Purpose and aims

One main aim of this project is to test Phase-II drugs on different cancer cell lines to explore drug-modulated pathways and thereby identify biomarkers for new companion diagnostic tests. The work will mainly be performed using a mass spectrometry (MS) phosphoproteomics platform.

Cancer kills approximately 10 million people worldwide each year1. Tumor growth and metastasis can be treated by inhibiting specific enzymes that play important roles in cellular signaling pathways. Many of these pathways are regulated by kinases and phosphatases, enzymes that control protein phosphorylation2-3. The development of drugs that target key pathway regulating kinases (e.g. Trastuzumab for HER2 in breast cancer 4) is a powerful strategy to fight the disease5-6. However, cancer is known for its potential to mutate with potential to acquire immunity to the treatment. Therefore, it is essential to assess which drugs would be more efficient for each patient prior treatment.

Thanks to advances in mass spectrometry, researchers have been able to identify a large number of dysregulated phosphorylation signaling pathways that represent potential therapeutic targets6. This proposed study aims at implementing an MS-based phosphoproteomics predictive biomarker platform for effective drug assignment to cancer patients. Other aims include applying the MS-based phosphoprotoemic approach to other scientific questions and projects, specifically to a panel of preclinical ovarian cancer cell line models.

This project collaborates with Acrivon AB which will provide the cell lines and perform the drug-treatment experiments. The Phase-II drugs have been developed by Acrivon Therapeutics and are anticipated to affect cellular signaling in cancer cells from which MS-based phosphoproteome profiling experiments will be carried out to screen for significantly altered phosphorylation-regulated pathways that would indicate positive reaction to the treatment.

References

1. Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021.
2. Taylor, S. S.; Kornev, A. P., Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem Sci 2011,36 (2), 65-77.
3. Meharena, H. S.; Fan, X.; Ahuja, L. G.; Keshwani, M. M.; McClendon, C. L.; Chen, A. M.; Adams, J. A.; Taylor, S. S., Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases. PLoS Biol 2016,14 (11), e2000127.
4. Sawyers, C. L., Herceptin: A First Assault on Oncogenes that Launched a Revolution. Cell 2019,179 (1), 8-12.
5. Gonzalez de Castro, D.; Clarke, P. A.; Al-Lazikani, B.; Workman, P., Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance. Clin Pharmacol Ther 2013,93 (3), 252-9.
6. Deb, B.; George, I. A.; Sharma, J.; Kumar, P., Phosphoproteomics Profiling to Identify Altered Signaling Pathways and Kinase-Targeted Cancer Therapies. Methods Mol Biol 2020,2051, 241-264.