Docetaxel response characterization and identification of predictive biomarkers in metastatic castration resistant prostate cancer

Resumen

Prostate cancer is the most common malignancy in men and the cause of highest mortality in developed countries. Although radical prostatectomy and radiotherapy are the established treatments for localized disease, androgen deprivation therapy represents the mainstay for the treatment of locally advanced, recurrent or metastatic prostate cancer. Chemical castration is temporarily effective in these patients, but eventually 30% of them progress and develop resistance to castration (CRPC) that can lead to the emergence of new metastases. The first line Docetaxel treatment has shown a survival benefit in patients with mCRPC, but unfortunately, part of them end up developing resistance to treatment. The search for new response biomarkers for treatment with DOC is one of the main objectives of this doctoral thesis, using circulating tumor cells (CTCs) as a surrogate marker of the prostate tumor. In our case, we detected in CTCs the presence of two markers, related to the activity of the DOC, to define its correlation with the response: a mitosis arrest biomarker, phospho-histone-H3 (pHH3), and apoptosis biomarker, cytokeratin M30 (CK-M30). Preclinical models generated from metastatic prostate cancer, by orthotopic injection of human tumor cells in NOD Scid Gamma mice, have faithfully reproduced the clinical progression of patients with mCRPC and have been key to identifying and validating biomarkers in CTCs, as well as to understand the biology of prostate cancer. On the other hand, the detection and counting of CTCs has been shown to be a sensitive marker to control the disease status during the response to treatment with DOC. In addition, we have shown that patients who are more likely to obtain a clinical benefit from DOC treatment can be pre-selected by detecting an increase in CTC pHH3 + in the first treatment cycles.