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STAT3 in Prostate Cancer

Don-Doncow, Nicholas LU (2017)
Abstract
Prostate cancer is the second most common diagnosed cancer among men. Currently there are no reliable
biomarkers to distinguish between indolent and aggressive disease. When men progress to advanced stages of the disease treatment options are limited and resistance to treatments available today is a growing problem. Recently the signal transducer and activator of transcription 3 (STAT3) has been suggested as both a potential target for treatment, and a biomarker in advanced prostate cancer.
In this work we explored the potential of activated STAT3 (pSTAT3) as a tissue biomarker in two different cohorts. We also investigated the mechanism of action of the STAT3 inhibitor galiellalactone as well as its effect in combination... (More)
Prostate cancer is the second most common diagnosed cancer among men. Currently there are no reliable
biomarkers to distinguish between indolent and aggressive disease. When men progress to advanced stages of the disease treatment options are limited and resistance to treatments available today is a growing problem. Recently the signal transducer and activator of transcription 3 (STAT3) has been suggested as both a potential target for treatment, and a biomarker in advanced prostate cancer.
In this work we explored the potential of activated STAT3 (pSTAT3) as a tissue biomarker in two different cohorts. We also investigated the mechanism of action of the STAT3 inhibitor galiellalactone as well as its effect in combination treatments with chemotherapeutic agent docetaxel.
In a rapid autopsy cohort of patients that have died of metastatic prostate cancer we found that expression of pSTAT3 was present in all metastases, with highest expression in the bone, likely an effect of the tumor microenvironment. A second cohort of hormone naïve patients with localized prostate cancer showed that pSTAT3 expression was higher in benign tissue compared with tumor tissue. Lower pSTAT3 expression in tumor cells was predictive of shorter time to recurrent disease. These two cohorts suggest that targeting pSTAT3 would be valuable at later stages of the disease.
We also investigated galiellalactone, a natural fungal compound, and its mechanism of action in inhibiting STAT3. We found that galiellalactone binds directly to STAT3, thus blocking the ability of STAT3 to bind to DNA. When galiellalactone was used in combination with docetaxel it was able to produce a synergistic inhibitory effect, which was likely due to the observed downregulation of genes involved in docetaxel resistance.
In conclusion, our results suggest that STAT3 is a promising treatment target in late stage prostate cancer and may lead to benefit when used in combination with docetaxel. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Leung, Hing, Institute of Cancer Sciences, University of Glasgow, United Kingdom
organization
publishing date
type
Thesis
publication status
published
subject
keywords
prostate cancer, STAT3, biomarker, Immunohistochemestry, Drug Resistance
pages
79 pages
publisher
Lund University, Faculty of Medicine
defense location
Lilla Aulan, Jan Waldenströms gata 5, ing 59, Skånes Universitetssjukhus i Malmö.
defense date
2017-02-02 13:00
ISBN
978-91-7619-400-3
language
English
LU publication?
yes
id
20f55aaa-cf3c-4a42-b172-9d12660db230
date added to LUP
2017-01-13 15:01:03
date last changed
2017-01-16 13:24:46
@phdthesis{20f55aaa-cf3c-4a42-b172-9d12660db230,
  abstract     = {Prostate cancer is the second most common diagnosed cancer among men. Currently there are no reliable<br/>biomarkers to distinguish between indolent and aggressive disease. When men progress to advanced stages of the disease treatment options are limited and resistance to treatments available today is a growing problem. Recently the signal transducer and activator of transcription 3 (STAT3) has been suggested as both a potential target for treatment, and a biomarker in advanced prostate cancer.<br/>In this work we explored the potential of activated STAT3 (pSTAT3) as a tissue biomarker in two different cohorts. We also investigated the mechanism of action of the STAT3 inhibitor galiellalactone as well as its effect in combination treatments with chemotherapeutic agent docetaxel.<br/>In a rapid autopsy cohort of patients that have died of metastatic prostate cancer we found that expression of pSTAT3 was present in all metastases, with highest expression in the bone, likely an effect of the tumor microenvironment. A second cohort of hormone naïve patients with localized prostate cancer showed that pSTAT3 expression was higher in benign tissue compared with tumor tissue. Lower pSTAT3 expression in tumor cells was predictive of shorter time to recurrent disease. These two cohorts suggest that targeting pSTAT3 would be valuable at later stages of the disease.<br/>We also investigated galiellalactone, a natural fungal compound, and its mechanism of action in inhibiting STAT3. We found that galiellalactone binds directly to STAT3, thus blocking the ability of STAT3 to bind to DNA. When galiellalactone was used in combination with docetaxel it was able to produce a synergistic inhibitory effect, which was likely due to the observed downregulation of genes involved in docetaxel resistance.<br/>In conclusion, our results suggest that STAT3 is a promising treatment target in late stage prostate cancer and may lead to benefit when used in combination with docetaxel.},
  author       = {Don-Doncow, Nicholas},
  isbn         = {978-91-7619-400-3},
  keyword      = {prostate cancer,STAT3,biomarker,Immunohistochemestry,Drug Resistance},
  language     = {eng},
  pages        = {79},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {STAT3 in Prostate Cancer},
  year         = {2017},
}