Comprehensive Drug Testing of Patient-derived Conditionally Reprogrammed Cells from Castration-resistant Prostate Cancer.

BACKGROUND: Technology development to enable the culture of human prostate cancer (PCa) progenitor cells is required for the identification of new, potentially curative therapies for PCa. OBJECTIVE: We established and characterized patient-derived conditionally reprogrammed cells (CRCs) to assess their biological properties and to apply these to test the efficacies of drugs. DESIGN, SETTING, AND PARTICIPANTS: CRCs were established from seven patient samples with disease ranging from primary PCa to advanced castration-resistant PCa (CRPC). The CRCs were characterized by genomic, transcriptomic, protein expression, and drug profiling. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The phenotypic quantification of the CRCs was done based on immunostaining followed by image analysis with Advanced Cell Classifier using Random Forest supervised machine learning. Copy number aberrations (CNAs) were called from whole-exome sequencing and transcriptomics using in-house pipelines. Dose-response measurements were used to generate multiparameter drug sensitivity scores using R-statistical language. RESULTS AND LIMITATIONS: We generated six benign CRC cultures which all had an androgen receptor-negative, basal/transit-amplifying phenotype with few CNAs. In three-dimensional cell culture, these cells could re-express the androgen receptor. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Using the benign CRCs as controls, we identified the Bcl-2 family inhibitor navitoclax as the most potent cancer-specific drug for the CRCs from a CRPC patient. Other drug efficacies included taxanes, mepacrine, and retinoids. CONCLUSIONS: Comprehensive cancer pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently being tested in clinical trials of CRPC. PATIENT SUMMARY: We describe an approach to generate patient-derived cancer cells from advanced prostate cancer and apply such cells to discover drugs that could be applied in clinical trials for castration-resistant prostate cancer.

The effects of short-term oral phytoestrogen supplementation on the hypothalamic-pituitary-testicular axis in prostate cancer patients.

BACKGROUND: Here we evaluate the effects of oral phytoestrogen supplementation on hypothalamic-pituitary-testicular (HPT) axis in CaP patients. METHODS: We recruited 40 men about to undergo radical prostatectomy for CaP to receive either 240 mg of clover phytoestrogens or placebo daily for 2 weeks. Serum hormone levels were measured before and after treatment. In addition, recombinant cell bioassay was used to measure serum androgen bioactivity (ABA). RESULTS: Phytoestrogen treatment increased serum LH from mean of 3.4-5.2 IU, P = 0.03. Concomitantly, non-significant trend towards decline in serum T, cfT and ABA values was noted. However, mean serum LH/T ratio was upregulated from 0.20 to 0.48 IU/nM, P = 0.004, suggesting compensated hypogonadism. During the course of treatment, serum concentration of equol correlated strongly with the concomitant decrease in ABA (r = -0.586, P = 0.022). CONCLUSIONS: Phytoestrogen treatment interferes with HPT axis in CaP patients by inducing testicular resistance to LH and compensated hypogonadism.

Plasma and prostate phytoestrogen concentrations in prostate cancer patients after oral phytoestogen supplementation.

BACKGROUND: Phytoestrogens have been suggested to reduce the risk of prostate cancer (CaP), but no data exists on how oral phytoestrogen supplementation influences phytoestrogen concentrations in prostate tissue. METHODS: Forty men with CaP, assigned for radical prostatectomy, received 240 mg of clover phytoestrogens or placebo daily for a 2-week period before their operation in a prospective and randomized study. Phytoestrogens were measured in plasma and prostate tissue by time-resolved fluoroimmunoassay (TR-FIA). RESULTS: All patients had low baseline phytoestrogen concentrations and only 35% had a detectable plasma concentration of equol. Oral supplementation with phytoestrogens induced a statistically significant (P<0.001) 23- and 7-fold increase in prostate tissue concentrations of the phytoestrogens genistein and daidzein, respectively. Supplemented patients demonstrated prostate tissue genistein and daidzein concentrations that were over twofold higher than their plasma. Interestingly, even though the placebo group did not receive phytoestrogen challenge, they also demonstrated twofold prostate tissue genistein and daidzein concentrations compared to their plasma values, suggesting that the prostate can concentrate available phytoestrogens. In addition, after the supplementation, 90% of the supplemented patients had a detectable plasma equol concentration. CONCLUSIONS: We conclude that prostate tissue can concentrate genistein and daidzein. Significant elevation of intraprostatic genistein and daidzein concentrations can be achieved with a short-term dietary phytoestrogen supplementation.

Tranexamic acid in control of primary hemorrhage during transurethral prostatectomy.

OBJECTIVES: To determine whether short-term treatment of patients about to undergo transurethral resection of the prostate (TURP) with tranexamic acid (TXA) would be beneficial in reducing the associated blood loss. METHODS: A prospective and randomized trial was conducted with 136 men requiring TURP for obstructive urinary symptoms. The treatment group received 2 g TXA three times daily on the day of, and first day after, the operation. RESULTS: Short-term TXA treatment significantly reduced the operative blood loss associated with TURP (128 mL versus 250 mL, P = 0.018), and this difference was not a result of the amount of tissue resected between the two groups (16 g versus 16 g, P = 0.415). In addition, TXA treatment reduced the amount of blood loss per gram of resected tissue (8 mL/g versus 13 mL/g, P = 0.020). Furthermore, the volume of irrigating fluid required (15 L versus 18 L, P = 0.004) and operating time (36 minutes versus 48 minutes, P = 0.001) were also reduced. However, TXA treatment did not influence the number of patients requiring a blood transfusion. Six patients in the treatment group (7.2%) and five in the control group (6.8%) required a transfusion (P = 0.709). Moreover, TXA treatment did not affect the duration of catheterization (1 day versus 1 day, P = 0.342) or hospitalization (3 days versus 3 days, P = 0.218). CONCLUSIONS: Short-term TXA treatment is effective in reducing the operative blood loss associated with TURP.