Pazopanib, a drug that targets a class of genes known as ‘kinases’, was recently approved for the treatment of advanced sarcoma. While some patients respond well to pazopanib, the drug does not work in all cases, meaning that some patients are exposed to the potential side effects of the treatment for little or no benefit. At present, it is challenging to predict who will respond to pazopanib, and it would be helpful to find tumour markers that enable doctors to identify the right patients to administer the drug. Furthermore, because it is unknown as to why some patients do not respond to pazopanib, there is no rational basis for selecting alternative treatments in such cases. Data from other cancer types suggest that kinase drug therapy ‘rewires’ the cellular communication machinery in cancer cells to drive drug resistance.
In this project, the team proposed to identify these 'rewiring’ events as potential targets for the treatment of sarcomas. Using a tool known as mass spectrometry, they will map the cellular communication machinery activated in sarcoma cell lines of different types. By assessing how this ‘rewiring’ maps from different sarcoma cells using computational methods, they can determine which cellular components are commonly found in resistant cells and are responsible for conferring drug resistance. The data from this project will be used as a starting point for further research.
This research will not only provide a molecular portrait of sarcoma biology, but also result in the identification of predictive markers to identify patients who are likely to benefit from pazopanib treatment. Additionally, gaining an understanding of the ‘rewiring’ events in sarcoma cells that are resistant to pazopanib, will provide a starting point for the rational selection of alternative treatment for patients who do not respond to the drug.
End of Project Summary
Pazopanib is a drug that is approved for the treatment of advanced sarcoma. We do not fully understand why some patients do not respond to this drug. This project sought to understand the cellular communication machinery in tumour cells that drive drug resistance or sensitivity in patients. In this project, we used a tool known as mass spectrometry to identify specific proteins in sarcoma cell lines that confer sensitivity to pazopanib. We further identify sarcoma subtypes that are particularly sensitive to the treatment with pazopanib. Our work will provide a starting point for new clinical trials for pazopanib in selected patient populations which will lead to better outcomes and personalised medicine in this class of complex diseases.
This project is now completed and we will not be pursuing further laboratory work. We are focused on publishing this work in 2016 to facilitate future clinical trials evaluating pazopanib in MRT patients.
Mutations identified in this work are found in ~20% of cancers. Based on our results, we have applied for a grant to look at drug targets lung cancer. We have received funding of £50,000 from the Lung Cancer Research Foundation in Oct 2015 to pursue this follow-on work.
- Wong, J.P. et al. (2016) Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors. Cell Reports, 17(5). Read more: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098123/
- Vyse, S. et al. (2018) Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib. Journal of Proteomics, 170. Read more: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673060/
Presentations & Workshops
- Huang, P. Pazopanib resistance: why does it happen? Presentation given at Sarcoma UK’s Talking Research day. June, 2015. Manchester, UK.
- Huang, P. Mechanisms of pazopanib resistance. Presentation given at Sarcoma UK’s Sarcoma Research Symposium (Basic Science). September, 2016. London, UK.