Objectives

The purpose of this study was to assess the efficacy and safety of low-dose (1mg) daily diethylstilbestrol (DES) for the treatment of castrate-resistant prostate cancer (CRPC).

Methods and Materials

A retrospective chart review was performed on patients treated with low-dose DES who had CRPC despite anti-androgen withdrawal. The study population consists of 63 patients treated in the pre- and post-chemotherapy settings based on a database review; 58 had sufficient data for efficacy, all were analyzed for safety.

Results

A PSA decrease of ≥50% was observed in 19 of 49 pre-chemotherapy patients (39%) with a median time to progression (TTP) of 30 weeks (95% CI, 21.9, 68.7). A PSA decrease of <50% was seen in another 16 patients (33%) with a median TTP of 16.4 weeks (95% CI, 13.0, 37.6). Fourteen patients (29%) had progressive disease by PSA testing; their median TTP was 6.9 weeks (95% CI, 5.6, 12.9). Thromboembolic events included 2 patients with DVTs and 1 patient who developed primary fibrinolysis syndrome. Additional adverse events included gynecomastia in 37 of 63 patients (59%). Secondary observations include PSA responses in 3 of 9 patients treated with DES after chemotherapy progression and a high rate of PSA responses in patients retreated with DES after a drug holiday.

Conclusions

Low-dose DES is safe and effective in a modern cohort of men with CRPC despite anti-androgen treatment. Its potential role in the post-chemotherapy setting and the suggestion of efficacy on re-challenge merits additional consideration.

Objectives

Bladder cancer expresses many potential therapeutic targets of biological agents including the vascular endothelial growth factor receptor (VEGFR). Pazopanib is a small molecule inhibitor of VEGFR-1, -2 -3, platelet derived growth factor receptor (PDGFR) and c-Kit. The current study investigates the efficacy of pazopanib, both alone and in combination with docetaxel, in bladder cancer cells.

Materials and Methods

Using human bladder cancer cells HTB3, HT1376, J82, RT4, CRL1749, T24, Sup and HTB9, the treatment effect of pazopanib and cytotoxic chemotherapy was assessed using a tetrazolium-based assay. The combinatorial effect of these agents on clonogenic growth was further examined. Western blotting was employed to assess changes in relevant downstream targets including phospho-AKT, phospho-FAK, total AKT and total FAK.

Results

Single-agent pazopanib had modest activity. However, synergy was seen with the combination of docetaxel and pazopanib in multiple these cells lines. J82 and T24 cells were selected for additional clonogenic testing due to their resistance to single-agent docetaxel chemotherapy. 1.25 nM of docetaxel had little effect on clonogenic formation; however, in combination with pazopanib, significant inhibition of colony formation was observed. This combination treatment additionally decreased phospho-AKT, an important mediator of cell survival in all cell lines, while phospho-FAK expression was variably affected.

Conclusions

The present study demonstrates synergistic efficacy of pazopanib with docetaxel in docetaxel-resistant bladder cancer cells. This work supports future evaluation of pazopanib with docetaxel for the treatment of bladder cancer with the potential of improved efficacy and toxicity.

Prostate cancer is the most common cancer among men in the United States. For decades, the cornerstone of medical treatment for advanced prostate cancer has been hormonal therapy, intended to lower testosterone levels, known as Androgen Deprivation Therapy (ADT). The development of hormone-resistant prostate cancer (now termed castration-resistant prostate cancer:CRPC) remains the key roadblock in successful long-term management of prostate cancer. New advancements in medical therapy for prostate cancer have added to the hormonal therapy armamentarium. These new therapeutic agents not only provide a survival benefit but also show potential for reversing hormonal resistance in metastatic CRPC, and thus redefining hormonally sensitive disease.

Introduction

The detection of circulating tumor cells (CTC) is prognostic in several cancer types. This trial examines the incidence and prognostic value of CTCs in urothelial cancer (UC).

Materials and Methods

44 subjects with UC were assessed for CTCs using CellSearch® Technology (Veridex, LLC, Raritan, NJ), using 7.5 ml of peripheral blood, sorted by magnetic separation (EpCaM positive, and immunofluorescent staining, (Cytokeratin 8, 18, or 19 positive, CD 45 negative, DAPI positive cells) to identify CTCs.

Results

Five of 30 (17%) subjects with clinically localized and 7 of 14 (50%) patients with metastatic UC had at least 1 detectable CTC, with a range of 1–177 CTCs. Six subjects had 5 or more CTCs. FISH analysis was performed in 20 samples from 18 unique subjects, using the UroVysion probe set. Copy number gains consistent with neoplasm were observed in cases with measurable CTCs, but not in any of the CTC-negative samples tested. With a median follow-up of 337 days, all 7 metastatic subjects with detectable CTCs had died, versus 3 of 7 (43%) metastatic subjects without detectable CTCs.

Conclusions

CTCs were observed in 50% of the metastatic UC patients tested. FISH analysis confirmed the aneusomic chromosomal content in the CTCs. The findings suggest measurable CTCs may be prognostic for shortened survival in metastatic UC patients, although the optimal threshold for a “positive” finding is unknown. CTCs were also detected in a subset of patients with clinically-localized disease, identifying a potential high-risk, pre-operative group for future study.

Purpose

Men with high-risk features (extraprostatic extension or high Gleason grade) face a high risk of prostate cancer recurrence after radical prostatectomy. Clinical trials of adjuvant systemic therapy for such patients have been limited.

Patients and Methods

The SWOG (Southwest Oncology Group) S9921 study randomly assigned 983 men with high-risk features at prostatectomy to receive adjuvant therapy with androgen deprivation (ADT) alone or in combination with mitoxantrone chemotherapy. ADT consisted of goserelin and bicalutamide for 2 years.

Results

Although the final primary treatment comparison results are not ready for publication, this article reports results in the ADT-alone control arm with a median follow-up of 4.4 years. For these 481 men, the estimated 5-year biochemical failure-free survival is 92.5% (95% CI, 90 to 95), and 5-year overall survival is 95.9% (95% CI, 93.9 to 97.9).

Conclusion

The results of this trial, taken in context, make a compelling argument for counseling all high-risk patients with prostate cancer about adjuvant ADT. This article discusses the challenges in the design and implementation of clinical trials to take the next step forward in adjuvant therapy for prostate cancer because of the excellent survival achieved with currently available therapies and highlights the need for better molecular markers to personalize care.

Abstract

Recognition of micro-RNA function and their contribution to the biology of disease has given a new insight into disease mechanisms, with these discoveries potentially improving clinical diagnostic and therapeutic options. miR-125b has been identified as an important regulator in various cancers, including prostate cancer, but the mechanism of this regulation remains incompletely understood. In these studies, the effect of castration on miR-125b serum expression was evaluated in mice, simulating androgen deprivation. Furthermore, miR-125b expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LNCaP prostate cancer cells treated with the antiandrogen bicalutamide. Using LNCaP cells, the effect of miR-125b modulation on apoptotic protein and NCOR2, a co-repressor of androgen receptor (AR), was examined by Western blot. A 3′-untranslated region (UTR) luciferase-binding assay was performed to confirm that miR-125b targets NCOR2. We found that surgical castration induced an initial increase in the expression of circulating miR-125b in mice, while sham surgery did not. In addition, AR blockade via bicalutamide was associated with the rapid release of miR-125b into the cell culture medium of prostate cancer cells. A previously studied target of miR-125b, a regulator in the apoptotic pathway, BAK1, could not completely account for the role of miR-125b in prostate cancer. Thus, we looked for additional targets of miR-125b and found that NCOR2, which is a repressor of AR, is a direct target of miR-125b. We found that NCOR2 protein expression was blocked by mimics of miR-125b, and a luciferase-binding assay confirmed that NCOR2 is a direct target of miR-125b. Our data provide novel evidence that miR-125b is an important regulator of the AR with specific ramification for the effectiveness of antiandrogens and other hormonal therapies in prostate cancer.

Prostate cancer (PCa), like most human cancers, features dysregulated CD44 expression. Expression of CD44 standard (CD44s), present in benign epithelium, is lost in PCa while pro-invasive splice variant isoform CD44v7-10 is overexpressed. The role of CD44 in silibinin's anti-growth effects was uncertain. To assess silibinin's effects on CD44 promoter activity, PC-3M PCa cells were transfected with luciferase-CD44 promoter construct 24 h prior to 25–200 μM silibinin treatment for 48 h. Also, cells' expression of CD44 RNA (by qRT-PCR) and protein (Western blot analysis) was studied. Silibinin was further tested preoperatively on a pilot cohort of 6 men with PCa compared with 7 matched placebo-treated men, with immunostaining for CD44v7-10 in their prostates. In PC-3M cells, silibinin dose-dependently inhibited CD44 promoter activity up to 87%, caused a 90% inhibition of total CD44 and 70% decrease in CD44v7-10 RNA, and at the protein level, decreased total CD44 at 100–200 μM dose and decreased CD44v7-10 after 3 days. Silibinin decreased adhesion to hyaluronan and fibronectin. Silibinin at 100–200 μM inhibited Egr-1, a regulator of CD44 promoter activity. Men treated with silibinin did not differ in tissue CD44v7-10 expression. In conclusion, CD44 inhibition is one mechanism by which silibinin reduces PCa tumorigenicity.

BACKGROUND

Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.

METHODS

We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.

RESULTS

After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.

CONCLUSIONS

The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)