Prostate cancer is a major societal problem with 11.000 new cases every year in the Netherlands. The advanced stage of the disease, castration-resistant prostate cancer, is especially deadly and is often accompanied with (bone) metastases. In this PhD-thesis, we have explored several strategies to improve current therapeutics for advanced prostate cancer. These approaches encompass the use of targeted, nanomedicinal, drug delivery systems, the reversal of chemotherapy resistance and the selective inhibition of cancer stem cells. First, we have investigated the utility of a liposomal formulation of dexamethasone in a series of preclinical studies. Dexamethasone is regularly clinically-used in advanced prostate cancer patients. Liposomal dexamethasone was shown to exhibit potent antitumor efficacy, was well tolerated and significantly outperformed the administration of free dexamethasone. Second, we have identified an important role of the glucocorticoid receptor, the receptor for dexamethasone, in the acquisition of chemotherapy resistance in prostate cancer. The glucocorticoid receptor was shown to be functionally involved in chemotherapy resistance and therapeutic targeting of the glucocorticoid receptor was shown to restore sensitivity to chemotherapeutic drugs. Third, we evaluated the performance of a micellar formulation of docetaxel. Docetaxel is currently used as the first line treatment in advanced prostate cancer. Micellar docetaxel was shown to exhibit robust antitumor activity in a preclinical model for prostate cancer and, strikingly, the micellar formulation of docetaxel prevents side effects that are associated with conventional docetaxel administration. Finally, we demonstrate that depletion of cancer stem cells results in diminished tumorigenic and metastatic potential of prostate cancer cells, and may therefore provide a viable target for prostate cancer therapy.
|Qualification||Doctor of Philosophy|
|Award date||20 Jan 2016|
|Place of Publication||Enschede|
|Publication status||Published - 20 Jan 2016|