ABSTRACT
Advanced disease accounts for the majority of prostate cancer-related deaths and androgen deprivation therapy (ADT) is the standard of care for these patients. Many patients undergoing ADT become resistant to its effects and progress to castrate-resistant prostate cancer (CRPC). Current therapies for CRPC patients are inadequate, with progression-free survival rates as low as 2 months. The molecular events that promote CRPC are poorly understood. ETS (v-ets erythroblastosis virus E26 oncogene) transcription factors are regulators of carcinogenesis. Protein levels of the archetypical ETS factor, ETS1, are increased in clinical and latent prostate cancer relative to benign prostatic hyperplasia and normal prostate to promote multiple cancer-associated processes, such as energy metabolism, matrix degradation, survival, angiogenesis, migration and invasion. Our studies have found that ETS1 expression is highest in high-grade prostate cancer (Gleason 7 and above). Increased ETS1 expression and transcriptional activity promotes an aggressive and castrate-resistant phenotype in immortalized prostate cancer cells. Elevated AKT (v-akt murine thymoma viral oncogene homolog) activity was demonstrated to increase ETS1 protein levels specifically in castrate-resistant cells and exogenous ETS1 expression was sufficient to rescue invasive potential decreased by inhibition of AKT activity. Significantly, targeted androgen receptor activity altered ETS1 expression, which in turn altered the castrate-resistant phenotype. These data suggest a role for oncogenic ETS1 transcriptional activity in promoting aggressive prostate cancer and the castrate-resistant phenotype.
Subject(s)
Prostatic Neoplasms/metabolism , Proto-Oncogene Protein c-ets-1/metabolism , Transcription, Genetic , Androgens/deficiency , Cell Line, Tumor , Disease-Free Survival , Humans , Male , Neoplasm Grading , Oncogene Protein v-akt/biosynthesis , Oncogene Protein v-akt/genetics , Oncogene Protein v-akt/metabolism , Orchiectomy , Phenotype , Prostate , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Proto-Oncogene Protein c-ets-1/biosynthesis , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Signal Transduction , Transcriptional ActivationABSTRACT
BACKGROUND: Although clinical trials with sunitinib and sorafenib in metastatic renal cell carcinoma (mRCC) have included patients with moderate renal insufficiency (RI), the incidence of renal toxicity induced by their administration as well as the safety of these agents in patients with more severe renal insufficiency has not been extensively reported. PATIENTS AND METHODS: Patients with mRCC treated with vascular endothelial growth factor-targeted therapy with either RI at time of treatment initiation or who developed RI during therapy were identified. RI was defined as serum creatinine (Cr) > or = 1.9 mg/dl or a creatinine clearance (CrCl) < 60 ml/min/1.73 m(2) for >3 months before treatment. Objective outcomes and toxic effects of treatment were also measured. RESULTS: A total of 39 patients were identified: 21 patients who initiated therapy with preexisting RI and 18 patients who developed RI during treatment. In patients with RI at the start of therapy, Cr increased in 57%, and 48% of patients required dose reduction. The median time to maximum RI was 6.6 months (range 0.4-19.6 months). In patients who developed RI while receiving therapy, median serum Cr and CrCl at the start of therapy were 1.5 mg/dl (range 1.1-1.8) and 61 ml/min (range 43-105), respectively. Patients experienced a median increase in serum Cr of 0.8 mg/dl (range 0.3-2.8) and a median decrease in CrCl of 25 ml/min (range 8.54-64.76). Overall, 5 patients (24%) achieved a partial response (PR), 13 (62%) had stable disease (SD) and 3 (14%) had progressive disease (PD). Estimated progression-free survival (PFS) was 8.4 months. The most common toxic effects (all grades) were fatigue (81%), hand-foot syndrome (HFS) (52%) and diarrhea (48%). Six patients experienced grade III toxicity (29%), primarily HFS. CONCLUSIONS: Sunitinib and sorafenib can be safely given to patients with renal insufficiency, provided adequate monitoring of renal function. For those patients developing an increase in Cr, dose modifications may be required to allow continuation of therapy. The clinical outcome of patients with baseline renal dysfunction and patients who develop renal dysfunction does not appear to be compromised.
