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Adjudication committee
- First opponent: Professor Yuzhuo Wang, Department of Urologic Sciences, University of British Columbia, Canada
- Second opponent: Professor Johannes V. Swinnen, Laboratory of Lipid Metabolism and Cancer, KU Leuven, Belgium
- Third member and chair of the evaluation committee: Professor Lars Eide, Institute of Clinical Medicine, University of Oslo
Chair of defence
Professor II Therese Sørlie, Institute of Clinical Medicine, University of Oslo
Principal Supervisor
Professor II Kristin Austlid Taskén, Institute of Clinical Medicine, University of Oslo
Summary
Prostate cancer is the second leading cause of cancer-related death among Norwegian men. Metastatic prostate adenocarcinomas are primarily treated with androgen deprivation therapy (ADT). Although this treatment is initially effective in most patients, castration-resistant prostate cancer (CRPC) nearly always develops.
Resistance to ADT appears to be driven by molecular mechanisms driving reactivation of or enhanced androgen signaling. The treatment landscape of CRPC is rapidly changing and is associated with appearance of more clinically aggressive disease variants that often are indifferent to androgen signaling, such as neuroendocrine prostate cancer (NEPC). NEPC is likely preceded by neuroendocrine transdifferentiation (NEtD), a process induced by both ADT and β2-adrenergic receptor (ADRB2) signaling.
The aims of this thesis were to investigate the role of ADRB2 in development of therapy-resistant prostate cancer. Protein and mRNA levels of ADRB2 were associated with clinical endpoints across multiple cohorts. Preclinical model systems with varying ADRB2 expression levels were challenged with androgen-targeted therapies to unravel the functional involvement of ADRB2 in development of therapy resistance.
We showed that tumors with low pre-treatment ADRB2 levels resisted androgen-targeted therapy through better retaining androgen levels. Low-ADRB2 tumors were unable to undergo ADT-induced NEtD and represent a model for androgen-driven CRPC adenocarcinoma. ADRB2 was shown to be essential for ADT-induced NEtD, which suggests that high-ADRB2 tumors are more likely to develop aggressive, androgen-indifferent prostate cancers like NEPC.
In keeping with the pivotal role of sympathetic nerves in prostate cancer, and epidemiological studies showing a benefit of β-adrenergic receptor blockade, the presented findings suggest that targeting ADRB2 signaling is a promising therapeutic strategy in the management of advanced prostate cancer.
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