Identification of novel mechanisms driving the development of metastatic, castration resistant prostate cancer (mCRPC)

Prostate cancer is the most common male cancer1. It is normally treated with androgen deprivation therapy but at its final stage, it becomes resistant to it 2. This final stage is known as metastatic, castration resistant prostate cancer (mCRPC) and it accounts for the majority of deaths related to prostate cancer3. This project aims to identify novel mechanism by which mCRPC develops using bioinformatics and wet lab approaches. The first step of the project will be to identify proteins that differ in abundance between naïve and resistant cancer. To do so, patients' data sets will be obtained from publicly available data bases and the proteins that differ in abundance between those data sets will be identified. Next, various algorithms will be used to identify to which pathways these proteins belong to. Proteins of particular interest will be those involved in crosstalk between tumour cells and macrophages. It is because macrophages are known to drive tumour resistance and metastasis4. The next step will be to test whether the identified proteins really contribute to the development of resistance. To do so, the genes encoding them will be knocked out one by one in prostate cancer cell culture using CRISPR. Next it will be tested, also in cell culture, whether existing inhibitors can stop these proteins form contributing to resistance. If the novel mechanisms leading to the development of resistance in prostate cancer are successfully identified, the next stage of the project will be to identify such mechanisms in breast cancer. Similarly, as in prostate cancer, proteins involved in interaction between macrophages and tumour cell will be of particular interest. The identified mechanisms driving the development of resistance could be used as novel drug targets.

References
1. Rawla, P. Epidemiology of Prostate Cancer. World J. Oncol. 10, 63-89 (2019).
2. Iglesias-Gato, D. et al. The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications. Clin. Cancer Res. 24, 5433 LP - 5444 (2018).
3. Semenas, J., Dizeyi, N. & Persson, J. L. Enzalutamide as a second generation antiandrogen for treatment of advanced prostate cancer. Drug Des. Devel. Ther. 7, 875-881 (2013).
4. Nielsen, S. R. & Schmid, M. C. Macrophages as Key Drivers of Cancer Progression and Metastasis. Mediators Inflamm. 2017, 9624760 (2017).