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Kar S, Mehrotra S, Prajapati VK. From infection to remedy: Harnessing oncolytic viruses in cancer treatment. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:213-257. [PMID: 39978967 DOI: 10.1016/bs.apcsb.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.
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Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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2
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Zhang Y, Shi X, Shen Y, Dong X, He R, Chen G, Zhang Y, Tan H, Zhang K. Nanoengineering-armed oncolytic viruses drive antitumor response: progress and challenges. MedComm (Beijing) 2024; 5:e755. [PMID: 39399642 PMCID: PMC11467370 DOI: 10.1002/mco2.755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/01/2024] [Accepted: 09/03/2024] [Indexed: 10/15/2024] Open
Abstract
Oncolytic viruses (OVs) have emerged as a powerful tool in cancer therapy. Characterized with the unique abilities to selectively target and lyse tumor cells, OVs can expedite the induction of cell death, thereby facilitating effective tumor eradication. Nanoengineering-derived OVs overcome traditional OV therapy limitations by enhancing the stability of viral circulation, and tumor targeting, promising improved clinical safety and efficacy and so on. This review provides a comprehensive analysis of the multifaceted mechanisms through which engineered OVs can suppress tumor progression. It initiates with a concise delineation on the fundamental attributes of existing OVs, followed by the exploration of their mechanisms of the antitumor response. Amid rapid advancements in nanomedicine, this review presents an extensive overview of the latest developments in the synergy between nanomaterials, nanotechnologies, and OVs, highlighting the unique characteristics and properties of the nanomaterials employed and their potential to spur innovation in novel virus design. Additionally, it delves into the current challenges in this emerging field and proposes strategies to overcome these obstacles, aiming to spur innovation in the design and application of next-generation OVs.
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Affiliation(s)
- Yan Zhang
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
- Department of VIP ClinicGeneral Division, Shanghai East Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Xinyu Shi
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
- Department of VIP ClinicGeneral Division, Shanghai East Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Yifan Shen
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
- Department of VIP ClinicGeneral Division, Shanghai East Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Xiulin Dong
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Ruiqing He
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Guo Chen
- Department of VIP ClinicGeneral Division, Shanghai East Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Yan Zhang
- Department of Medical UltrasoundRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Honghong Tan
- Department of VIP ClinicGeneral Division, Shanghai East Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Kun Zhang
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
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Ghaleh HEG, Vakilzadeh G, Zahiri A, Farzanehpour M. Investigating the potential of oncolytic viruses for cancer treatment via MSC delivery. Cell Commun Signal 2023; 21:228. [PMID: 37667271 PMCID: PMC10478302 DOI: 10.1186/s12964-023-01232-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/16/2023] [Indexed: 09/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted considerable interest as a promising approach for cancer treatment due to their ability to undergo tumor-trophic migration. MSCs possess the unique ability to selectively migrate to tumors, making them an excellent candidate for targeted delivery of oncolytic viruses (OVs) to treat isolated tumors and metastatic malignancies. OVs have attracted attention as a potential treatment for cancer due to their ability to selectively infect and destroy tumor cells while sparing normal cells. In addition, OVs can induce immunogenic cell death and contain curative transgenes in their genome, making them an attractive candidate for cancer treatment in combination with immunotherapies. In combination with MSCs, OVs can modulate the tumor microenvironment and trigger anti-tumor immune responses, making MSC-releasing OVs a promising approach for cancer treatment. This study reviews researches on the use of MSC-released OVs as a novel method for treating cancer. Video Abstract.
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Affiliation(s)
| | - Gazal Vakilzadeh
- Applied Virology Research Center, Baqiyatallah University of Medical sciences, Tehran, Iran
| | - Ali Zahiri
- Students Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdieh Farzanehpour
- Applied Virology Research Center, Baqiyatallah University of Medical sciences, Tehran, Iran.
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Wang X, Shen Y, Wan X, Hu X, Cai WQ, Wu Z, Xin Q, Liu X, Gui J, Xin HY, Xin HW. Oncolytic virotherapy evolved into the fourth generation as tumor immunotherapy. J Transl Med 2023; 21:500. [PMID: 37491263 PMCID: PMC10369732 DOI: 10.1186/s12967-023-04360-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 07/16/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND Oncolytic virotherapy (OVT) is a promising anti-tumor modality that utilizes oncolytic viruses (OVs) to preferentially attack cancers rather than normal tissues. With the understanding particularly in the characteristics of viruses and tumor cells, numerous innovative OVs have been engineered to conquer cancers, such as Talimogene Laherparepvec (T-VEC) and tasadenoturev (DNX-2401). However, the therapeutic safety and efficacy must be further optimized and balanced to ensure the superior safe and efficient OVT in clinics, and reasonable combination therapy strategies are also important challenges worthy to be explored. MAIN BODY Here we provided a critical review of the development history and status of OVT, emphasizing the mechanisms of enhancing both safety and efficacy. We propose that oncolytic virotherapy has evolved into the fourth generation as tumor immunotherapy. Particularly, to arouse T cells by designing OVs expressing bi-specific T cell activator (BiTA) is a promising strategy of killing two birds with one stone. Amazing combination of therapeutic strategies of OVs and immune cells confers immense potential for managing cancers. Moreover, the attractive preclinical OVT addressed recently, and the OVT in clinical trials were systematically reviewed. CONCLUSION OVs, which are advancing into clinical trials, are being envisioned as the frontier clinical anti-tumor agents coming soon.
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Affiliation(s)
- Xianwang Wang
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China.
| | - Yihua Shen
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Xingxia Wan
- College of Arts and Sciences, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Xiaoqing Hu
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Wen-Qi Cai
- Xinzhou Traditional Chinese Medicine Hospital, Zhongnan Hospital of Wuhan University (Xinzhou), Wuhan, 430000, Hubei, China
| | - Zijun Wu
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Qiang Xin
- School of Graduate Students, Inner Mongolia Medical University, Inner Mongolian Autonomous Region, Hohhot, 010110, China
| | - Xiaoqing Liu
- College of Arts and Sciences, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Jingang Gui
- Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Hong-Yi Xin
- The Doctoral Scientific Research Center, People's Hospital of Lianjiang, Guangdong, 524400, China.
- The Doctoral Scientific Research Center, Affiliated People's Hospital of Lianjiang, Guangdong Medical University, Guangdong, 524400, China.
| | - Hong-Wu Xin
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China.
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CD24 Expression Dampens the Basal Antiviral State in Human Neuroblastoma Cells and Enhances Permissivity to Zika Virus Infection. Viruses 2022; 14:v14081735. [PMID: 36016357 PMCID: PMC9416398 DOI: 10.3390/v14081735] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 11/17/2022] Open
Abstract
Zika virus (ZIKV) exhibits distinct selectivity for infection of various cells and tissues, but how host cellular factors modulate varying permissivity remains largely unknown. Previous studies showed that the neuroblastoma cell line SK-N-AS (expressing low levels of cellular protein CD24) was highly restricted for ZIKV infection, and that this restriction was relieved by ectopic expression of CD24. We tested the hypothesis that CD24 expression allowed ZIKV replication by suppression of the antiviral response. SK-N-AS cells expressing an empty vector (termed CD24-low cells) showed elevated basal levels of phosphorylated STAT1, IRF-1, IKKE, and NFκB. In response to exogenously added type I interferon (IFN-I), CD24-low cells had higher-level induction of antiviral genes and activity against two IFN-I-sensitive viruses (VSV and PIV5-P/V) compared to SK-N-AS cells with ectopic CD24 expression (termed CD24-high cells). Media-transfer experiments showed that the inherent antiviral state of CD24-low cells was not dependent on a secreted factor such as IFN-I. Transcriptomics analysis revealed that CD24 expression decreased expression of genes involved in intracellular antiviral pathways, including IFN-I, NFκB, and Ras. Our findings that CD24 expression in neuroblastoma cells represses intracellular antiviral pathways support the proposal that CD24 may represent a novel biomarker in cancer cells for susceptibility to oncolytic viruses.
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Yang L, Gu X, Yu J, Ge S, Fan X. Oncolytic Virotherapy: From Bench to Bedside. Front Cell Dev Biol 2021; 9:790150. [PMID: 34901031 PMCID: PMC8662562 DOI: 10.3389/fcell.2021.790150] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/12/2021] [Indexed: 01/23/2023] Open
Abstract
Oncolytic viruses are naturally occurring or genetically engineered viruses that can replicate preferentially in tumor cells and inhibit tumor growth. These viruses have been considered an effective anticancer strategy in recent years. They mainly function by direct oncolysis, inducing an anticancer immune response and expressing exogenous effector genes. Their multifunctional characteristics indicate good application prospects as cancer therapeutics, especially in combination with other therapies, such as radiotherapy, chemotherapy and immunotherapy. Therefore, it is necessary to comprehensively understand the utility of oncolytic viruses in cancer therapeutics. Here, we review the characteristics, antitumor mechanisms, clinical applications, deficiencies and associated solutions, and future prospects of oncolytic viruses.
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Affiliation(s)
- Ludi Yang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Xiang Gu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jie Yu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
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7
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Santos Apolonio J, Lima de Souza Gonçalves V, Cordeiro Santos ML, Silva Luz M, Silva Souza JV, Rocha Pinheiro SL, de Souza WR, Sande Loureiro M, de Melo FF. Oncolytic virus therapy in cancer: A current review. World J Virol 2021; 10:229-255. [PMID: 34631474 PMCID: PMC8474975 DOI: 10.5501/wjv.v10.i5.229] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate "danger signals" that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.
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Affiliation(s)
- Jonathan Santos Apolonio
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - João Victor Silva Souza
- Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Wedja Rafaela de Souza
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
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8
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Kabacaoglu D, Ciecielski KJ, Ruess DA, Algül H. Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options. Front Immunol 2018; 9:1878. [PMID: 30158932 PMCID: PMC6104627 DOI: 10.3389/fimmu.2018.01878] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 07/30/2018] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), as the most frequent form of pancreatic malignancy, still is associated with a dismal prognosis. Due to its late detection, most patients are ineligible for surgery, and chemotherapeutic options are limited. Tumor heterogeneity and a characteristic structure with crosstalk between the cancer/malignant cells and an abundant tumor microenvironment (TME) make PDAC a very challenging puzzle to solve. Thus far, targeted therapies have failed to substantially improve the overall survival of PDAC patients. Immune checkpoint inhibition, as an emerging therapeutic option in cancer treatment, shows promising results in different solid tumor types and hematological malignancies. However, PDAC does not respond well to immune checkpoint inhibitors anti-programmed cell death protein 1 (PD-1) or anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) alone or in combination. PDAC with its immune-privileged nature, starting from the early pre-neoplastic state, appears to escape from the antitumor immune response unlike other neoplastic entities. Different mechanisms how cancer cells achieve immune-privileged status have been hypothesized. Among them are decreased antigenicity and impaired immunogenicity via both cancer cell-intrinsic mechanisms and an augmented immunosuppressive TME. Here, we seek to shed light on the recent advances in both bench and bedside investigation of immunotherapeutic options for PDAC. Furthermore, we aim to compile recent data about how PDAC adopts immune escape mechanisms, and how these mechanisms might be exploited therapeutically in combination with immune checkpoint inhibitors, such as PD-1 or CTLA-4 antibodies.
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Affiliation(s)
| | | | | | - Hana Algül
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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9
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Terai K, Bi D, Liu Z, Kimura K, Sanaat Z, Dolatkhah R, Soleimani M, Jones C, Bright A, Esfandyari T, Farassati F. A Novel Oncolytic Herpes Capable of Cell-Specific Transcriptional Targeting of CD133± Cancer Cells Induces Significant Tumor Regression. Stem Cells 2018; 36:1154-1169. [PMID: 29658163 DOI: 10.1002/stem.2835] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 02/16/2017] [Accepted: 03/10/2017] [Indexed: 12/11/2022]
Abstract
The topic of cancer stem cells (CSCs) is of significant importance due to its implications in our understanding of the tumor biology as well as the development of novel cancer therapeutics. However, the question of whether targeting CSCs can hamper the growth of tumors remains mainly unanswered due to the lack of specific agents for this purpose. To address this issue, we have developed the first mutated version of herpes simplex virus-1 that is transcriptionally targeted against CD133+ cells. CD133 has been portrayed as one of the most important markers in CSCs involved in the biology of a number of human cancers, including liver, brain, colon, skin, and pancreas. The virus developed in this work, Signal-Smart 2, showed specificity against CD133+ cells in three different models (hepatocellular carcinoma, colorectal cancer, and melanoma) resulting in a loss of viability and invasiveness of cancer cells. Additionally, the virus showed robust inhibitory activity against in vivo tumor growth in both preventive and therapeutic mouse models as well as orthotopic model highly relevant to potential clinical application of this virus. Therefore, we conclude that targeting CD133+ CSCs has the potential to be pursued as a novel strategy against cancer. Stem Cells 2018;36:1154-1169.
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Affiliation(s)
- Kaoru Terai
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Danse Bi
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Zhengian Liu
- Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center, Kansas, Missouri, USA
| | - Kyle Kimura
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Zohreh Sanaat
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Roya Dolatkhah
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Mina Soleimani
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Christopher Jones
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Allison Bright
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Tuba Esfandyari
- Molecular Medicine Laboratory, The University of Kansas Medical School, Kansas, Missouri, USA
| | - Faris Farassati
- Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center, Kansas, Missouri, USA.,Saint Luke's Cancer Institute-Saint Luke's Marion Bloch Neuroscience Institute, Kansas, Missouri, USA
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10
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Moghadam AR, Patrad E, Tafsiri E, Peng W, Fangman B, Pluard TJ, Accurso A, Salacz M, Shah K, Ricke B, Bi D, Kimura K, Graves L, Najad MK, Dolatkhah R, Sanaat Z, Yazdi M, Tavakolinia N, Mazani M, Amani M, Ghavami S, Gartell R, Reilly C, Naima Z, Esfandyari T, Farassati F. Ral signaling pathway in health and cancer. Cancer Med 2017; 6:2998-3013. [PMID: 29047224 PMCID: PMC5727330 DOI: 10.1002/cam4.1105] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 04/10/2017] [Accepted: 04/14/2017] [Indexed: 12/12/2022] Open
Abstract
The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.
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Affiliation(s)
- Adel Rezaei Moghadam
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Elham Patrad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Elham Tafsiri
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Warner Peng
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Benjamin Fangman
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Timothy J Pluard
- Saint Luke's HospitalUniversity of Missouri at Kansas CityKansas CityMissouri
| | - Anthony Accurso
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Michael Salacz
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kushal Shah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Brandon Ricke
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Danse Bi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kyle Kimura
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Leland Graves
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Marzieh Khajoie Najad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Roya Dolatkhah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zohreh Sanaat
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mina Yazdi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Naeimeh Tavakolinia
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mohammad Mazani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Mojtaba Amani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Robyn Gartell
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Colleen Reilly
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zaid Naima
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Tuba Esfandyari
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Faris Farassati
- Research Service (151)Kansas City Veteran Affairs Medical Center & Midwest Biomedical Research Foundation4801 E Linwood BlvdKansas CityMissouri64128‐2226
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11
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Howells A, Marelli G, Lemoine NR, Wang Y. Oncolytic Viruses-Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer. Front Oncol 2017; 7:195. [PMID: 28944214 PMCID: PMC5596080 DOI: 10.3389/fonc.2017.00195] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 08/15/2017] [Indexed: 12/13/2022] Open
Abstract
Oncolytic viruses (OVs) are an emerging treatment option for many cancer types and have recently been the focus of extensive research aiming to develop their therapeutic potential. The ultimate aim is to design a virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long lasting tumor-specific immunity. There are a number of viruses which are either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells. This means they are able to infect only tumor cells and healthy tissue remains unharmed. This specificity is imperative in order to reduce the side effects of oncolytic virotherapy. These viruses can also be modified by various methods including insertion and deletion of specific genes with the aim of improving their efficacy and safety profiles. In this review, we have provided an overview of the various virus species currently being investigated for their oncolytic potential and the positive and negative effects of a multitude of modifications used to increase their infectivity, anti-tumor immunity, and treatment safety, in particular focusing on the interaction of tumor cells and OVs.
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Affiliation(s)
- Anwen Howells
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Giulia Marelli
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Nicholas R Lemoine
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yaohe Wang
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
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12
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Colao I, Pennisi R, Venuti A, Nygårdas M, Heikkilä O, Hukkanen V, Sciortino MT. The ERK-1 function is required for HSV-1-mediated G1/S progression in HEP-2 cells and contributes to virus growth. Sci Rep 2017; 7:9176. [PMID: 28835716 PMCID: PMC5569015 DOI: 10.1038/s41598-017-09529-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/17/2017] [Indexed: 12/22/2022] Open
Abstract
The herpes simplex virus 1 is able to readdress different cellular pathways including cell cycle to facilitate its replication and spread. During infection, the progression of the cell cycle from G1 to S phase makes the cellular replication machinery accessible to viral DNA replication. In this work we established that HSV-1, in asynchronized HEp-2 cells, strictly controls cell cycle progression increasing S-phase population from 9 hours post infection until the end of HSV-1 replication. The G1/S phases progression depends on two important proteins, cyclin E and CDK2. We demonstrate that their phosphorylated status and then their activity during the infection is strongly correlated to viral replication events. In addition, HSV-1 is able to recruit and distribute ERK1/2 proteins in a spatio-temporal fashion, highlighting its downstream regulatory effects on cellular processes. According with this data, using chemical inhibitor U0126 and ERK dominant negative cells we found that the lack of ERK1 activity affects cyclin E protein accumulation, viral gene transcription and percentage of the cells in S phase, during the viral replication. These data suggested a complex interaction between ERK, cell cycle progression and HSV-1 replication.
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Affiliation(s)
- Ivana Colao
- Department of Biological and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166, Messina, Italy
| | - Rosamaria Pennisi
- Department of Biological and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166, Messina, Italy
| | - Assunta Venuti
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
| | | | - Outi Heikkilä
- Department of Virology, University of Turku, Turku, Finland
| | - Veijo Hukkanen
- Department of Virology, University of Turku, Turku, Finland
| | - Maria Teresa Sciortino
- Department of Biological and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166, Messina, Italy.
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13
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Bommareddy PK, Patel A, Hossain S, Kaufman HL. Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma. Am J Clin Dermatol 2017; 18:1-15. [PMID: 27988837 DOI: 10.1007/s40257-016-0238-9] [Citation(s) in RCA: 214] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Many mammalian viruses have properties that can be commandeered for the treatment of cancer. These characteristics include preferential infection and replication in tumor cells, the initiation of tumor cell lysis, and the induction of innate and adaptive anti-tumor immunity. Furthermore, viruses can be genetically engineered to reduce pathogenicity and increase immunogenicity resulting in minimally toxic therapeutic agents. Talimogene laherparepvec (T-VEC; Imlygic™), is a genetically modified herpes simplex virus, type 1, and is the first oncolytic virus therapy to be approved for the treatment of advanced melanoma by the US FDA. T-VEC is attenuated by the deletion of the herpes neurovirulence viral genes and enhanced for immunogenicity by the deletion of the viral ICP47 gene. Immunogenicity is further supported by expression of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, which helps promote the priming of T cell responses. T-VEC demonstrated significant improvement in durable response rate, objective response rate, and progression-free survival in a randomized phase III clinical trial for patients with advanced melanoma. This review will discuss the optimal selection of patients for such treatment and describe how therapy is optimally delivered. We will also discuss future directions for oncolytic virus immunotherapy, which will likely include combination T-VEC clinical trials, expansion of T-VEC to other types of non-melanoma skin cancers, and renewed efforts at oncolytic virus drug development with other viruses.
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14
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Ginn KF, Fangman B, Terai K, Wise A, Ziazadeh D, Shah K, Gartrell R, Ricke B, Kimura K, Mathur S, Borrego-Diaz E, Farassati F. RalA is overactivated in medulloblastoma. J Neurooncol 2016; 130:99-110. [PMID: 27566179 DOI: 10.1007/s11060-016-2236-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 07/21/2016] [Indexed: 12/18/2022]
Abstract
Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl-geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells), higher levels of RalA activation was observed. These data not only bring RalA to light as an important contributor to the malignant phenotype of MDB but introduces this pathway as a novel target in the treatment of this malignancy.
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Affiliation(s)
- Kevin F Ginn
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA.,Division of Hematology and Oncology, Children's Mercy Hospital and Clinics, Kansas City, MO, USA
| | - Ben Fangman
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Kaoru Terai
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Amanda Wise
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Daniel Ziazadeh
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Kushal Shah
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Robyn Gartrell
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Brandon Ricke
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Kyle Kimura
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Sharad Mathur
- Research Service (151), Kansas City Veteran Affairs Medical Center & Midwest Biomedical Research Foundation-Saint Luke's Marion Bloch Brain Tumor Research Program, 4801 E Linwood Blvd, F5-123, Kansas City, MO, 64128, USA
| | - Emma Borrego-Diaz
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA
| | - Faris Farassati
- Molecular Medicine Laboratory, Department of Medicine, University of Kansas Medical School, Kansas City, KS, USA. .,Research Service (151), Kansas City Veteran Affairs Medical Center & Midwest Biomedical Research Foundation-Saint Luke's Marion Bloch Brain Tumor Research Program, 4801 E Linwood Blvd, F5-123, Kansas City, MO, 64128, USA.
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15
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Kosmidis C, Sapalidis K, Kotidis E, Mixalopoulos N, Zarogoulidis P, Tsavlis D, Baka S, Man YG, Kanellos J. Pancreatic cancer from bench to bedside: molecular pathways and treatment options. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:165. [PMID: 27275478 PMCID: PMC4876273 DOI: 10.21037/atm.2016.05.11] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 03/24/2016] [Indexed: 12/15/2022]
Abstract
In the last forty years the pancreatic cancer treatment has made advances, however; still novel drugs are needed. It is known that the five year survival rate remains around 5%. The best treatment option still remains surgery, if patients are diagnosed early. In the last decade the biology of pancreatic cancer has been vastly explored and novel agents such as; tyrosine kinase agents, or vaccines have been added as a treatment perspective. The big challenge is now to translate this knowledge in better outcomes for patients. In this current review we will present information from pancreatic cancer diagnosis to molecular pathways and treatment options; current and future.
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16
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Ibrahim AM, Wang YH. Viro-immune therapy: A new strategy for treatment of pancreatic cancer. World J Gastroenterol 2016; 22:748-763. [PMID: 26811622 PMCID: PMC4716074 DOI: 10.3748/wjg.v22.i2.748] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/26/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses (TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1 (PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.
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17
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Peters C, Rabkin SD. Designing Herpes Viruses as Oncolytics. MOLECULAR THERAPY-ONCOLYTICS 2015; 2:S2372-7705(16)30012-2. [PMID: 26462293 PMCID: PMC4599707 DOI: 10.1038/mto.2015.10] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because herpes simplex virus (HSV) is a natural human pathogen that can cause serious disease, it is incumbent that it be genetically-engineered or significantly attenuated for safety. Here we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are non-essential for growth in tissue culture cells but are important for growth in post-mitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be 'armed' with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate anti-tumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity.
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Affiliation(s)
- Cole Peters
- Program in Virology, Harvard Medical School, Boston, MA, and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston MA
| | - Samuel D Rabkin
- Program in Virology, Harvard Medical School, Boston, MA, and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston MA
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18
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Ultrasound as a method to enhance antitumor ability of oncolytic herpes simplex virus for head and neck cancer. Cancer Gene Ther 2015; 22:163-8. [PMID: 25656776 DOI: 10.1038/cgt.2015.3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 12/26/2014] [Accepted: 12/29/2014] [Indexed: 11/08/2022]
Abstract
Low-intensity ultrasound is a useful method to enhance the delivery of drugs to target cells via a range of mechanisms including the transient formation of micropores in the cell membrane, a process known as sonoporation. The effect of ultrasound on oncolytic herpes simplex virus type-1 (HSV-1) infection in oral squamous cell carcinoma (SCC) was examined. Human SCC cell line SAS and oncolytic HSV-1 RH2, which was deficient in the neurovirulent γ134.5 gene and exhibited cell fusion actions, were used. Cells grown in multi-well plates were infected with HSV-1 and exposed to ultrasound in the presence or absence of microbubbles after an adsorption period. The number of plaques was significantly greater than that of the untreated control. SAS cells were inoculated subcutaneously into nude mice and tumors were produced. Tumors were injected with HSV-1 RH2 with or without microbubbles and then exposed to ultrasound through the covering skin. The amount of the virus in tumor tissues 3 days after the injection was higher in tumors treated with HSV-1 RH2 and ultrasound than in tumors treated with RH2 only. The expression of the HSV-1 antigen was also increased by ultrasound and microbubbles. Tumor growth was suppressed with HSV-1 RH2 in combination with ultrasound, especially with microbubbles. These results indicated that ultrasound increased the efficiency of the HSV-1 infection in SAS cells and nude mouse tumors. This method can potentially be useful to enhance the antitumor effects of oncolytic HSV-1 on head and neck cancer treatment.
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19
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Ezzeldin M, Borrego-Diaz E, Taha M, Esfandyari T, Wise AL, Peng W, Rouyanian A, Asvadi Kermani A, Soleimani M, Patrad E, Lialyte K, Wang K, Williamson S, Abdulkarim B, Olyaee M, Farassati F. RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC). Mol Oncol 2014; 8:1043-53. [PMID: 24785097 DOI: 10.1016/j.molonc.2014.03.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/12/2014] [Accepted: 03/24/2014] [Indexed: 12/23/2022] Open
Abstract
Ral (Ras like) leads an important proto-oncogenic signaling pathway down-stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non-malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene-specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl-geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR-Knockout) also revealed an elevated level of RalA-GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.
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Affiliation(s)
- Mohamad Ezzeldin
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Emma Borrego-Diaz
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Mohammad Taha
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Tuba Esfandyari
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Amanda L Wise
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Warner Peng
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Alex Rouyanian
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Atabak Asvadi Kermani
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Mina Soleimani
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Elham Patrad
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Kristina Lialyte
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Kun Wang
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Stephen Williamson
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Bashar Abdulkarim
- The University of Kansas Medical Center, Department of Surgery, Kansas City, KS, USA
| | - Mojtaba Olyaee
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA
| | - Faris Farassati
- The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
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20
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Smith TT, Roth JC, Friedman GK, Gillespie GY. Oncolytic viral therapy: targeting cancer stem cells. Oncolytic Virother 2014; 2014:21-33. [PMID: 24834430 PMCID: PMC4018757 DOI: 10.2147/ov.s52749] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy. To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus. Specifically, we review current literature regarding first-generation oncolytic viruses with their innate ability to replicate in CSCs, as well as second-generation viruses engineered to enhance the oncolytic effect and CSC-targeting through transgene expression.
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Affiliation(s)
- Tyrel T Smith
- Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Justin C Roth
- Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gregory K Friedman
- Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - G Yancey Gillespie
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA
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21
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Goldufsky J, Sivendran S, Harcharik S, Pan M, Bernardo S, Stern RH, Friedlander P, Ruby CE, Saenger Y, Kaufman HL. Oncolytic virus therapy for cancer. Oncolytic Virother 2013; 2:31-46. [PMID: 27512656 DOI: 10.2147/ov.s38901] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The use of oncolytic viruses to treat cancer is based on the selection of tropic tumor viruses or the generation of replication selective vectors that can either directly kill infected tumor cells or increase their susceptibility to cell death and apoptosis through additional exposure to radiation or chemotherapy. In addition, viral vectors can be modified to promote more potent tumor cell death, improve the toxicity profile, and/or generate host antitumor immunity. A variety of viruses have been developed as oncolytic therapeutics, including adenovirus, vaccinia virus, herpesvirus, coxsackie A virus, Newcastle disease virus, and reovirus. The clinical development of oncolytic viral therapy has accelerated in the last few years, with several vectors entering clinical trials for a variety of cancers. In this review, current strategies to optimize the therapeutic effectiveness and safety of the major oncolytic viruses are discussed, and a summary of current clinical trials is provided. Further investigation is needed to characterize better the clinical impact of oncolytic viruses, but there are increasing data demonstrating the potential promise of this approach for the treatment of human and animal cancers.
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Affiliation(s)
- Joe Goldufsky
- Department of Immunology & Microbiology, Rush University Medical Center, Chicago IL, USA
| | - Shanthi Sivendran
- Department of Hematology/Oncology Medical Specialists, Lancaster General Health, Lancaster, PA, USA
| | - Sara Harcharik
- Department of Medical Oncology, Tisch Cancer Institute, The Mount Sinai School of Medicine, New York, NY, USA
| | - Michael Pan
- Department of Medical Oncology, Tisch Cancer Institute, The Mount Sinai School of Medicine, New York, NY, USA
| | - Sebastian Bernardo
- Department of Medical Oncology, Tisch Cancer Institute, The Mount Sinai School of Medicine, New York, NY, USA
| | - Richard H Stern
- Department of Radiology, Tisch Cancer Institute, The Mount Sinai School of Medicine, New York, NY, USA
| | - Philip Friedlander
- Department of Medical Oncology, Tisch Cancer Institute, The Mount Sinai School of Medicine, New York, NY, USA
| | - Carl E Ruby
- Department of Immunology & Microbiology, Rush University Medical Center, Chicago IL, USA; Department of Surgery, Rush University Medical Center, Chicago IL, USA
| | - Yvonne Saenger
- Department of Medical Oncology, Tisch Cancer Institute, The Mount Sinai School of Medicine, New York, NY, USA
| | - Howard L Kaufman
- Department of Immunology & Microbiology, Rush University Medical Center, Chicago IL, USA; Department of Surgery, Rush University Medical Center, Chicago IL, USA
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22
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Abstract
Oncolytic virotherapy is a new strategy to reduce tumor burden through selective virus replication in rapidly proliferating cells. Oncolytic viruses are members of at least ten virus families, each with its advantages and disadvantages. Here, I briefly review the recent advances and key challenges, as exemplified by the best-studied platforms. Recent advances include preclinical proof of feasibility, clinical evidence of tolerability and effectiveness, and the development of new strategies to improve efficacy. These include engineered tumor selectivity and expression of antitumorigenic genes that could function independently of virus replication, identification of combinatorial therapies that accelerate intratumoral virus propagation, and modification of immune responses and vascular delivery for treatment of metastatic disease. Key challenges are to select "winners" from the distinct oncolytic platforms that can stimulate anti-cancer immunity without affecting virus replication and can lyse cancer stem cells, which are most likely responsible for tumor maintenance, aggressiveness, and recurrence. Preventing the emergence of resistant tumor cells during virotherapy through the activation of multiple death pathways, the development of a better understanding of the mechanisms of cancer stem-cell lysis, and the development of more meaningful preclinical animal models are additional challenges for the next-generation of engineered viruses.
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Affiliation(s)
- Laure Aurelian
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
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23
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In vitro antiviral activity of dehydroepiandrosterone, 17 synthetic analogs and ERK modulators against herpes simplex virus type 1. Antiviral Res 2012; 95:37-48. [PMID: 22584352 DOI: 10.1016/j.antiviral.2012.05.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 04/24/2012] [Accepted: 05/01/2012] [Indexed: 11/22/2022]
Abstract
In the present study the in vitro antiviral activity of dehydroepiandrosterone (DHEA) and 17 synthetic derivatives against herpes simplex type 1 (HSV-1) was determined. DHEA, epiandrosterone (EA), two synthetic DHEA analogs and three synthetic EA analogs showed a selective inhibitory effect on HSV in vitro multiplication. DHEA and E2, a synthetic derivative of EA, were not found to be virucidal to cell-free HSV-1 and did not impair virus adsorption or penetration. We determined that treatment with both compounds decreased viral protein synthesis. Moreover, inhibitory effect of DHEA and E2 on extracellular viral titer was stronger than the inhibition found on total viral infectivity, suggesting that the antiherpetic activity of these compounds may also be in part due to an inhibition in virus formation and release. Since DHEA is a known Raf/MEK/ERK signaling pathway activator, we studied the role of this pathway on HSV-1 infection. ERK1/2 phosphorylation was stimulated in HSV-1 infected cultures. UO126, a Raf/MEK/ERK signaling pathway inhibitor, impaired viral multiplication, while anisomycin, an activator of this pathway, enhanced it. Treatment with DHEA 6 h before infection enhanced HSV-1 multiplication. On the contrary, pre-treatment with E2, which does not modulate Raf/MEK/ERK signaling pathway, did not produce an increase of viral replication. Taking together these results, the antiviral activity of DHEA seems to occur via a mechanism independent of its ability to modulate ERK phosphorylation.
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24
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Borrego-Diaz E, Terai K, Lialyte K, Wise AL, Esfandyari T, Behbod F, Mautner VF, Spyra M, Taylor S, Parada LF, Upadhyaya M, Farassati F. Overactivation of Ras signaling pathway in CD133+ MPNST cells. J Neurooncol 2012; 108:423-34. [DOI: 10.1007/s11060-012-0852-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 03/13/2012] [Indexed: 01/06/2023]
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Filippakis H, Dimitropoulou P, Eliopoulos AG, Spandidos DA, Sourvinos G. The enhanced host-cell permissiveness of human cytomegalovirus is mediated by the Ras signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2011; 1813:1872-82. [PMID: 21782855 DOI: 10.1016/j.bbamcr.2011.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 07/08/2011] [Accepted: 07/08/2011] [Indexed: 12/14/2022]
Abstract
Human cytomegalovirus utilizes cellular signal transduction pathways to activate viral or cellular transcription factors involved in the control of viral gene expression and DNA replication. In the present study, we demonstrate that Harvey-ras-transformed cells show increased permissiveness to human cytomegalovirus when compared to their parental non-transformed cells. Both the progeny viral yield and the protein levels were elevated in the human cytomegalovirus-infected Harvey-ras-transformed cells requiring active viral gene replication, as shown by the infection with UV-inactivated human cytomegalovirus. Inhibition of Ras or of key molecules of the Ras pathway, effectively suppressed viral infection in the Harvey-ras-transformed cells. On a cellular level, the human cytomegalovirus-infected Harvey-ras-transformed cells formed larger cellular foci, which were significantly higher in number, compared to the uninfected cells and preferentially recruited human cytomegalovirus virions, thereby incriminating human cytomegalovirus infection for the increased transformation of these cells. Furthermore, proliferation assays revealed a higher rate for the human cytomegalovirus-infected Harvey-ras-transformed cells compared to mock-infected cells, whereas human cytomegalovirus infection had no considerable effect on the proliferation of the non-transformed cells. Higher susceptibility to apoptosis was also detected in the human cytomegalovirus-infected ras-transformed cells, which in combination with the higher progeny virus reveals a mode by which human cytomegalovirus achieves efficient spread of infection in the cells expressing the oncogenic Harvey-ras (12V) gene. Collectively, our data suggest that human cytomegalovirus employs the host-cell Ras signaling pathway to ensue viral expression and ultimately successful propagation. Transformed cells with an activated Ras signaling pathway are therefore particularly susceptible to human cytomegalovirus infection.
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Takaoka H, Takahashi G, Ogawa F, Imai T, Iwai S, Yura Y. A novel fusogenic herpes simplex virus for oncolytic virotherapy of squamous cell carcinoma. Virol J 2011; 8:294. [PMID: 21663640 PMCID: PMC3131258 DOI: 10.1186/1743-422x-8-294] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Accepted: 06/10/2011] [Indexed: 01/09/2023] Open
Abstract
Background R849 is a neurovirulent γ134.5 gene-deficient form of herpes simplex virus type 1 (HSV-1) and has LacZ genes at the deleted sites of the γ134.5 gene. HF is a spontaneously occurring, fusogenic HSV-1 strain. The purpose of this work was to generate a virus that has the syncytial character of HF, while preserving the γ134.5 gene inactivation profile of R849 virus. Results Vero cells were infected with R849 and HF simultaneously and two viruses, RH1 and RH2, expressing the LacZ gene and inducing extensive cell fusion were selected. A polymerase chain reaction (PCR)-based analysis suggested that one copy of the γ134.5 gene is lost in RH1, whereas both copies are lost in RH2, and that the γ134.5 gene is replaced by a R849-derived DNA fragment with the LacZ gene. These viruses produced larger plaques and more progeny than the parental viruses. Infection with RH2 decreased the viability of oral squamous cell carcinoma (SCC) cells most strongly. When RH2 was injected into xenografts of oral SCC in nude mice, multinucleated cells were produced and the growth of the tumors was suppressed significantly. Conclusion These results indicate that novel oncolytic HSV-1 vectors can be produced with the genetic background of the oncolytic HSV-1 HF, and that RH2 is deficient in γ134.5 genes and shows extensive cytopathic effects in oral SCC cells. RH2 may be useful in oncolytic virotherapy for oral SCC.
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Affiliation(s)
- Hiroo Takaoka
- Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
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Abstract
The mortality of colorectal carcinoma often results from the progression of metastatic disease, which is predominantly hepatic. Although recent advances in surgical, locoregional, and systemic therapies have yielded modest improvements in survival, treatment of these aggressive lesions is limited to palliation for the vast majority of patients. Oncolytic viral therapy represents a promising novel therapeutic modality that has achieved tumor regression in several preclinical and clinical models. Evidence further suggests that locoregional viral administration may improve viral efficacy while minimizing toxicity. This study will review the theories behind hepatic arterial infusion of oncolytic virus, as well as herpes viral design, preclinical data, and clinical progress in regional liver therapy using oncolytic virus to treat hepatic colorectal carcinoma metastases.
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Affiliation(s)
- Susanne G Carpenter
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Filippakis H, Spandidos DA, Sourvinos G. Herpesviruses: hijacking the Ras signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2010; 1803:777-85. [PMID: 20303365 DOI: 10.1016/j.bbamcr.2010.03.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2009] [Revised: 02/24/2010] [Accepted: 03/10/2010] [Indexed: 12/25/2022]
Abstract
Cancer is the final result of the accumulation of several genetic alterations occurring in a cell. Several herpesviruses and especially gamma-herpesviruses have played an important role in Cancer Biology, contributing significantly to our comprehension of cell signaling and growth control pathways which lead to malignancy. Unlike other infectious agents, herpesviruses persist in the host by establishing a latent infection, so that they can reactivate periodically. Interestingly, some herpesviruses are able to either deliver or induce the expression of cellular oncogenes. Such alterations can result in the derailment of the normal cell cycle and ultimately shift the balance between continuous proliferation and programmed cell death. Herpesvirus infection employs key molecules of cellular signaling cascades mostly to enhance viral replication. However, most of these molecules are also involved in essential cellular functions, such as proliferation, cellular differentiation and migration, as well as in DNA repair mechanisms. Ras proteins are key molecules that regulate a wide range of cellular functions, including differentiation, proliferation and cell survival. A broad field of medical research is currently focused on elucidating the role of ras oncogenes in human tumor initiation as well as tumor progression and metastasis. Upon activation, Ras proteins employ several downstream effector molecules such as phosphatidylinositol 3-kinase (PI3-K) and Raf and Ral guanine nucleotide-dissociation stimulators (RALGDS) to regulate a cascade of events ranging from cell proliferation and survival to apoptosis and cellular death. In this review, we give an overview of the impact that herpesvirus infection has on the host-cell Ras signaling pathway, providing an outline of their interactions with the key cascade molecules with which they associate. Several of these interactions of viral proteins with member of the Ras signaling pathway may be crucial in determining herpesviruses' oncogenic potential or their oncomodulatory behavior. The questions that emerge concern the potential role of these molecules as therapeutic targets both for viral infections and cancer. Understanding the means by which viruses may cause oncogenesis would therefore provide a deeper knowledge of the overall oncogenic process.
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Affiliation(s)
- Harilaos Filippakis
- Department of Clinical Virology, Faculty of Medicine, University of Crete, Heraklion 71003, Crete, Greece
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Wong HH, Lemoine NR, Wang Y. Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles. Viruses 2010; 2:78-106. [PMID: 20543907 PMCID: PMC2883714 DOI: 10.3390/v2010078] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2009] [Revised: 01/02/2010] [Accepted: 01/06/2010] [Indexed: 12/22/2022] Open
Abstract
Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.
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Affiliation(s)
- Han Hsi Wong
- Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; E-Mails: (H.H.W.); (N.R.L.)
| | - Nicholas R. Lemoine
- Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; E-Mails: (H.H.W.); (N.R.L.)
- Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou 450052, China
| | - Yaohe Wang
- Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; E-Mails: (H.H.W.); (N.R.L.)
- Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou 450052, China
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