- Title
- Investigating the development of new treatments for lung cancer
- Creator
- Pickles, Sophie May
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Lung cancer (LC) is the fifth most common cancer diagnosed in Australia, and the leading cause of cancer-related death. LC can be classified into two subtypes, the most common of which is non-small cell lung cancer (NSCLC) that accounts for 83% of all newly diagnosed LC. The main risk factor for LC development is the inhalation of cigarette smoke (CS). Despite recent advancements in therapeutic options including targeted therapy, the 5-year survival rate for NSCLC is low at ~19%. Deregulation of cellular energetics and the avoidance of immune destruction are two hallmark features of lung cancer that may provide therapeutic targets, against which we can develop novel therapies. Our group has established several novel short-term mouse models of NNK and CS-induced NSCLC, whereby NNK is administered before or after a period of nose-only CS exposure followed by a period of air rest. These recapitulate the progression of LC similar to that observed in humans and are therefore valuable models for therapeutic studies. Hypothesis and Aims: We hypothesised that metabolic and immune pathways may be altered and can be targeted with novel and/or repurposed drugs to provide new treatment options for patients with NSCLC. To test this, the following pathways and novel and/or repurposed treatments were assessed for involvement and efficacy in NNK and CS-induced NSCLC; oxidative stress and mitochondria targeted H2S donors (AP39, RT01), immunometabolic changes and metformin and 2-deoxy-D-glucose (2DG), and inflammasomes and a specific NLRP3 inflammasome inhibitor (MCC950). Methods: Three models of NNK and CS-induced NSCLC were used throughout these studies. NNK was administered before or after CS and in one model NNK was administered alone. Treatments were administered throughout the air rest periods of the models, where tumour multiplicity is known to increase, to assess for therapeutic efficacy. On the day of the endpoint, mice were anaesthetised, and lung function parameters assessed, BALF was collected to examine airway inflammation followed by tumour dissection from the lungs. Lungs and tumours were analysed via histology and molecular assays. Results: Systemic administration of mitochondria targeted H2S donors, AP39 and RT01, showed no decrease in tumour incidence, multiplicity, or burden in NSCLC. However, systemic AP39 treatment reduced mRNA expression of oxidative stress markers, Gstp1 and Ho1 in lung tumours. There was no change in tumour incidence or burden with local AP39 and RT01 treatment and interestingly, local RT01 treatment increased tumour multiplicity. Local AP39 and RT01 treatment reduced mRNA expression of oxidative stress marker, Gclc in lung non-tumour tissue. Systemic AP39 and RT01 treatment increased levels of oxidative stress marker 4-Hydroxynonenal (4-HNE) in the lung, however, local treatment did not increase 4-HNE levels. Metformin and 2DG combination therapy significantly reduced airway inflammation, however, did not alter tumour incidence, multiplicity, or burden. Metformin and 2DG combination treatment increased mRNA expression of oxidative stress markers Gstp1 and Nqo1 in lung non-tumour tissue and decreased 3-nitrotyrosine levels in the lung. MCC950, a specific NLRP3 inflammasome inhibitor, reduced levels of active caspase-1 in the lung. MCC950 significantly increased tumour multiplicity and burden compared to controls in NNKinduced NSCLC. Conclusion: Results suggest that AP39, RT01, metformin and 2DG have potential to prevent the development of LC, as these agents show promising results including reduction of oxidative stress and airway inflammation. Reducing oxidative stress and inflammation in the lung leads to a less tumorigenic environment. These agents could also be effective adjunctive therapies, as reduction in oxidative stress can increase sensitivity to existing chemotherapeutic options. MCC950 and inhibition of NLRP3 inflammasomes to treat NSCLC requires further investigation and currently does not pose a viable therapeutic option for NSCLC.
- Subject
- lung cancer; treatment; non-small cell lung cancer (NSCLC); therapies
- Identifier
- http://hdl.handle.net/1959.13/1483934
- Identifier
- uon:51233
- Rights
- Copyright 2021 Sophie May Pickles
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 17 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 359 KB | Adobe Acrobat PDF | View Details Download |