Improving platinum-based chemotherapy by targeting drug metabolism in lung cancer

Overview

Lung cancer is the deadliest cancer accounting for 18.4% of all cancer-related deaths. Platinum-based chemotherapy remains a key treatment option for most people living with this disease, either as adjuvant therapy or in combination with immunotherapy. However, resistance to therapy is a significant issue in the treatment of lung cancer. Novel therapeutic strategies combined with predictive biomarkers chemotherapy response are needed to transform the clinical management of NSCLC.

Our published work has identified novel biomarkers and druggable proteins from deregulated protein networks that are involved in the cellular response to chemotherapy [1]. One key mechanism is the activation of chemotherapy-induced xenobiotic/drug metabolism. We identified that the drug metabolism enzyme ALDH3A1 is significantly upregulated by platinum agents and has druggable potential. Activity of ALDH3A1, as an aldehyde dehydrogenase enzyme, is increased following platinum-based chemotherapy, suggesting that this enzyme can metabolise cytotoxic aldehydes and confer resistance to platinum agents.

Our current work warrants further investigation into ALDH3A1 as potential druggable target to improve the chemotherapeutic response in lung cancer.

References

1. Ryan, S.-L., et al., Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer. Frontiers in Oncology, 2021. 11(241).

Hypothesis and aims

We hypothesise that combining ALDH3A1 inhibitors with chemotherapy will improve the effectiveness of platinum agents in lung tumours. The project aims are:

1. To identify optimal compounds that inhibit recombinant and cellular ALDH3A1 activity.
2. Characterise cellular impact of ALDH3A1 inhibition on lung cancer biology.
3. Determine the additive or synergistic effect of combining ALDH3A1 inhibitors with platinum-based chemotherapy.

Research activities

Skills and techniques you will develop and master over the course of the project include:

• in vitro recombinant protein assays
• cellular enzyme activity assays
• 2D and 3D mammalian cell culture systems including drug treatments and transfections (e.g. ALDH3A1 knockdown with siRNA)
• cell survival (dose response) and proliferation assays
• western blot analysis
• high content immunofluorescence imaging and quantification
• short term ex vivo culture and drug treatment of lung tumours
• immunohistochemistry and quantification of stained tissue.

Outcomes

Our ongoing work has identified 10 compounds that target ALDH3A1. We expect that at least one of these compounds will inhibit the in vitro and ex vivo activity of ALDH3A1. We also expect that strategies to block drug metabolism, perhaps via inhibiting enzymes such as ALDH3A1, will improve the effectiveness of chemotherapy in lung tumours.

Skills and experience

There are no required skills for this project other than to be curious and have an interest in cancer biology. By undertaking this project, you will develop a broad skillset and knowledge base.

Scholarships

You may be eligible to apply for a research scholarship.

Explore our research scholarships

Keywords

• lung cancer
• cisplatin
• platinum-based chemotherapy
• therapeutic targets
• aldehyde dehydrogenase

Contact

Contact Dr Mark Adams for more information.