- Title
- Investigation of oncolytic coxsackievirus A21 as a potential treatment for lung cancer
- Creator
- Wong, Yvonne Vern Yee
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2016
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Lung cancer is the most frequently diagnosed and the second most common mortalityrelated cancer in the world, with the majority of cases diagnosed only at an advanced/late stage. Lung cancer is a complex malignant disease with numerous histological subtypes classified into two main categories, namely non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Conventional therapies, including surgery, radiation therapy and chemotherapy have yielded limited success in the treatment of lung cancer, especially in cases involving metastatic spread. Lung cancer is a difficult cancer to treat as it is a highly metastatic disease and consists of two main differing phenotypes which require differing treatment regimens. Therefore, there is the crucial need to develop new therapeutic strategies against this cancer type. Oncolytic virotherapy, a rapidly growing field in which a broad range of viruses have been developed to specifically attack and target cancer cells, is one of the few novel approaches for the treatment of lung cancer. Among the various viruses used in oncolytic virotherapy, of particular focus is Coxsackievirus A21 (CVA21), a wild-type naturally occurring positive-sense single stranded RNA human enterovirus that demonstrated potent oncolytic effects against a range of cancer types such as melanoma, breast, prostate, glioma, multiple myeloma, pancreatic, and bladder carcinoma. CVA21 selectively targets and lytically infects susceptible cancer cells that overexpress the viral cellular receptors, intercellular adhesion molecule-1 (ICAM-1) and/or decay accelerating factor (DAF). In this dissertation, CVA21 is shown to be an effective oncolytic agent against lung cancer, particularly of the NSCLC phenotype. A proprietary formulation of CVA21 (commercial trade name CAVATATM) is currently being evaluated in several Phase I and II clinical trials across a variety of cancer indications. Previous trials of CVA21 for the treatment of malignant melanoma have shown that it is generally well-tolerated in patients. The oncolytic efficacy of CVA21 against lung cancer was further investigated as either a single agent therapy or in combination with chemotherapy, in particular the current standard of care agent, docetaxel. Until the introduction of docetaxel (Taxotere®, Sanofi-aventis, Paris, France), a semisynthetic taxane drug, no previous chemotherapeutic agents displayed significant improvement in survival or quality of life in randomised trials of second-line treatment of advanced or metastatic NSCLC. Docetaxel was the first chemotherapeutic agent to show efficacy by increasing the survival and quality of life in lung cancer patients when given as a single agent first- and second-line treatment, and as a first-line in platinumbased doublet therapy. Docetaxel works by primarily stimulating microtubule assembly and polymerisation, leading ultimately to cell cycle arrest and death. Through the hyperstabilisation of growing microtubules, the drug upsets the equilibrium between tubulin composition and disintegration, leading to the deterioration of mitosis and the eventual arrest of the cell cycle. Clinically, the use of CVA21 in combination with current standard chemotherapeutics may be a more effective method for destroying lung cancer cells than with single agents administered as monotherapies. Novel findings from this thesis support this combination treatment approach, demonstrating the enhancement of CVA21 efficacy via combination with the chemotherapeutic agent, docetaxel.
- Subject
- oncolytic coxsackievirus A21; lung cancer; mortalityrelated cancer; oncolytic virotherapy
- Identifier
- http://hdl.handle.net/1959.13/1314627
- Identifier
- uon:22791
- Rights
- Copyright 2016 Yvonne Vern Yee Wong
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 26 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 1 MB | Adobe Acrobat PDF | View Details Download |