inflammatory molecules. On the other hand, engaging the immune system in the anti-GBM response seems to be a potential avenue to explore further. We suggest that a plausible strategy is to focus on viral vectors which efficiently transduce brain cells via a non-selective, ubiquitous mechanism and which target (ideally irreversibly) processes that are critical only for dividing tumor cells and are dispensable for quiescent brain cells.
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Affiliation(s)
- Oleg Mozhei
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia
| | - Anja G. Teschemacher
- School of Physiology, Neuroscience and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;
| | - Sergey Kasparov
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia
- School of Physiology, Neuroscience and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;
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15
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Huang J. Current developments of targeting the p53 signaling pathway for cancer treatment. Pharmacol Ther 2020; 220:107720. [PMID: 33130194 DOI: 10.1016/j.pharmthera.2020.107720] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 10/26/2020] [Indexed: 12/23/2022]
Abstract
p53 is one of the most well-studied tumor suppressors. It is mutated or deleted in half of all cancers. In the other half carrying wild type p53, the p53 signaling pathway is disrupted by abnormalities of other components in the pathway. Due to its paramount role in tumor suppression, p53 has attracted great interest in drug development as any clinically successful therapeutic agent to target the p53 pathway will save millions of lives. However, designing therapeutics targeting the pathway has been extremely challenging, despite more than forty years of research. This review will summarize past and current efforts of developing p53-based gene therapy and targeted therapies for cancer treatment. In addition, the current efforts of exploiting the immunogenicity of p53 protein for cancer immunotherapy will be reviewed. Challenges and future directions for targeting the p53 pathway will be discussed.
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Affiliation(s)
- Jing Huang
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, United States.
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16
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Goradel NH, Negahdari B, Ghorghanlu S, Jahangiri S, Arashkia A. Strategies for enhancing intratumoral spread of oncolytic adenoviruses. Pharmacol Ther 2020; 213:107586. [PMID: 32479843 DOI: 10.1016/j.pharmthera.2020.107586] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023]
Abstract
Oncolytic viruses, effectively replicate viruses within malignant cells to lyse them without affecting normal ones, have recently shown great promise in developing therapeutic options for cancer. Adenoviruses (Ads) are one of the candidates in oncolytic virotheraoy due to its easily manipulated genomic DNA and expression of wide rane of its receptors on the various cancers. Although systematic delivery of oncolytic adenoviruses can target both primary and metastatic tumors, there are some drawbacks in the effective systematic delivery of oncolytic adenoviruses, including pre-existing antibodies and liver tropism. To overcome these limitations, intratumural (IT) administration of oncolytic viruses have been proposed. However, IT injection of Ads leaves much of the tumor mass unaffected and Ads are not able to disperse more in the tumor microenvironment (TME). To this end, various strategies have been developed to enhance the IT spread of oncolytic adenoviruses, such as using extracellular matrix degradation enzymes, junction opening peptides, and fusogenic proteins. In the present paper, we reviewed different oncolytic adenoviruses, their application in the clinical trials, and strategies for enhancing their IT spread.
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Affiliation(s)
- Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Sajjad Ghorghanlu
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Jahangiri
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arash Arashkia
- Department of Molecular Virology, Pasteur Institute of Iran, Tehran, Iran.
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17
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Kiyokawa J, Wakimoto H. Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma. Oncolytic Virother 2019; 8:27-37. [PMID: 31750274 PMCID: PMC6817710 DOI: 10.2147/ov.s196403] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/20/2019] [Indexed: 01/01/2023] Open
Abstract
Replication conditional oncolytic human adenovirus has long been considered a promising biological therapeutic to target high-grade gliomas (HGG), a group of essentially lethal primary brain cancer. The last decade has witnessed initiation and some completion of a number of Phase I and II clinical investigations of oncolytic adenovirus for HGG in the US and Europe. Results of these trials in patients are pivotal for not only federal approval but also filling an existing knowledge gap that primarily derives from the stark differences in permissivity to human adenovirus between humans and preclinical mouse models. DNX-2401 (Delta-24-RGD), the current mainstream oncolytic adenovirus with modifications in E1A and the fiber, has been shown to induce impressive objective response and long-term survival (>3 years) in a fraction of patients with recurrent HGG. Responders exhibited initial enlargement of the treated lesions for a few months post treatment, followed by shrinkage and near complete resolution. In accord with preclinical research, post-treatment specimens revealed virus-mediated alteration of the immune tumor microenvironment as evidenced by infiltration of CD8+ T cells and M1-polarized macrophages. These findings are encouraging and together with further information from ongoing studies have a potential to make oncolytic adenovirus a viable option for clinical management of HGG. This review deals with this timely topic; we will describe both preclinical and clinical development of oncolytic adenovirus therapy for HGG, summarize updated knowledge on clinical trials and discuss challenges that the field currently faces.
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Affiliation(s)
- Juri Kiyokawa
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Hiroaki Wakimoto
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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18
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Tejera B, López RE, Hidalgo P, Cárdenas R, Ballesteros G, Rivillas L, French L, Amero C, Pastor N, Santiago Á, Groitl P, Dobner T, Gonzalez RA. The human adenovirus type 5 E1B 55kDa protein interacts with RNA promoting timely DNA replication and viral late mRNA metabolism. PLoS One 2019; 14:e0214882. [PMID: 30943256 PMCID: PMC6447194 DOI: 10.1371/journal.pone.0214882] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 03/21/2019] [Indexed: 12/25/2022] Open
Abstract
The E1B 55kDa produced by human adenovirus type 5 is a multifunctional protein that participates in the regulation of several steps during the viral replication cycle. Previous studies suggest this protein plays an important role in postranscriptional regulation of viral and cellular gene expression, as it is required for the selective accumulation of maximal levels of viral late mRNA in the cytoplasm of the infected cell; however the molecular mechanisms that are altered or regulated by this protein have not been elucidated. A ribonucleoprotein motif that could implicate the direct interaction of the protein with RNA was initially predicted and tested in vitro, but the interaction with RNA could not be detected in infected cells, suggesting the interaction may be weak or transient. Here it was determined that the E1B 55kDa interacts with RNA in the context of the viral infection in non-transformed human cells, and its contribution to the adenovirus replication cycle was evaluated. Using recombinant adenoviruses with amino acid substitutions or a deletion in the ribonucleoprotein motif the interaction of E1B 55kDa with RNA was found to correlate with timely and efficient viral DNA replication and viral late mRNA accumulation and splicing.
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Affiliation(s)
- Berto Tejera
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Raúl E. López
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
- Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, México
| | - Paloma Hidalgo
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Reinier Cárdenas
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
- Laboratorio de Bioquímica y Resonancia Magnética Nuclear, Centro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Grisel Ballesteros
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Lina Rivillas
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Leidys French
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
- Laboratorio de Bioquímica y Resonancia Magnética Nuclear, Centro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Carlos Amero
- Laboratorio de Bioquímica y Resonancia Magnética Nuclear, Centro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Nina Pastor
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Ángel Santiago
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | - Peter Groitl
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
| | - Thomas Dobner
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Ramón A. Gonzalez
- Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
- * E-mail:
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19
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Guo W, Song H. Development of Gene Therapeutics for Head and Neck Cancer in China: From Bench to Bedside. Hum Gene Ther 2018; 29:180-187. [PMID: 29334764 DOI: 10.1089/hum.2017.230] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Affiliation(s)
- Wei Guo
- Department of Oral and Maxillofacial—Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, P.R. China
| | - Hao Song
- Department of Oral and Maxillofacial—Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, P.R. China
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20
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Fountzilas C, Patel S, Mahalingam D. Review: Oncolytic virotherapy, updates and future directions. Oncotarget 2017; 8:102617-102639. [PMID: 29254276 PMCID: PMC5731986 DOI: 10.18632/oncotarget.18309] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 05/03/2017] [Indexed: 12/14/2022] Open
Abstract
Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells while spare their normal counterparts. OVs can access cells through binding to receptors on their surface or through fusion with the plasma membrane and establish a lytic cycle in tumors, while leaving normal tissue essentially unharmed. Multiple viruses have been investigated in humans for the past century. IMLYGIC™ (T-VEC/Talimogene Laherparepvec), a genetically engineered Herpes Simplex Virus, is the first OV approved for use in the United States and the European Union for patients with locally advanced or non-resectable melanoma. Although OVs have a favorable toxicity profile and are impressively active anticancer agents in vitro and in vivo the majority of OVs have limited clinical efficacy as a single agent. While a virus-induced antitumor immune response can enhance oncolysis, when OVs are used systemically, the antiviral immune response can prevent the virus reaching the tumor tissue and having a therapeutic effect. Intratumoral administration can provide direct access to tumor tissue and be beneficial in reducing side effects. Immune checkpoint stimulation in tumor tissue has been noted after OV therapy and can be a natural response to viral-induced oncolysis. Also for immune checkpoint inhibition to be effective in treating cancer, an immune response to tumor neoantigens and an inflamed tumor microenvironment are required, both of which treatment with an OV may provide. Therefore, direct and indirect mechanisms of tumor killing provide rationale for clinical trials investigating the combination of OVs other forms of cancer therapy, including immune checkpoint inhibition.
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Affiliation(s)
- Christos Fountzilas
- The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Sukeshi Patel
- The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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21
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Ajina A, Maher J. Prospects for combined use of oncolytic viruses and CAR T-cells. J Immunother Cancer 2017; 5:90. [PMID: 29157300 PMCID: PMC5696728 DOI: 10.1186/s40425-017-0294-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 10/17/2017] [Indexed: 12/18/2022] Open
Abstract
With the approval of talimogene laherparepvec (T-VEC) for inoperable locally advanced or metastatic malignant melanoma in the USA and Europe, oncolytic virotherapy is now emerging as a viable therapeutic option for cancer patients. In parallel, following the favourable results of several clinical trials, adoptive cell transfer using chimeric antigen receptor (CAR)-redirected T-cells is anticipated to enter routine clinical practice for the management of chemotherapy-refractory B-cell malignancies. However, CAR T-cell therapy for patients with advanced solid tumours has proved far less successful. This Review draws upon recent advances in the design of novel oncolytic viruses and CAR T-cells and provides a comprehensive overview of the synergistic potential of combination oncolytic virotherapy with CAR T-cell adoptive cell transfer for the management of solid tumours, drawing particular attention to the methods by which recombinant oncolytic viruses may augment CAR T-cell trafficking into the tumour microenvironment, mitigate or reverse local immunosuppression and enhance CAR T-cell effector function and persistence.
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Affiliation(s)
- Adam Ajina
- Department of Oncology, Royal Free London NHS Foundation Trust, London, UK
| | - John Maher
- King’s College London, CAR Mechanics Group, School of Cancer and Pharmaceutical Sciences, Guy’s Hospital Campus, Great Maze Pond, London, SE1 9RT UK
- Department of Clinical Immunology and Allergy, King’s College Hospital NHS Foundation Trust, London, UK
- Department of Immunology, Eastbourne Hospital, East Sussex, UK
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22
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Yuan F, Liu L, Lei Y, Tang P. p53 inhibits the upregulation of sirtuin 1 expression induced by c-Myc. Oncol Lett 2017; 14:4396-4402. [PMID: 28943955 DOI: 10.3892/ol.2017.6661] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 05/16/2017] [Indexed: 01/08/2023] Open
Abstract
Sirtuin 1 (Sirt1), a conserved NAD+ dependent deacetylase, is a mediator of life span by calorie restriction. However, Sirt1 may paradoxically increase the risk of cancer. Accordingly, the expression level of Sirt1 is selectively elevated in numerous types of cancer cell; however, the mechanisms underlying the differential regulation remain largely unknown. The present study demonstrated that oncoprotein c-Myc was a direct regulator of Sirt1, which accounts for the upregulation of Sirt1 expression only in the cells without functional p53. In p53 deficient cells, the overexpression of c-Myc increased Sirt1 mRNA and protein expression levels as well as its promoter activity, whereas the inhibitor of c-Myc, 10058-F4, induced decreased Sirt1 basal mRNA and protein expression levels. Deletion/mutation mapping analyses revealed that c-Myc bound to the conserved E-box[-189 to -183 base pair (bp)] of the Sirt1 promoter. In addition, p53 and c-Myc shared at least response element and the presence of p53 may block the binding of c-Myc to the Sirt1 promoter, thus inhibit the c-Myc mediated upregulation of Sirt1 promoter activity. The present study indicated that the expression level of Sirt1 was tightly regulated by oncoprotein c-Myc and tumor suppressor p53, which aids an improved understanding of its expression regulation and tumor promoter role in certain conditions.
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Affiliation(s)
- Fang Yuan
- Department of Oncology, General Hospital of Chinese PLA, Beijing 100853, P.R. China
| | - Lu Liu
- Department of Clinical Nutrition, General Hospital of Chinese PLA, Beijing 100853, P.R. China
| | - Yonghong Lei
- Key Laboratory of Wound Repair and Regeneration of The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, P.R. China
| | - Peifu Tang
- Department of Orthopedics, General Hospital of Chinese PLA, Beijing 100853, P.R. China
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23
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Panek WK, Kane JR, Young JS, Rashidi A, Kim JW, Kanojia D, Lesniak MS. Hitting the nail on the head: combining oncolytic adenovirus-mediated virotherapy and immunomodulation for the treatment of glioma. Oncotarget 2017; 8:89391-89405. [PMID: 29179527 PMCID: PMC5687697 DOI: 10.18632/oncotarget.20810] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 08/26/2017] [Indexed: 12/31/2022] Open
Abstract
Glioblastoma is a highly aggressive malignant brain tumor with a poor prognosis and the median survival 14.6 months. Immunomodulatory proteins and oncolytic viruses represent two treatment approaches that have recently been developed for patients with glioblastoma that could extend patient survival and result in better treatment outcomes for patients with this disease. Together, these approaches could potentially augment the treatment efficacy and strength of these anti-tumor therapies. In addition to oncolytic activities, this combinatory approach introduces immunomodulation locally only where cancerous cells are present. This thereby results in the change of the tumor microenvironment from immune-suppressive to immune-vulnerable via activation of cytotoxic T cells or through the removal of glioma cells immune-suppressive capability. This review discusses the strengths and weaknesses of adenoviral oncolytic therapy, and highlights the genetic modifications that result in more effective and targeted viral agents. Additionally, the mechanism of action of immune-activating agents is described and the results of previous clinical trials utilizing these treatments in other solid tumors are reviewed. The feasibility, synergy, and limitations for treatments that combine these two approaches are outlined and areas for which more work is needed are considered.
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Affiliation(s)
- Wojciech K Panek
- Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - J Robert Kane
- Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - Jacob S Young
- Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Aida Rashidi
- Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - Julius W Kim
- Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - Deepak Kanojia
- Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA
| | - Maciej S Lesniak
- Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA
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Sakhawat A, Liu Y, Ma L, Muhammad T, Wang S, Zhang L, Cong X, Huang Y. Upregulation of Coxsackie Adenovirus Receptor Sensitizes Cisplatin-Resistant Lung Cancer Cells to CRAd-Induced Inhibition. J Cancer 2017. [PMID: 28638457 PMCID: PMC5479248 DOI: 10.7150/jca.18371] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective. Conditionally replicating adenoviruses (CRAds) have been proven potent oncolytic viruses in previous studies. They selectively replicate in the tumor cells because of incorporated survivin promoter and ultimately lead to their killing with minimal side effects on normal tissue. Chemotherapy with cisplatin is commonly employed for treating tumors, but its cytotoxic effects and development of resistance remained major concerns to be dealt with. The aim of this study was to explore the anticancer potential of survivin regulated CRAd alone or in combination with cisplatin in the A549 lung cancer cell line and cisplatin-resistant lung cancer cell line, A549-DDPR. Methods. CRAd was genetically engineered in our laboratory by removing its E1B region and adding survivin promoter to control its replication. A549, H292, and H661 lung cancer cell lines were procured from the CAS-China. The anti-tumor effectiveness of combined treatment (cisplatin plus CRAd) was evaluated in vitro through MTS assays and in vivo through mouse model experimentation. RT- PCR was used to assess MDR gene and mRNA expression of coxsackie adenoviral receptor (CAR). Results. Results of in vitro studies established that A549 lung cancer cells were highly sensitive to cisplatin showing dose-dependent inhibition. The resistant cells of A549-DDPR exhibited very less sensitivity to cisplatin but were infected with CRAd more efficiently as compared to A549. A549-DDPR cells exhibited higher expression of MDR gene and CAR in the RT-PCR analysis. The nearly similar rise in the CAR expression was seen when lung cancer cell lines received cisplatin in combined treatment (cisplatin plus CRAd). Combined anti-cancer therapy (cisplatin plus oncolytic virus) proved more efficient than monotherapy in the killing of cancer cells. Results of in vivo experiments recapitulated nearly similar tumor inhibition activities. Conclusion. This study highlighted the significant role of survivin in gene therapy as it has the potential to render CRAd more tumor specific. It also establishes that higher CAR expression plays a vital role in the success of adenovirus-based therapies. Furthermore, a careful combination of chemotherapy drugs and oncolytic viruses can culminate in significant therapeutic achievements against cancer.
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Affiliation(s)
- Ali Sakhawat
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, China
| | - Yanan Liu
- Basic Medical College, Jilin University, China
| | - Ling Ma
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, China
| | - Tahir Muhammad
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, China
| | - Shensen Wang
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, China
| | - Lina Zhang
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, China
| | | | - Yinghui Huang
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, China
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25
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He CB, Lin XJ. Inflammation scores predict the survival of patients with hepatocellular carcinoma who were treated with transarterial chemoembolization and recombinant human type-5 adenovirus H101. PLoS One 2017; 12:e0174769. [PMID: 28355305 PMCID: PMC5371390 DOI: 10.1371/journal.pone.0174769] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 03/15/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The systemic inflammatory response plays an important role in cancer development and progression. An original inflammation-based staging system for predicting survival in patients undergoing transarterial chemoembolization (TACE) combined with recombinant human type-5 adenovirus H101 is not available. This study aimed to validate the prognostic value of inflammation scores for patients with hepatocellular carcinoma (HCC) who were treated with TACE combined with H101. METHODS The data from 216 patients with HCC who underwent TACE combined with H101 from January 2007 to July 2015 were retrospectively collected, and the association of the inflammation scores with overall survival (OS) was analyzed. Univariate and multivariate analyses were performed to identify variables associated with OS. The prognostic value of the inflammation scores, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil/ platelet-to-lymphocyte ratio (NLR-PLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), prognostic index (PI), tumor-node-metastasis (TNM), Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP) staging systems were analyzed and compared using the areas under the receiver operating characteristic curves (AUROCs). RESULTS The estimated 1-, 2-, and 3-year OS rates were 61.3%, 44.2%, and 40.5% for the entire study cohort, respectively; the median OS was 17 months. According to the multivariate Cox proportional hazards model, the pretreatment NLR, tumor diameter and pretreatment alpha-fetoprotein (AFP) levels were independent predictors of OS. The CLIP score had superior discriminative abilities compared with other staging systems, and the NLR-PLR score consistently displayed a higher AUROC value than the other inflammation-based prognostic scores. The combination of the NLR-PLR and CLIP scores exhibited a superior prognostic ability for OS compared to the NLR-PLR or CLIP scores alone. CONCLUSIONS The NLR-PLR score is a more powerful predictive system than the other inflammation-based scores for patients with HCC who were treated with TACE and H101. The predictive ability may be improved by utilizing a combination of the NLR-PLR and CLIP scores.
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Affiliation(s)
- Chao-Bin He
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China
| | - Xiao-Jun Lin
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China
- * E-mail:
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Rodriguez-Brenes IA, Hofacre A, Fan H, Wodarz D. Complex Dynamics of Virus Spread from Low Infection Multiplicities: Implications for the Spread of Oncolytic Viruses. PLoS Comput Biol 2017; 13:e1005241. [PMID: 28107341 PMCID: PMC5249046 DOI: 10.1371/journal.pcbi.1005241] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 11/08/2016] [Indexed: 12/22/2022] Open
Abstract
While virus growth dynamics have been well-characterized in several infections, data are typically collected once the virus population becomes easily detectable. Earlier dynamics, however, remain less understood. We recently reported unusual early dynamics in an experimental system using adenovirus infection of human embryonic kidney (293) cells. Under identical experimental conditions, inoculation at low infection multiplicities resulted in either robust spread, or in limited spread that eventually stalled, with both outcomes occurring with approximately equal frequencies. The reasons underlying these observations have not been understood. Here, we present further experimental data showing that inhibition of interferon-induced antiviral states in cells results in a significant increase in the percentage of robust infections that are observed, implicating a race between virus replication and the spread of the anti-viral state as a central mechanism. Analysis of a variety of computational models, however, reveals that this alone cannot explain the simultaneous occurrence of both viral growth outcomes under identical conditions, and that additional biological mechanisms have to be invoked to explain the data. One such mechanism is the ability of the virus to overcome the antiviral state through multiple infection of cells. If this is included in the model, two outcomes of viral spread are found to be simultaneously stable, depending on initial conditions. In stochastic versions of such models, the system can go by chance to either state from identical initial conditions, with the relative frequency of the outcomes depending on the strength of the interferon-based anti-viral response, consistent with the experiments. This demonstrates considerable complexity during the early phase of the infection that can influence the ability of a virus to become successfully established. Implications for the initial dynamics of oncolytic virus spread through tumors are discussed. We investigate in vitro adenovirus spread starting from the lowest infection multiplicities. This phase of virus dynamics remains poorly understood and is likely critical for ensuring that engineered oncolytic viruses successfully spread and destroy tumors. We find unexpectedly complex dynamics, which are analyzed with a combination of experiments and mathematical models. The experiments indicate that the induction of an interferon-based anti-viral state is a crucial underlying mechanism. The mathematical models demonstrate that this mechanism alone cannot explain the experiments, and that additional mechanisms must be invoked to account for the data. The models suggest that the ability of the virus to overcome the anti-viral state through multiple infection of cells might be one such mechanism.
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Affiliation(s)
- Ignacio A. Rodriguez-Brenes
- Department of Mathematics, University of California, Irvine, Irvine, California, United States of America
- Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California, United States of America
| | - Andrew Hofacre
- Department of Molecular Biology and Biochemistry, Cancer Research Institute, University of California, Irvine, Irvine, California, United States of America
| | - Hung Fan
- Department of Molecular Biology and Biochemistry, Cancer Research Institute, University of California, Irvine, Irvine, California, United States of America
| | - Dominik Wodarz
- Department of Mathematics, University of California, Irvine, Irvine, California, United States of America
- Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California, United States of America
- * E-mail:
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27
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Oncolytic adenoviruses as a therapeutic approach for osteosarcoma: A new hope. J Bone Oncol 2016; 9:41-47. [PMID: 29226089 PMCID: PMC5715440 DOI: 10.1016/j.jbo.2016.12.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/16/2016] [Accepted: 12/02/2016] [Indexed: 01/07/2023] Open
Abstract
Osteosarcoma is the most common bone cancer among those with non-hematological origin and affects mainly pediatric patients. In the last 50 years, refinements in surgical procedures, as well as the introduction of aggressive neoadjuvant and adjuvant chemotherapeutic cocktails, have increased to nearly 70% the survival rate of these patients. Despite the initial therapeutic progress the fight against osteosarcoma has not substantially improved during the last three decades, and almost 30% of the patients do not respond or recur after the standard treatment. For this group there is an urgent need to implement new therapeutic approaches. Oncolytic adenoviruses are conditionally replicative viruses engineered to selectively replicate in and kill tumor cells, while remaining quiescent in healthy cells. In the last years there have been multiple preclinical and clinical studies using these viruses as therapeutic agents in the treatment of a broad range of cancers, including osteosarcoma. In this review, we summarize some of the most relevant published literature about the use of oncolytic adenoviruses to treat human osteosarcoma tumors in subcutaneous, orthotopic and metastatic mouse models. In conclusion, up to date the preclinical studies with oncolytic adenoviruses have demonstrated that are safe and efficacious against local and metastatic osteosarcoma. Knowledge arising from phase I/II clinical trials with oncolytic adenoviruses in other tumors have shown the potential of viruses to awake the patient´s own immune system generating a response against the tumor. Generating osteosarcoma immune-competent adenoviruses friendly models will allow to better understand this potential. Future clinical trials with oncolytic adenoviruses for osteosarcoma tumors are warranted.
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28
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Jiang Y, Zhong B, Kawamura K, Morinaga T, Shingyoji M, Sekine I, Tada Y, Tatsumi K, Shimada H, Hiroshima K, Tagawa M. Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma. BMC Cancer 2016; 16:455. [PMID: 27405588 PMCID: PMC4942884 DOI: 10.1186/s12885-016-2483-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 07/04/2016] [Indexed: 02/07/2023] Open
Abstract
Background Approximately 80 % of mesothelioma specimens have the wild-type p53 gene, whereas they contain homozygous deletions in the INK4A/ARF locus that encodes p14ARF and the 16INK4A genes. Consequently, the majority of mesothelioma is defective of the p53 pathways. We examined whether zoledronic acid (ZOL), a third generation bisphosphonate, and adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55), which augments p53 levels in the infected tumors, could produce combinatory anti-tumor effects on human mesothelioma cells bearing the wild-type p53 gene. Methods Cytotoxicity of ZOL and Ad-delE1B55 was assessed with a WST assay. Cell cycle changes were tested with flow cytometry. Expression levels of relevant molecules were examined with western blot analysis to investigate a possible mechanism of cytotoxicity. Furthermore, the expressions of Ad receptors on target cells and infectivity were estimated with flow cytometry. Viral replication was assayed with the tissue culture infection dose method. Results A combinatory use of ZOL and Ad-delE1B55 suppressed cell growth and increased sub-G1 or S-phase populations compared with a single agent, depending on cells tested. The combinatory treatment up-regulated p53 levels and subsequently enhanced the cleavage of caspase-3, 8, 9 and poly (ADP-ribose) polymerase, but expression of molecules involved in autophagy pathways were inconsistent. ZOL-treated cells also increased Ad infectivity with a dose-dependent manner and augmented Ad replication although the expression levels of integrin molecules, one of the Ad receptors, were down-regulated. Conclusions These findings indicated that ZOL and Ad-delE1B55 achieved combinatory anti-tumor effects through augmented apoptotic pathways or increased viral replication. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2483-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yuanyuan Jiang
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan.,Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Boya Zhong
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan.,Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kiyoko Kawamura
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan
| | - Takao Morinaga
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan
| | | | - Ikuo Sekine
- Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yuji Tada
- Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Koichiro Tatsumi
- Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hideaki Shimada
- Department of Surgery, School of Medicine, Toho University, Tokyo, Japan
| | - Kenzo Hiroshima
- Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan
| | - Masatoshi Tagawa
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan. .,Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
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29
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Cheng PH, Wechman SL, McMasters KM, Zhou HS. Oncolytic Replication of E1b-Deleted Adenoviruses. Viruses 2015; 7:5767-79. [PMID: 26561828 PMCID: PMC4664978 DOI: 10.3390/v7112905] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 10/23/2015] [Accepted: 10/26/2015] [Indexed: 01/30/2023] Open
Abstract
Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads) are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viral mRNA export, and cell cycle disruption.
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Affiliation(s)
- Pei-Hsin Cheng
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Stephen L Wechman
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
| | - Kelly M McMasters
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
- Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
| | - Heshan Sam Zhou
- Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40292, USA.
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
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Cheng PH, Rao XM, Wechman SL, Li XF, McMasters KM, Zhou HS. Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice. BMC Cancer 2015; 15:716. [PMID: 26475304 PMCID: PMC4609153 DOI: 10.1186/s12885-015-1731-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 10/08/2015] [Indexed: 12/20/2022] Open
Abstract
Background Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads. Methods Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies. Results Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment. Conclusion Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1731-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Pei-Hsin Cheng
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Xiao-Mei Rao
- James Graham Brown Cancer Center, University of Louisville Medical School, 505 South Hancock Street, CTR Building, Room 306, Louisville, KY, 40202, USA.
| | - Stephen L Wechman
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. .,Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Xiao-Feng Li
- Department of Diagnostic Radiology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Kelly M McMasters
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. .,Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Heshan Sam Zhou
- James Graham Brown Cancer Center, University of Louisville Medical School, 505 South Hancock Street, CTR Building, Room 306, Louisville, KY, 40202, USA. .,Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA. .,Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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31
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Cheng PH, Rao XM, Duan X, Li XF, Egger ME, McMasters KM, Zhou HS. Virotherapy targeting cyclin E overexpression in tumors with adenovirus-enhanced cancer-selective promoter. J Mol Med (Berl) 2014; 93:211-23. [PMID: 25376708 DOI: 10.1007/s00109-014-1214-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/16/2014] [Accepted: 10/10/2014] [Indexed: 12/31/2022]
Abstract
Oncolytic virotherapy can selectively destroy cancer cells and is a potential approach in cancer treatment. A strategy to increase tumor-specific selectivity is to control the expression of a key regulatory viral gene with a tumor-specific promoter. We have previously found that cyclin E expression is augmented in cancer cells after adenovirus (Ad) infection. Thus, the cyclin E promoter that is further activated by Ad in cancer cells may have unique properties for enhancing oncolytic viral replication. We have shown that high levels of viral E1a gene expression are achieved in cancer cells infected with Ad-cycE, in which the endogenous Ad E1a promoter was replaced with the cyclin E promoter. Ad-cycE shows markedly selective oncolytic efficacy in vitro and destroys various types of cancer cells, including those resistant to ONYX-015/dl1520. Furthermore, Ad-cycE shows a strong capacity to repress A549 xenograft tumor growth in nude mice and significantly prolongs survival. This study suggests the potential of Ad-cycE in cancer therapy and indicates the advantages of using promoters that can be upregulated by virus infection in cancer cells in development of oncolytic viruses. Key messages: Cyclin E promoter activity is high in cancer cells and enhanced by adenovirus infection. Cyclin E promoter is used to control the E1a gene of a tumor-specific oncolytic adenovirus. Ad-cycE efficiently targets cancer cells and induces oncolysis. Ad-cycE significantly repressed xenograft tumor and prolonged survival.
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Affiliation(s)
- Pei-Hsin Cheng
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA
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Malouli D, Howell GL, Legasse AW, Kahl C, Axthelm MK, Hansen SG, Früh K. Full genome sequence analysis of a novel adenovirus of rhesus macaque origin indicates a new simian adenovirus type and species. ACTA ACUST UNITED AC 2014; 3-4:18-29. [PMID: 25530944 DOI: 10.1016/j.virep.2014.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Multiple novel simian adenoviruses have been isolated over the past years and their potential to cross the species barrier and infect the human population is an ever present threat. Here we describe the isolation and full genome sequencing of a novel simian adenovirus (SAdV) isolated from the urine of two independent, never co-housed, late stage simian immunodeficiency virus (SIV)-infected rhesus macaques. The viral genome sequences revealed a novel type with a unique genome length, GC content, E3 region and DNA polymerase amino acid sequence that is sufficiently distinct from all currently known human- or simian adenovirus species to warrant classifying these isolates as a novel species of simian adenovirus. This new species, termed Simian mastadenovirus D (SAdV-D), displays the standard genome organization for the genus Mastadenovirus containing only one copy of the fiber gene which sets it apart from the old world monkey adenovirus species HAdV-G, SAdV-B and SAdV-C.
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Affiliation(s)
- Daniel Malouli
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America
| | - Grant L Howell
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America
| | - Alfred W Legasse
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America
| | - Christoph Kahl
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America
| | - Michael K Axthelm
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America
| | - Scott G Hansen
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America
| | - Klaus Früh
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America
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33
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Okura H, Smith CA, Rutka JT. Gene therapy for malignant glioma. MOLECULAR AND CELLULAR THERAPIES 2014; 2:21. [PMID: 26056588 PMCID: PMC4451964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 06/27/2014] [Indexed: 11/21/2023]
Abstract
Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.
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Affiliation(s)
- Hidehiro Okura
- />The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada
- />Department of Neurosurgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Christian A Smith
- />The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada
| | - James T Rutka
- />The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada
- />Department of Surgery, University of Toronto, 149 College Street, 5th Floor, Toronto, Ontario M5T 1P5 Canada
- />Division of Neurosurgery, The Hospital for Sick Children, Suite 1503, 555 University Avenue, Toronto, Ontario M5G 1X8 Canada
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Okura H, Smith CA, Rutka JT. Gene therapy for malignant glioma. MOLECULAR AND CELLULAR THERAPIES 2014; 2:21. [PMID: 26056588 PMCID: PMC4451964 DOI: 10.1186/2052-8426-2-21] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 06/27/2014] [Indexed: 01/01/2023]
Abstract
Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.
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Affiliation(s)
- Hidehiro Okura
- The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada ; Department of Neurosurgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Christian A Smith
- The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada
| | - James T Rutka
- The Arthur and Sonia Labatt Brain Tumour Research Centre, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4 Canada ; Department of Surgery, University of Toronto, 149 College Street, 5th Floor, Toronto, Ontario M5T 1P5 Canada ; Division of Neurosurgery, The Hospital for Sick Children, Suite 1503, 555 University Avenue, Toronto, Ontario M5G 1X8 Canada
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Li Y, Zhang B, Zhang H, Zhu X, Feng D, Zhang D, Zhuo B, Li L, Zheng J. Oncolytic adenovirus armed with shRNA targeting MYCN gene inhibits neuroblastoma cell proliferation and in vivo xenograft tumor growth. J Cancer Res Clin Oncol 2013; 139:933-41. [PMID: 23443256 DOI: 10.1007/s00432-013-1406-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 02/18/2013] [Indexed: 10/27/2022]
Abstract
PURPOSE MYCN amplification and p53 inactivation are two typical characteristics of aggressive neuroblastomas and are strongly associated with cancer progression and treatment failure. In an effort to develop new therapeutic agents to treat the aggressive neuroblastomas, we constructed ZD55-shMYCN, an oncolytic adenovirus ZD55 carrying short hairpin RNA (shRNA) targeting MYCN gene, and investigated the effects on proliferation of the p53-null and MYCN-amplified neuroblastoma cell line LA1-55N in vitro and in vivo by ZD55-shMYCN. METHODS In this study, we used ZD55-shMYCN to treat p53-null and MYCN-amplified neuroblastoma cells. To confirm the ability of selective replication of the ZD55-shMYCN, we examined the expression of E1A protein by western blotting. We used quantitative real-time PCR analysis and western blotting analysis to determine the inhibitory effect of ZD55-shMYCN on MYCN expression. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cell proliferation assay and xenograft mouse model were used to test the antigrowth efficacy of ZD55-shMYCN. RESULTS The results showed that ZD55-shMYCN selectively replicated and significantly downregulated the MYCN expression in LA1-55N cells. ZD55-shMYCN effectively inhibited the proliferation in LA1-55N cells in vitro and significantly inhibited tumor growth in vivo xenograft tumor in nude mice. CONCLUSIONS ZD55-shMYCN provides a novel agent for treating MYCN-amplified and p53-inactive aggressive neuroblastoma, representing a promising approach for further clinical development.
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Affiliation(s)
- Yuan Li
- Department of Pediatric Surgery, Xuzhou Children's Hospital, 18 Suti North Road, Xuzhou, 221006, Jiangsu, China.
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E1B-55 kDa-defective adenoviruses activate p53 in mesothelioma and enhance cytotoxicity of anticancer agents. J Thorac Oncol 2013; 7:1850-1857. [PMID: 23154556 DOI: 10.1097/jto.0b013e3182725fa4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways. METHODS We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents. RESULTS Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model. CONCLUSIONS Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.
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Cheng PH, Rao XM, McMasters KM, Zhou HS. Molecular basis for viral selective replication in cancer cells: activation of CDK2 by adenovirus-induced cyclin E. PLoS One 2013; 8:e57340. [PMID: 23437375 PMCID: PMC3577715 DOI: 10.1371/journal.pone.0057340] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 01/21/2013] [Indexed: 11/18/2022] Open
Abstract
Adenoviruses (Ads) with deletion of E1b55K preferentially replicate in cancer cells and have been used in cancer therapies. We have previously shown that Ad E1B55K protein is involved in induction of cyclin E for Ad replication, but this E1B55K function is not required in cancer cells in which deregulation of cyclin E is frequently observed. In this study, we investigated the interaction of cyclin E and CDK2 in Ad-infected cells. Ad infection significantly increased the large form of cyclin E (cyclin EL), promoted cyclin E/CDK2 complex formation and increased CDK2 phosphorylation at the T160 site. Activated CDK2 caused pRb phosphorylation at the S612 site. Repression of CDK2 activity with the chemical inhibitor roscovitine or with specific small interfering RNAs significantly decreased pRb phosphorylation, with concomitant repression of viral replication. Our results suggest that Ad-induced cyclin E activates CDK2 that targets the transcriptional repressor pRb to generate a cellular environment for viral productive replication. This study reveals a new molecular basis for oncolytic replication of E1b-deleted Ads and will aid in the development of new strategies for Ad oncolytic virotherapies.
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Affiliation(s)
- Pei-Hsin Cheng
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
| | - Xiao-Mei Rao
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
| | - Kelly M. McMasters
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
- Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
| | - Heshan Sam Zhou
- Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
- * E-mail:
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Yao Y, Wang L, Zhang H, Wang H, Zhao X, Zhang Y, Zhang L, Fan X, Qian G, Hu JF, Ge S. A novel anticancer therapy that simultaneously targets aberrant p53 and Notch activities in tumors. PLoS One 2012; 7:e46627. [PMID: 23071601 PMCID: PMC3468572 DOI: 10.1371/journal.pone.0046627] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Accepted: 09/07/2012] [Indexed: 12/17/2022] Open
Abstract
Notch signaling pathway plays an important role in tumorigenesis by maintaining the activity of self-renewal of cancer stem cells, and therefore, it is hypothesized that interference of Notch signaling may inhibit tumor formation and progression. H101 is a recombinant oncolytic adenovirus that is cytolytic in cells lacking intact p53, but it is unable to eradicate caner stem cells. In this study, we tested a new strategy of tumor gene therapy by combining a Notch1-siRNA with H101 oncolytic adenovirus. In HeLa-S3 tumor cells, the combined therapy blocked the Notch pathway and induced apoptosis in tumors that are p53-inactive. In nude mice bearing xenograft tumors derived from HeLa-S3 cells, the combination of H101/Notch1-siRNA therapies inhibited tumor growth. Moreover, Notch1-siRNA increased Hexon gene expression at both the transcriptional and the translational levels, and promoted H101 replication in tumors, thereby enhancing the oncolytic activity of H101. These data demonstrate the feasibility to combine H101 p53-targted oncolysis and anti-Notch siRNA activities as a novel anti-cancer therapy.
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Affiliation(s)
- Yuting Yao
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Li Wang
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - He Zhang
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- VA Palo Alto Health Care System, Stanford University Medical School, Palo Alto, California, United States of America
| | - Haibo Wang
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Xiaoping Zhao
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Yidan Zhang
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Leilei Zhang
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Xianqun Fan
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Guanxiang Qian
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- * E-mail: (J-FH); (SG); (SG); (JH)
| | - Ji-Fan Hu
- VA Palo Alto Health Care System, Stanford University Medical School, Palo Alto, California, United States of America
- * E-mail: (J-FH); (SG); (SG); (JH)
| | - Shengfang Ge
- Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- * E-mail: (J-FH); (SG); (SG); (JH)
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Reduced infectivity of adenovirus type 5 particles and degradation of entering viral genomes associated with incomplete processing of the preterminal protein. J Virol 2012; 86:13554-65. [PMID: 23035217 DOI: 10.1128/jvi.02337-12] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
To investigate further the contribution of the adenovirus type 5 (Ad5) E1B 55-kDa protein to genome replication, viral DNA accumulation was examined in primary human fibroblasts and epithelial cells infected with Ad5 or the E1B 55-kDa-null mutant Hr6. Unexpectedly, all cell types were observed to contain a significantly higher concentration of entering Hr6 than of Ad5 DNA, as did an infectious unit of Hr6. However, the great majority of the Hr6 genomes were degraded soon after entry. As this unusual phenotype cannot be ascribed to the Hr6 E1B frameshift mutation (J. S. Chahal and S. J. Flint, J. Virol. 86:3064-3072, 2012), the sequences of the Ad5 and Hr6 genomes were compared by using high-throughput sequencing. Seven previously unrecognized mutations were identified in the Hr6 genome, two of which result in substitutions in virion proteins, G315V in the preterminal protein (preTP) and A406V in fiber protein IV. Previous observations and the visualization by immunofluorescence of greater numbers of viral genomes entering the cytosol of Hr6-infected cells than of Ad5-infected cells indicated that the fiber mutation could not be responsible for the low-infectivity phenotype of Hr6. However, comparison of the forms of terminal protein present in purified virus particles indicated that the production of mature terminal protein from a processing intermediate is impaired in Hr6 particles. We therefore propose that complete processing of preTP within virus particles is necessary for the ability of viral genomes to become localized at appropriate sites and persist in infected cells.
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Chahal JS, Qi J, Flint SJ. The human adenovirus type 5 E1B 55 kDa protein obstructs inhibition of viral replication by type I interferon in normal human cells. PLoS Pathog 2012; 8:e1002853. [PMID: 22912576 PMCID: PMC3415460 DOI: 10.1371/journal.ppat.1002853] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 06/26/2012] [Indexed: 12/24/2022] Open
Abstract
Vectors derived from human adenovirus type 5, which typically lack the E1A and E1B genes, induce robust innate immune responses that limit their therapeutic efficacy. We reported previously that the E1B 55 kDa protein inhibits expression of a set of cellular genes that is highly enriched for those associated with anti-viral defense and immune responses, and includes many interferon-sensitive genes. The sensitivity of replication of E1B 55 kDa null-mutants to exogenous interferon (IFN) was therefore examined in normal human fibroblasts and respiratory epithelial cells. Yields of the mutants were reduced at least 500-fold, compared to only 5-fold, for wild-type (WT) virus replication. To investigate the mechanistic basis of such inhibition, the accumulation of viral early proteins and genomes was compared by immunoblotting and qPCR, respectively, in WT- and mutant-infected cells in the absence or presence of exogenous IFN. Both the concentration of viral genomes detected during the late phase and the numbers of viral replication centers formed were strongly reduced in IFN-treated cells in the absence of the E1B protein, despite production of similar quantities of viral replication proteins. These defects could not be attributed to degradation of entering viral genomes, induction of apoptosis, or failure to reorganize components of PML nuclear bodies. Nor was assembly of the E1B- and E4 Orf6 protein- E3 ubiquitin ligase required to prevent inhibition of viral replication by IFN. However, by using RT-PCR, the E1B 55 kDa protein was demonstrated to be a potent repressor of expression of IFN-inducible genes in IFN-treated cells. We propose that a primary function of the previously described transcriptional repression activity of the E1B 55 kDa protein is to block expression of IFN- inducible genes, and hence to facilitate formation of viral replication centers and genome replication. The most frequently used therapeutic vectors for gene transfer or cancer treatment are derived from human adenovirus type 5 (Ad5). We have observed previously that the E1B 55 kDa protein encoded by a gene routinely deleted from these vectors represses expression of numerous cellular genes regulated by interferon (IFN) α and β, which are important components of the innate immune response to viral infection. We therefore compared synthesis of pre-mRNA from IFN-inducible genes, viral yields and early reactions in the infectious cycle in normal human cells exposed to exogenous IFN and infected by wild-type or E1B 55 kDa null-mutant viruses. We report that the E1B 55 kDa protein is a potent repressor of expression of IFN-regulated genes, and protects viral replication against anti-viral actions of IFN by blocking inhibition of formation of viral replication centers and genome replication. These observations provide the first information about the function of the transcription repression activity of E1B during the infectious cycle. Importantly, they also suggest new design considerations for adenoviral vectors that can circumvent induction of innate immune responses, currently a major therapeutic limitation.
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Affiliation(s)
- Jasdave S. Chahal
- Princeton University, Department of Molecular Biology, Lewis Thomas Laboratory, Princeton, New Jersey, United States of America
| | - Ji Qi
- Princeton University, Department of Molecular Biology, Lewis Thomas Laboratory, Princeton, New Jersey, United States of America
| | - S. J. Flint
- Princeton University, Department of Molecular Biology, Lewis Thomas Laboratory, Princeton, New Jersey, United States of America
- * E-mail:
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Oncolytic viruses in the treatment of bladder cancer. Adv Urol 2012; 2012:404581. [PMID: 22899907 PMCID: PMC3414001 DOI: 10.1155/2012/404581] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2012] [Accepted: 06/05/2012] [Indexed: 01/22/2023] Open
Abstract
Bladder carcinoma is the second most common malignancy of the urinary tract. Up to 85% of patients with bladder cancer are diagnosed with a tumor that is limited to the bladder mucosa (Ta, T1, and CIS). These stages are commonly termed as non-muscle-invasive bladder cancer (NMIBC). Although the treatment of NMIBC has greatly improved in recent years, there is a need for additional therapies when patients fail bacillus Calmette-Guérin (BCG) and chemotherapeutic agents. We propose that bladder cancer may be an ideal target for oncolytic viruses engineered to selectively replicate in and lyse tumor cells leaving normal cells unharmed. In support of this hypothesis, here we review current treatment strategies for bladder cancer and their shortcomings, as well as recent advancements in oncolytic viral therapy demonstrating encouraging safety profiles and antitumor activity.
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Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. Adenoviral gene therapy in hepatocellular carcinoma: a review. Hepatol Int 2012. [DOI: 10.1007/s12072-012-9367-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Zhang KJ, Qian J, Wang SB, Yang Y. Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma. J Biomed Sci 2012; 19:20. [PMID: 22321574 PMCID: PMC3311074 DOI: 10.1186/1423-0127-19-20] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 02/09/2012] [Indexed: 12/18/2022] Open
Abstract
Background Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells. Methods By using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay. Results The recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro) than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects. Conclusion The AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system.
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Affiliation(s)
- Kang-Jian Zhang
- State key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai 200031, China
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Timely synthesis of the adenovirus type 5 E1B 55-kilodalton protein is required for efficient genome replication in normal human cells. J Virol 2012; 86:3064-72. [PMID: 22278242 DOI: 10.1128/jvi.06764-11] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Previous studies have indicated that the adenovirus type 5 E1B 55-kDa protein facilitates viral DNA synthesis in normal human foreskin fibroblasts (HFFs) but not in primary epithelial cells. To investigate this apparent difference further, viral DNA accumulation was examined in primary human fibroblasts and epithelial cells infected by the mutant AdEasyE1Δ2347, which carries the Hr6 frameshift mutation that prevents production of the E1B 55-kDa protein, in an E1-containing derivative of AdEasy. Impaired viral DNA synthesis was observed in normal HFFs but not in normal human bronchial epithelial cells infected by this mutant. However, acceleration of progression through the early phase, which is significantly slower in HFFs than in epithelial cells, eliminated the dependence of efficient viral DNA synthesis in HFFs on the E1B 55-kDa protein. These observations suggest that timely synthesis of the E1B 55-kDa protein protects normal cells against a host defense that inhibits adenoviral genome replication. One such defense is mediated by the Mre11-Rad50-Nbs1 complex. Nevertheless, examination of the localization of Mre11 and viral proteins by immunofluorescence suggested that this complex is inactivated similarly in AdEasyE1Δ2347 mutant-infected and AdEasyE1-infected HFFs.
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Schmid M, Kindsmüller K, Wimmer P, Groitl P, Gonzalez RA, Dobner T. The E3 ubiquitin ligase activity associated with the adenoviral E1B-55K-E4orf6 complex does not require CRM1-dependent export. J Virol 2011; 85:7081-94. [PMID: 21561915 PMCID: PMC3126608 DOI: 10.1128/jvi.02368-10] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Accepted: 05/03/2011] [Indexed: 11/20/2022] Open
Abstract
The adenovirus type 5 (Ad5) E1B-55K and E4orf6 (E1B-55K/E4orf6) proteins are multifunctional regulators of Ad5 replication, participating in many processes required for virus growth. A complex containing the two proteins mediates the degradation of cellular proteins through assembly of an E3 ubiquitin ligase and induces shutoff of host cell protein synthesis through selective nucleocytoplasmic viral late mRNA export. Both proteins shuttle between the nuclear and cytoplasmic compartments via leucine-rich nuclear export signals (NES). However, the role of their NES-dependent export in viral replication has not been established. It was initially shown that mutations in the E4orf6 NES negatively affect viral late gene expression in transfection/infection complementation assays, suggesting that E1B-55K/E4orf6-dependent viral late mRNA export involves a CRM1 export pathway. However, a different conclusion was drawn from similar studies showing that E1B-55K/E4orf6 promote late gene expression without active CRM1 or functional NES. To evaluate the role of the E1B-55K/E4orf6 NES in viral replication in the context of Ad-infected cells and in the presence of functional CRM1, we generated virus mutants carrying amino acid exchanges in the NES of either or both proteins. Phenotypic analyses revealed that mutations in the NES of E1B-55K and/or E4orf6 had no or only moderate effects on viral DNA replication, viral late protein synthesis, or viral late mRNA export. Significantly, such mutations also did not interfere with the degradation of cellular substrates, indicating that the NES of E1B-55K or E4orf6 is dispensable both for late gene expression and for the activity associated with the E3 ubiquitin ligase.
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Affiliation(s)
| | | | - Peter Wimmer
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany
| | - Peter Groitl
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany
| | | | - Thomas Dobner
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany
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Infection with E1B-mutant adenovirus stabilizes p53 but blocks p53 acetylation and activity through E1A. Oncogene 2010; 30:865-75. [PMID: 20935676 DOI: 10.1038/onc.2010.461] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Wild-type adenovirus type 5 eliminates p53 through the E1B-55kDa and E4-34kDa gene products. Deletion or mutation of E1B-55kDa has long been thought to confer p53-selective replication of oncolytic viruses. We show here that infection with E1B-defective adenovirus mutants induces massive accumulation of p53, without obvious defects in p53 localization, phosphorylation, conformation and oligomerization. Nonetheless, p53 completely failed to induce its target genes in this scenario, for example, p21/CDKN1A, Mdm2 and PUMA. Two regions of the E1A gene products independently contributed to the suppression of p21 transcription. Depending on the E1A conserved region 3, E1B-defective adenovirus impaired the ability of the transcription factor Sp1 to bind the p21 promoter. Moreover, the amino terminal region of E1A, binding the acetyl transferases p300 and CREB-binding protein, blocked p53 K382 acetylation in infected cells. Mutating either of these E1A regions, in addition to E1B, partially restored p21 mRNA levels. Our findings argue that adenovirus attenuates p53-mediated p21 induction, through at least two E1B-independent mechanisms. Other virus species and cancer cells may employ analogous strategies to impair p53 activity.
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Combinatory cytotoxic effects produced by E1B-55kDa-deleted adenoviruses and chemotherapeutic agents are dependent on the agents in esophageal carcinoma. Cancer Gene Ther 2010; 17:803-13. [PMID: 20689571 PMCID: PMC2963731 DOI: 10.1038/cgt.2010.37] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
We examined possible combinatory antitumor effects of replication-competent type 5 adenoviruses (Ad) lacking E1B-55kDa molecules (Ad-delE1B55) and chemotherapeutic agents in nine human esophageal carcinoma cells. Ad-delE1B55 produced cytotoxic effects on all the carcinoma cells and the cytotoxicity is not directly linked with the p53 status of the tumors or with the infectivity to respective tumors. A combinatory treatment with Ad-delE1B55 and an anticancer agent, 5-fluorouracil (5-FU), mitomycin C or etoposide, produced greater cytotoxic effects than that with either the Ad or the agent. Administration of 5-FU could minimally inhibit the viral replication and a simultaneous treatment with the Ad and 5-FU achieved better cytotoxicity than sequential treatments. We also confirmed the antitumor effects by the combination of Ad-delE1B55 with 5-FU in vivo. Cisplatin, however, did not achieve the combinatory effects in most of the cells tested. These data indicate that the Ad-delE1B55 produce combinatory antitumor effects with a chemotherapeutic agent irrespective of the administration schedule, but the effects depend on an agent in esophageal carcinoma.
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Cherry T, Longo SL, Tovar-Spinoza Z, Post DE. Second-generation HIF-activated oncolytic adenoviruses with improved replication, oncolytic, and antitumor efficacy. Gene Ther 2010; 17:1430-41. [PMID: 20664541 PMCID: PMC2978277 DOI: 10.1038/gt.2010.100] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
There is a need to develop more potent oncolytic adenoviruses that exhibit increased anti-tumor activity in patients. The HYPR-Ads are targeted oncolytic adenoviruses that specifically kill tumor cells which express active hypoxia-inducible factor (HIF). While therapeutically efficacious, the HYPR-Ads exhibited attenuated replication and oncolytic activity. To overcome these deficiencies and improve anti-tumor efficacy, we created new HIF-activated oncolytic Ads, HIF-Ad and HIF-Ad-IL4, which have two key changes: (i) a modified HIF-responsive promoter to regulate the E1A replication gene and (ii) insertion of the E3 gene region. The HIF-Ads demonstrated conditional activation of E1A expression under hypoxia. Importantly, the HIF-Ads exhibit hypoxia-dependent replication, oncolytic, and cellular release activities and potent anti-tumor efficacy, all of which are significantly greater than the HYPR-Ads. Notably, HIF-Ad-IL4 treatment led to regressions in tumor size by 70% and extensive tumor infiltration by leukocytes resulting in an anti-tumor efficacy that is up to 6-fold greater than the HYPR-Ads, HIF-Ad, and wild-type adenovirus treatment. These studies demonstrate that treatment with a HIF-activated oncolytic adenovirus leads to a measurable therapeutic response. The novel design of the HIF-Ads represents a significant improvement compared to first-generation oncolytic Ads and has great potential to increase the efficacy of this cancer therapy.
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Affiliation(s)
- T Cherry
- Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA
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Liu CC, Liu JH, Wu SC, Yen CC, Chen WS, Tsai YC. A novel E1B-55kD-deleted oncolytic adenovirus carrying mutant KRAS-regulated hdm2 transgene exerts specific antitumor efficacy on colorectal cancer cells. Mol Cancer Ther 2010; 9:450-60. [PMID: 20124454 DOI: 10.1158/1535-7163.mct-09-0704] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
E1B-55kD-deleted adenoviruses have been used as conditionally replicative adenoviruses (CRAds) for therapeutic purposes in tumors with loss-of-function p53 mutation. To target cancer cells that harbor activating mutant KRAS (KRAS(aMut)) but spare p53(wild) normal cells, we constructed and examined by reporter assays a KRAS(aMut) but not p53-responsive promoter, the Deltap53REP2 promoter. The Deltap53REP2 promoter, derived from human double minute 2 (hdm2) P2 promoter with its p53 response elements being deleted, was used to regulate the expression of the hdm2 transgene in a novel E1B-55kD-deleted CRAd, the Ad-KRhdm2. The Ad-KRhdm2 selectively replicated in and exerted cytopathic effects on KRAS(aMut) colorectal cancer cell lines (HCT116, LoVo, LS174T, LS123, and SW620), regardless of their p53 gene statuses, by forming plaques and exhibiting cytopathic effect in cultured cells. Ad-KRhdm2, like other E1B-55kD-deleted adenoviruses, also exerted selective cytopathic effects on tumor cells with loss-of-function p53 mutant. The multiplicities of infection of Ad-KRhdm2 required to decrease 50% viability of KRAS(aMut) tumor cells cultured for 7 days were 440 to 3,400 times less than those of MRC5 normal fibroblasts and KRAS(wild)/p53(wild) RKO tumor cells. Intratumoral injection of Ad-KRhdm2 vectors exhibited specific lytic activities in nude mouse xenografts of KRAS(aMut) cell lines (LoVo, SW620, and LS174T) but not in xenografts of RKO cells. Transduction of KRAS(aMut)/p53(wild) HCT116, LoVo, and LS174T cells by Ad-KRhdm2 significantly increased Hdm2 expression, decreased p53 level, and abolished the p53-transactivating p21(Cip1) promoter activity. Ad-KRhdm2 has shown its therapeutic potential in KRAS(aMut) cancer cells and warrants further clinical trials.
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Affiliation(s)
- Chin-Cheng Liu
- Institute of Biochemistry and Molecular Biology, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
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Kühnel F, Gürlevik E, Wirth TC, Strüver N, Malek NP, Müller-Schilling M, Manns MP, Carnero A, Zender L, Kubicka S. Targeting of p53-transcriptional dysfunction by conditionally replicating adenovirus is not limited by p53-homologues. Mol Ther 2009; 18:936-46. [PMID: 20040911 DOI: 10.1038/mt.2009.298] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
A hallmark of human tumors is the loss of p53 or its transcriptional functions. In this study, we describe the generation of the conditionally replicating adenovirus Adp53sensor for the treatment of p53-dysfunctional tumors. p53-selective attenuation of viral replication was achieved by using p53-dependent expression of the transcriptional repressor Gal4-KRAB that was directed against the adenoviral E1A locus. Adp53sensor shows efficient replication in p53-dysfunctional, but not in p53-active cells. In p53-dysfunctional cells, p53-analogous transcriptional activity by other p53 family members was not sufficient to compromise replication of Adp53sensor. In comparison with a genetically similar, but p53-insensitive virus, Adp53sensor replication was inhibited after systemic infection of p53-wt-mice, but not in p53-ko-mice thus confirming the correct function of the chosen approach. Adp53sensor showed efficient lytic and replicative properties in all investigated cells with p53-dysfunction and successfully inhibited the growth of subcutaneous xenotransplants in vivo. We further demonstrated that intravenous injection of Adp53sensor lead to significantly reduced liver damage compared to the control virus. Together, our data show that Adp53sensor is an oncolytic, p53-selective adenovirus for efficient treatment of p53-dysfunctional tumors with a favorable toxicity profile. Moreover, Adp53sensor provides a strategy that should be applicable to other transcriptionally regulated DNA viruses.
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Affiliation(s)
- Florian Kühnel
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany
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