Progression to androgen independence remains the main obstacle to improving survival and quality of life in patients with advanced prostate cancer. Induction of differentiation may serve as a rational basis for prevention of progression to androgen independence by modulating gene expression activated by castration or upregulated during androgen-independent progression. The objectives of this study were to characterize the in vitro effects of sodium butyrate on human prostate cancer cell growth, PSA gene expression, and differentiation in the LNCaP tumor model and to determine whether tumor progression in vivo is delayed by isobutyramide, an orally bioavailable butyrate analogue with a longer half-life. The effects of isobutyramide on LNCaP tumor growth and serum PSA levels in both intact and castrate male mice were compared to controls. At concentrations >1 mM, butyrate induced dose-dependent changes towards a more differentiated phenotype, G1 cell cycle arrest, and an 80% decrease in LNCaP cell growth rates. PSA gene expression was increased threefold by butyrate, indicative of differentiation-enhanced gene expression. The half-life of isobutyramide in athymic mice was determined by gas chromatography to be 4 h. During a 4 week period in intact-placebo mice, tumor volume and serum PSA increased 4.1- and 6.6-fold, respectively, compared to twofold and 2.7-fold increases in tumor volume and serum PSA in intact-treated mice. During a 7 week period in castrate-placebo mice, tumor volume and serum PSA levels increased 2.4-fold and fourfold, respectively, compared to a 50% reduction in tumor volume and a twofold increase in serum PSA above nadir levels in castrate mice treated with adjuvant isobutyramide. Isobutyramide treatment induced pronounced morphological changes in LNCaP tumor cells, with loss of defined nucleoli and dispersion of chromatin distribution. LNCaP tumor PSA mRNA levels actually increased threefold, indicative of differentiation-enhanced gene expression. This study demonstrates that butyrate causes LNCaP cell cycle arrest and increased PSA gene expression, both indicative of differentiation. The combination of castration and adjuvant isobutyramide was synergistic in delaying tumor progression. Decreased tumor cell proliferation and increased PSA gene expression induced by isobutyramide results in disconcordant changes in serum PSA and tumor volume and reduces the utility of serum PSA as a marker of response to therapy.

Introduction: Prostate cancer recurrence following primary radiation is common. If the recurrence remains localized to the prostate gland, surgical removal may result in long-term local control or cure. Despite the well-established oncological outcomes, salvage prostatectomy is infrequently performed or reported. We present our experience with salvage prostatectomy at a Canadian centre. Methods:We identified all patients undergoing salvage prostatectomy at the Vancouver General Hospital between 1995 and 2010 from a prospectively recorded and maintained prostate cancer database. Details regarding initial presentation, delivery of radiotherapy, clinical features at the time of recurrence, as well as oncological and functional outcomes, were collected. Information regarding postoperative morbidity was collected prospectively and confirmed by retrospective chart review. Results: Over a 15-year period, salvage prostatectomy was successfully completed in 21 patients. With a median follow-up period of 68 months (range: 2-122), 9 (43%) patients experienced a biochemical recurrence, with most failing within the first 2 years of surgery. There were 3 deaths in the cohort, all from prostate cancer, giving a prostate cancer specific and overall survival of 86%. The main postoperative morbidity was bladder neck contracture, occurring in 40%. One patient each developed a recto-urethral fistula and osteitis pubis. Physician-recorded data regarding continence was available in 13 (62%). Of these 13 patients, 10 (85%) men were recorded as dry or using 1 pad per day. Conclusions: This is the first Canadian centre to report that salvage prostatectomy can be performed with favourable oncological and functional outcomes.

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<div>Abstract<p>Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three <i>in vivo</i>, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. <i>In vivo, SLFN5</i> depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, <i>SLFN5</i> depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC.</p>Significance:<p>This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.</p></div>

<p>ATF4_binding sites</p>