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Cellular mechanisms of taxane therapy in castration resistant prostate cancer

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Author

Summary, in English

Chemotherapy of castration resistant prostate cancer (CRPC) is based on taxane formulations worldwide. Only 30-50 % of patients respond to this therapy and the exact cellular mechanisms of taxane resistance in PC cells are not fully elucidated. There is convincing evidence that androgen receptor (AR) is affected by exposure to these compounds. The studies presented in this doctoral thesis identify c-jun, a proto-oncogene as a crucial key player which interacts with AR and thus determines the outcome of taxane therapy. We show that AR and c-jun physically interact on protein and gene level and this interaction is taxane specific. This results in different expression levels of AR regulated genes evidenced in alterations of PSA, KLK2 and NKX3.1 in a castration resistant cell model. Sustained downregulation of c-jun results in a significant increased efficacy of taxane therapy confirming that c-jun acts as a potent antiapoptotic factor. A major drawback of taxane compound is also their ability to reach the tumor cells in sufficient concentration. Studies performed in a xenograft model showed that a novel liquid crystal nanoparticle formulation of docetaxel (LNCP/docetaxel) more efficiently decreased tumor size with less side effects than the commercially available docetaxel. Taken together, our stydies identify c-jun as a key regulator of taxnae therapy. Targeting c-jun in combination with taxane treatment may increase efficacy of chemotherapy in future.

Department/s

  • Urological research, Malmö

Publishing year

2014

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

119

Document type

Dissertation

Publisher

Division of urological research

Topic

  • Urology and Nephrology

Keywords

  • Prostate cancer
  • chemotherapy
  • taxane
  • c-jun
  • androgen receptor
  • PSA

Status

Published

Research group

  • Urological research, Malmö

Supervisor

  • Per-Anders Abrahamsson
  • Nishtman Dizeyi

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-7619-048-7

Defence date

8 November 2014

Defence time

09:00

Defence place

CRC Aula, Jan Waldenströmsgata 35, Skånes Universitetssjukhus i Malmö.

Opponent

  • Jenster Guido (Prof)