RESUMEN
OBJECTIVES: ⢠Germline CAG repeat polymorphisms in the androgen receptor (AR-CAG) have been shown to influence the activity of the AR. ⢠The purpose of the present study was to determine if AR-CAG repeat length correlates with time to progression on androgen deprivation therapy (ADT). PATIENTS AND METHODS: ⢠Germline AR-CAG repeat lengths were determined in a cohort of 480 patients with recurrent or metastatic prostate cancer treated at a single tertiary care institution and correlated to time to progression (TTP) and overall survival. RESULTS: ⢠There was no significant correlation between differences in the AR-CAG repeat lengths and TTP or overall survival in patients with prostate cancer receiving ADT. ⢠AR-CAG repeat lengths did not significantly correlate with age, prostate-specific antigen (PSA), Gleason score or clinical stage at diagnosis. ⢠In patients with metastatic disease, longer AR-CAG repeat lengths (>23 vs ≤23) were associated with a longer TTP on ADT, but this finding was of borderline significance (median TTP 18.3 vs 15.5 months, P = 0.09; adjusted HR = 0.76, 95% confidence interval = 0.54-1.09). CONCLUSIONS: ⢠This is the largest published study to date investigating the association of germline AR-CAG repeat lengths and efficacy of ADT in prostate cancer. ⢠Germline AR-CAG repeat lengths do not predict response to ADT.
Asunto(s)
Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Receptores Androgénicos/genética , Anciano , Antagonistas de Andrógenos/uso terapéutico , Progresión de la Enfermedad , Células Germinativas , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Orquiectomía , Estudios Retrospectivos , Factores de TiempoRESUMEN
Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase beta (LPAAT-beta), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-beta converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-beta was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-beta using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-beta also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-beta was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-alpha. These findings identify LPAAT-beta as a potential prognostic and therapeutic target in ovarian and endometrial cancer.