- Title
- Low pathogenic human enteroviruses as novel anti-cancer agents against malignant glioma
- Creator
- Chan, Eric
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2014
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Malignant gliomas (MGs) are the most common tumours of the central nervous system (CNS) and respond poorly to surgery, radiotherapy and chemotherapy. Despite conven- tional therapy, this disease is fatal within 1 to 2 years of the onset of symptoms. Preclinical studies have shown that low pathogenic human enteroviruses such as Coxsackievirus A21 (CVA21), CVA21-DAFv and Echovirus 1 (EV1) possess anti-cancer (oncolytic) potential against many different tumours, including melanoma, multiple myeloma, breast, prostate, gastric and ovarian cancer. The selective targeting of CVA21, CVA21-DAFv and EV1 is based on the overexpression of the cellular receptors intercellular adhesion molecule- 1 (ICAM-1), decay accelerating factor (DAF) and integrin α2β1 on the surface of many cancer cells compared to normal cells. The employment of CVA21 to control cancer progression is currently under Phase I/II clinical trials for the treatment of melanoma, breast, bladder, prostate and lung cancer. The bioselected variant of CVA21 (CVA21-DAFv) is an enhanced DAF-using phenotype, compared to the parental CVA21 strain which utilizes ICAM-1 and/or DAF. Moreover, EV1 infection requires the cell surface expression of integrin α2β1, enabling binding of the viral capsid, internalization, and subsequent lytic infection. Prior to the study of the potential use of these enteroviruses for the treatment of MG, screening for these such cellular receptors was performed by confirming mRNA gene expression profiles of ICAM-1, DAF and integrin α2β1 in cancerous brain tissues, in comparison to normal brain tissue biopsy material. The presence of these cellular receptors on the surface of glioma cells was also assessed using flow cytometry and immunohistochemical (IHC) staining. The in vitro screening to evaluate the oncolytic capacity of enteroviruses was subsequently performed in a range of established glioma cell lines (U87 MG, A172, T98G, U118 and GBM6) and normal brain cells (HCN-2). To further investigate the role of CVA21 or CVA21-DAFv in the treatment of MG, an orthotopic model of MG was established in athymic nude mice. To evaluate the efficacy of CVA21 or CVA21-DAFv as a single agent, mice bearing intracranial (i.c.) U87 MG-luc tumours were administered with either viruses. Mice were initially injected with a single administration into the tumour and subsequent intravenous (i.v.) doses of either viruses. In vivo, both CVA21 and CVA21-DAFv significantly reduced tumour growth early on in the study, but tumours eventually recurred. Given that oncolytic viruses may be used in the clinic together with existing treatment modalities such as chemotherapy, the combinatorial effects of human enteroviruses with a panel of standard of care chemotherapeutic agents [including temozolomide (TMZ), cyclophosphamide (CPA) and carboplatin (Cb)] were examined. The effects of these chemotherapeutic agents on human enterovirus oncolysis and viral replication were assessed in vitro to identify synergistic, additive or antagonistic activities. In vivo, the combination of either TMZ or CPA with CVA21 improved the survival of mice, delayed tumour growth and caused complete tumour regressions in some mice bearing i.c. U118-luc or U87 MG-luc xenografts. In all three in vivo studies performed, it was observed that modest levels of neutralizing antibodies (nAbs) against CVA21 developed within seven days post virus treatment and at the same time, circulating levels of CVA21 in the serum dropped to undetectable levels. Nonetheless, the combination of CPA with CVA21 not only inhibited tumour growth, but also managed to “blunt” nAb production and allow circulating levels of CVA21 to remain in mice for two consecutive weeks. Taken together, the results of these studies provide evidence to support further clinical evaluation of these novel anti-cancer agents to treat MG patients.
- Subject
- oncolytic virotherapy; malignant glioma; chemotherapy
- Identifier
- http://hdl.handle.net/1959.13/1050162
- Identifier
- uon:15125
- Rights
- Copyright 2014 Eric Chan
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT02 | Thesis | 11 MB | Adobe Acrobat PDF | View Details Download |