While initial treatment for prostate cancer targets male hormones called androgens, cancer cells can become insensitive to these drugs, leading to the development of castration-resistant prostate cancer. This form of the disease is more aggressive and difficult to treat, and current therapies that target the androgen receptor, such as abiraterone and enzalutamide, have limited efficacy due to inherent and acquired resistance.
In the four studies forming Taavitsainen’s doctoral thesis, high-throughput sequencing data was analyzed to investigate mechanisms through which prostate cancer cells become resistant to current therapies. The studies were completed as an international collaboration between scientists at Tampere University and, among others, the University of Eastern Finland, Oslo University Hospital, and Vancouver Prostate Centre.
Using data from a clinical trial conducted in Canada, Taavitsainen and colleagues investigated the mechanisms of cross-resistance to castration-resistant prostate cancer treatments abiraterone and enzalutamide using samples of cell-free DNA released by cancer cells into the bloodstream. These so-called liquid biopsies allow repeated assessment of the status of a patient’s disease at different timepoints based on blood testing alone but require highly sensitive computational methods to detect and analyze the tumour-derived DNA in the patient’s circulation. The study showed that the androgen receptor continues to play a central role even after being targeted by multiple therapies, suggesting that a renewed targeting of the androgen receptor pathway may still benefit patients who have already received treatment for their cancer.
Through the analysis of liquid biopsies, in another study, Taavitsainen and colleagues were also able to propose a molecular mechanism behind mutations in the FOXA1 gene, frequently observed in patients suffering from castration-resistant prostate cancer.
The thesis also introduces a method called Differential Subclone Eradication and Resistance Analysis (DSER) to identify molecular targets for improved therapy in prostate cancer by comparing genomic and epigenomic changes in cancer cells that are eradicated by and resistant to treatment. The method was tested on a set of tumour samples from a patient with metastatic prostate cancer and identified changes in the DNA repair genes FANCI and EYA4 in his eradicated cancer cells that may have sensitized them to chemotherapy. With the aim of studying resistance mechanisms against enzalutamide in even more fine-grained detail, Taavitsainen and colleagues also utilized single-cell sequencing techniques in pre-clinical models. The research revealed gene expression profiles associated with pre-existing and persistent cell subpopulations, which could be used to stratify the treatment responses of prostate cancer patients.
The thesis concludes that the computational analysis of genomic, transcriptomic, and epigenomic cancer cell profiles can reveal cell populations involved in treatment resistance and provide mechanistic insights into the differential behaviour of cells in response to therapy. The study's findings contribute to knowledge on how to better treat each patient's unique prostate cancer, ultimately aiming at improving patient outcomes.
“Each tumour follows a unique evolutionary path, rendering them susceptible to different treatments. By understanding this heterogeneity and analyzing the subclones constituting a patient’s cancer, we can ensure that each patient gets the treatment or combination of treatments that targets the specific weak spots of their prostate cancer,” Sinja Taavitsainen says.
Taavitsainen performed her doctoral research in the Computational Biology Research Group at Tampere University.
Public defence on Friday 19 May 2023
The doctoral dissertation of MSc Sinja Taavitsainen in the field of bioinformatics, Computational Analysis of Treatment Resistance in Prostate Cancer, will be publicly examined at the Faculty of Medicine and Health Technology of Tampere University at 12 o’clock on Friday 19 May, 2023 in the auditorium F114, Arvo building, Arvo Ylpön katu 34, Tampere. Associate Professor Joachim Weischenfeldt from the University of Copenhagen will be the opponent, while Professor Matti Nykter from the Faculty of Medicine and Health Technology will act as the custos.
The doctoral dissertation is available online.
The public defence can be followed via remote connection.