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Prostate cancer is the second most common diagnosed cancer among men. Currently there are no reliablebiomarkers 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. |
