Hide metadata

dc.date.accessioned2020-02-28T17:10:32Z
dc.date.available2020-02-28T17:10:32Z
dc.date.issued2020
dc.identifier.urihttp://hdl.handle.net/10852/73459
dc.description.abstractProstate 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.en_US
dc.language.isoenen_US
dc.relation.haspartPaper I. Braadland PR, Grytli HH, Ramberg H, Katz B, Kellman R, Gauthier-Landry L, Fazli L, Krobert KA, Wang W, Levy FO, Bjartell A, Berge V, Rennie PS, Mellgren G, Mælandsmo GM, Svindland A, Barbier O, Taskén KA: Low ß2-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism. Oncotarget 2016; 7:1878-1894. DOI: 10.18632/oncotarget.6479. The article is included in the thesis. Also available in DUO http://urn.nb.no/URN:NBN:no-54705
dc.relation.haspartPaper II. Braadland PR, Ramberg H, Grytli HH, Urbanucci A, Nielsen HK, Guldvik IJ, Engedal A, Ketola K, Wang W, Svindland A, Mills IG, Bjartell A, Taskén KA: The ß2-adrenergic receptor is a molecular switch for neuroendocrine transdifferentiation of prostate cancer cells. Mol Can Res 2019; DOI: 10.1158/1541-7786.MCR-18-0605. Published November 2019. The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1158/1541-7786.MCR-18-0605
dc.relation.haspartPaper III. Braadland PR, Sivanesan S, Grytli HH, Ramberg H, Guldvik IJ, Katz B, Gemma, Berge V, Taskén KA: Bicalutamide treatment in hormone-naïve prostate cancer associates with crossresistance to androgen deprivation therapy (Manuscript). To be published. The paper is not available in DUO awaiting publishing.
dc.relation.urihttp://urn.nb.no/URN:NBN:no-54705
dc.relation.urihttps://doi.org/10.1158/1541-7786.MCR-18-0605
dc.titleTargeting therapy resistance in advanced prostate canceren_US
dc.typeDoctoral thesisen_US
dc.creator.authorBraadland, Peder Rustøen
dc.identifier.urnURN:NBN:no-76574
dc.type.documentDoktoravhandlingen_US
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/73459/1/PhD-Braadland-2020.pdf


Files in this item

Appears in the following Collection

Hide metadata