Hydralazine: Testing an off-label effect in Castration-Resistant Prostate Cancer


Prostate cancer (PCa) is one of the most commonly diagnosed malignancies worldwide and a leading cause of cancer-related deaths among men. In Portugal, it is the most incident cancer and the 3rd cause of death (1, 2). Although most of PCa are clinically indolent, a variable proportion of patients develop castration-resistant PCa (CRPC), an aggressive and lethal form of disease, associated with metastatic dissemination (3). Currently, most therapeutic strategies for CRPC are not curative and largely ineffective, only marginally increasing in survival (4). Therefore, novel therapeutics strategies, ideally based on PCa biology, are urgently needed. Androgen receptor (AR) plays a central role in PCa development and progression. Androgen deprivation therapy is the standard initial care for metastatic PCa (5). Most resistance mechanisms to ADT are related with AR overexpression or mutations, amplification, alternative splice variants, and epigenetic alterations (6, 7). However, 20-30% of CRPC are characterized by a wide loss of AR expression (8, 9) which is not related to either mutations or deletions (10, 11). Promoter hypermethylation is one of the main mechanisms for AR loss of expression (12, 13). Recently, we demonstrated that hydralazine, a non-nucleoside inhibitor of DNA methyltransferases (DNMTi), attenuates malignant phenotype of PCa cells (14). Remarkably, CRPC cell line harboring AR promoter methylation, DU145, achieved the best drug response. Hydralazine restored AR expression and re-sensitized these cells to conventional androgen deprivation therapy, showing promise as innovative therapy for PCa. The major aims of this project are to confirm Hydralazine’s mechanism of action in CRPC and define which subgroup of CRPC patients will benefit from this therapy. To achieve these goals, this project is based on the vast experience of a multidisciplinary team with knowhow in epigenetic editing, 2D and 3D in vitro cell culture, molecular biology, nanotechnology and pathology. The activities that will be carried out include a) AR in vitro methylation, in collaboration with an expert in this methodology; b) Assembly of 3D Prostate Cancer by CICECO members to test hydralazine effects in more complex cancer models; c) Test Hydralazine delivery in nanoliposomes, developed by NanoSTAR, to reduce drug concentration d) Identification of biomarkers predictive of response to hydralazine and subsequent validation in a cohort of PCa patients. This activity as well as all pharmacological and phenotypic assays.

Main Local Researcher

João Mano







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