Abstract
Prostate cancer (PCa) is a highly prevalent malignancy among men. In its early stages, diagnosed PCa has a quite good prognosis and responds well to first-line therapeutic interventions such as androgen deprivation therapy (ADT). However, despite initial responses to ADT, many PCa patients develop resistance over time and therefore this necessitates novel innovative therapeutic strategies. This cumulative dissertation investigates various aspects of PCa and potential new treatment options by focusing on metabolic vulnerabilities, drug combinations, the potential of dietary intervention as well as mitochondrial markers of PCa progression.
For developing effective treatments, it is crucial to understand the metabolic dependencies of different PCa subtypes. In the first chapter, we therefore examined the metabolic phenotype of different PCa cell lines. We found that androgen-sensitive PCa cells specifically rely on oxidative phosphorylation (OXPHOS) for energy production. This metabolic reliance on OXPHOS could be targeted with the mitochondrial complex I inhibitor IACS-10759 (“IACS”). Moreover, IACS showed high synergy with the androgen receptor antagonist apalutamide (ARN) by decreasing cell proliferation significantly. In addition, androgen-independent cells could be sensitized to IACS through forcing OXPHOS by depleting glucose levels.
In a next step, we transitioned to an in vivo mouse model to investigate the role of autophagy in PCa tumors (chapter II). Autophagy is a survival mechanism that could lead to treatment resistance. By combining the autophagy inhibitor Chloroquine with ARN, we could demonstrate a reduction in tumor weight and important autophagy markers. This combination therapy suggests a promising approach for anticancer therapy in PCa patients.
To elucidate further on the role of mitochondria in PCa treated with ARN and IACS, we studied mitochondrial dynamics in chapter III. Treatment with ARN and IACS induced significant changes in mitochondrial morphology and modulated fission and fusion processes. In addition, this treatment approach led to increased apoptotic cell death and increased oxidative stress in androgen-sensitive PCa cells.
In chapter IV, we investigated whether a ketogenic diet (KD) could potentially sensitize the effect of combined ARN and IACS treatment in a mouse xenograft model. KD was able to significantly reduce blood glucose levels, increase ketone bodies and when combined with ARN and IACS reduce tumor growth. Since IACS has been shown to potentially induce peripheral neuropathy in patients, we additionally investigated whether KD could alleviate these effects. KD appeared to mitigate IACS-induced toxic effects in the sciatic nerves of mice.
Finally, in chapter V, we assessed the expression levels of mitochondrial markers TOM20 (a marker for mitochondrial mass), DRP1 (mitochondrial fission) and OPA1 (mitochondrial fusion). These proteins were investigated in benign and malignant PCa tissues derived from patients at the University Hospital Zurich. Our aim was to evaluate whether there is an association between these markers and advanced PCa. We found that these markers if strongly expressed were significantly higher in advanced and metastatic tissues compared to benign controls. However, these markers did not show prognostic value in our survival analysis. Nonetheless, their strong association with PCa aggressiveness shows their important role in PCa progression.
Altogether, these studies collectively advance the understanding of mitochondrial function in PCa progression and propose novel approaches for targeting metabolic pathways to ultimately overcome treatment resistance mechanisms and improve patient outcomes.
Baumgartner, Valentin