Joice Rocha

Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer

We examined whether mTOR inhibition by RAD001 (Everolimus) could be therapeutically efficacious in the treatment of bladder cancer. RAD001 markedly inhibited proliferation of nine human urothelial carcinoma cell lines in dose- and sensitivity-dependent manners in vitro. FACS analysis showed that treatment with RAD001 for 48h induced a cell cycle arrest in the G0/G1 phase in all cell lines, without eliciting apoptosis. Additionally, RAD001 significantly inhibited the phosphorylation of S6 downstream of mTOR and VEGF production in all cell lines. We also found tumor weights from nude mice bearing human KU-7 subcutaneous xenografts treated with RAD001 were significantly reduced as compared to placebo-treated mice. This tumor growth inhibition was associated with significant decrease in cell proliferation rate and angiogenesis without changes in cell death. In conclusion inhibition of mTOR signaling in bladder cancer models demonstrated remarkable antitumor activity both in vitro and in vivo. This is the first study showing that RAD001 could be exploited as a potential therapeutic strategy in bladder cancer.

The Fer tyrosine kinase cooperates with interleukin-6 to activate signal transducer and activator of transcription 3 and promote human prostate cancer cell growth.

Androgen withdrawal is the most effective form of systemic therapy for men with advanced prostate cancer. Unfortunately, androgen-independent progression is inevitable, and the development of hormone-refractory disease and death occurs within 2 to 3 years in most men. The understanding of molecular mechanisms promoting the growth of androgen-independent prostate cancer cells is essential for the rational design of agents to treat advanced disease. We previously reported that Fer tyrosine kinase level correlates with the development of prostate cancer and aggressiveness of prostate cancer cell lines. Moreover, knocking down Fer expression interferes with prostate cancer cell growth in vitro. However, the mechanism by which Fer mediates prostate cancer progression remains elusive. We present here that Fer and phospho-Y705 signal transducer and activator of transcription 3 (STAT3) are barely detectable in human benign prostate tissues but constitutively expressed in the cytoplasm and nucleus of the same subsets of tumor cells in human prostate cancer. The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6). Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution. The modulation of Fer expression/activation resulted in inhibitory or stimulatory effects on STAT3 phosphorylation, nuclear translocation, and transcriptional activation. These effects translated in IL-6–mediated PC-3 cell growth. Taken together, these results support an important function of Fer in prostate cancer. (Mol Cancer Res 2009;7(1):142–55)

Botulinum toxin type A inhibits the growth of LNCaP human prostate cancer cells in vitro and in vivo.

Botulinum toxin type A (BTA) intraprostatic injection induces an improvement of urinary symptoms related to benign prostatic hypertrophy (BPH). Infra‐clinical prostate cancer (PCa) foci and pre‐neoplasic lesions occur concomitantly with BPH in a significant number of patients. The objective of this study was to address whether BTA influences the growth of prostate tumors.

Endoscopic Vascular Targeted Photodynamic Therapy with the Photosensitizer WST11 for Benign Prostatic Hyperplasia in the Preclinical Dog Model

PURPOSE Vascular targeted photodynamic therapy with WST11 (TOOKAD® Soluble) is in phase III clinical trials of an interstitial transperineal approach for focal therapy of prostate cancer. We investigated the safety and efficacy of the endourethral route in the context of benign prostatic hyperplasia in the dog model. MATERIALS AND METHODS An optical laser fiber was positioned in the prostatic urethra of 34 dogs, including 4 controls. It was connected to a 753 nm diode laser at 200 mW/cm fluence, delivering 200 to 300 J. WST11 (5 to 15 mg/kg) was infused intravenously in 2 modes, including continuous, starting 5 to 15 minutes before and during illumination, or a bolus 5 to 10 minutes before illumination. Prostate ultrasound, cystourethrogram, urodynamics and histopathology were performed. Followup was 1 week to 1 year. RESULTS Endourethral WST11 vascular targeted photodynamic therapy was uneventful in all except 1 dog, which experienced urinary retention but reached the 1-week end point. All prostates except those in controls showed hemorrhagic lesions. They consisted of 2 levels of concentric alterations, including periurethral necrosis with endothelial layer destruction and adjacent inflammation/atrophy with normal blood vessels. Prostatic urethral width increased as early as 6 weeks after treatment, while prostatic volume decreased, reaching 25% by 18 to 26 weeks. A parallel decrease in urethral pressure at 6 weeks lasted up to 1 year. CONCLUSIONS We confirmed the vascular effect of endourethral WST11 vascular targeted photodynamic therapy. To our knowledge we report for the first time that the resulting periurethral necrosis led to significant, sustained widening of the prostatic urethra, accompanied by long-term improvement in urodynamic parameters. These findings support future clinical applications of this minimally invasive approach to benign prostatic hyperplasia.

Refining the orthotopic dog prostate cancer (DPC)-1 model to better bridge the gap between rodents and men

Rodent models are often suboptimal for translational research on human prostate cancer (PCa). To better fill the gap with human, we refined the previously described orthotopic dog prostate cancer (DPC)‐1 model.

PD24-05 IMPACT OF ABIRATERONE ACETATE IN THE POST-DOCETAXEL SETTING ON THE SURVIVAL OF METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PATIENTS: A POPULATION-BASED STUDY IN QUEBEC

RESULTS: Overall, 42 and 1 out of 43 patients underwent radical prostatectomy and brachytherapy, respectively. Mean and median PSA value at PET/CT scan were 6.7 and 2.9 ng/ml (IQR 1.2-6.1), respectively. Open and laparoscopic sLNDs were performed in 37/49 (76%) and 12/49 (34%), respectively. Histological report was positive for PCa in 36/49 sLND (73%). Five of 36 patients were lost at follow up. Group A consisted of 4 patients and 2 had sTF. Group B and C consisted of 14 and 13 patients and all had sTF. Mean and median PSA value before sLND in Group A, B, C were 1.4 and 1.3 ng/ml (IQR 0.62.2), 9 and 3.5 ng/ml (IQR 1.6-12.9), 9.4 and and 3.5 ng/ml (IQR 2.316.9), respectively. Median PSA nadir in group B and C was 0.67 ng/ml (IQR 0.36-2.6) and 3.14 ng/ml (IQR 0.7-4.4), respectively (p1⁄40.3). Median time to sTF was 11 months (IQR 8-55 months), 5 months (IQR 1.7-13.2) and 4 months (IQR 2.0-10) for group A, B and C. Mean time to sTF in Group A was significantly superior to mean time in Group B and C together (p1⁄40.01). Only 2 of 43 patients were long-term free of recurrence. Limitations of this study are missing PET controls after sLND and PSA persistence, low patient numbers and the retrospective design. CONCLUSIONS: Only pts with positive histological report with a PSA nadir <0.01 ng/ml after sLND seem to have a long-term benefit. Pts with a PSA nadir >0.01ng/ml have a delay of systemic treatment of up to 5 months. Pts without PSA response do not benefit from sLND.

Treatment patterns and trends in patients dying of prostate cancer in Quebec: a population-based study

INTRODUCTION Since just after the year 2000 in Quebec, the management of metastatic castration-resistant prostate cancer (mcrpc) has evolved considerably, with the inclusion of docetaxel-based chemotherapy, bone-targeted therapies (zoledronic acid and denosumab), and more recently, abiraterone, enzalutamide, and cabazitaxel for docetaxel-refractory patients. In the present study, we aimed to analyze contemporary mcrpc management patterns and therapy utilization trends in Quebec. METHODS The study cohort consisted of patients dying of prostate cancer (pca) between January 2001 and December 2013, selected from Quebec public health care insurance databases. Patient selection was based on death from a pca-related cause or therapy used according to the Canadian Urological Association guidelines on mcrpc management. Treatments included chemotherapy (mitoxantrone before 2005 and docetaxel after 2005), abiraterone, bone-targeted therapy (zoledronic acid or denosumab, or both), and palliative radiation therapy (rt). During the study period, neither enzalutamide nor cabazitaxel was publicly reimbursed in Quebec, and as a result, no capture of their use was possible for this study. Multivariate logistic regression was used to identify factors associated with the probability of receiving chemotherapy, bone-targeted therapies, and palliative rt before death from pca. RESULTS Overall, the database search identified 3106 patients who died of pca between January 2001 and December 2013. Median age of death was 78 years. Of those 3106 patients, just 2568 (83%) received mcrpc-specific treatments: chemotherapy, abiraterone, palliative rt, or bone-targeted therapy; the other 17% of the patients were managed solely with maximum androgen blockade (androgen deprivation therapy plus anti-androgens) despite a record of pca-related death. Logistic regression analyses indicate that patients dying after 2005 were more likely to have received chemotherapy [odds ratio (or): 1.51; 95% ci: 1.22 to 1.85] and bone-targeted therapy (or: 1.97; 95% ci: 1.64 to 2.37). Age was a significant predictor for the use of chemotherapy, bone-targeted therapy, and palliative rt (ors in the range 0.96-0.98, p < 0.05). CONCLUSIONS Patient age seems to be a strong determinant in the of selection mcrpc therapy, affecting the probability of the use of chemotherapy, bone-targeted therapy, or palliative rt. Although chemotherapy is still used only in a small percentage of patients, the introduction of new therapies-such as bone-targeted therapy, docetaxel, and abiraterone-affected treatment selection over time. The availability of enzalutamide since February 2014 will likely produce additional changes in mcrpc management.

Current era clinical outcomes of castration-resistant prostate cancer in real-life population study in Quebec, Canada.

226 Background: Prostate cancer (PCa) death is mainly due to castration-resistant PCa (CRPC) which results from disease progression despite androgen ablation therapy (ADT). Little is known about clinical outcomes and trends of real-life CRPC management in the present era, which has become very complex. Our study aimed to analyze healthcare services use, clinical outcomes and survival trends in real-life management of CRPC in Quebec, Canada. Methods: The study cohort consisted of 7,123 patients which shown evidence of CRPC from January/2001 to July/2013, selected from the public healthcare insurance programs the Regie de l’Assurance Maladie du Quebec (RAMQ) databases. Survival was evaluated by Kaplan-Maier and the difference in survival between pre-/post-docetaxel (Doc) (2002-2005 vs 2008-2011) era by log-rank test. The association between Doc exposure and survival was evaluated by Cox proportional hazards model adjusted for several co-variables. Results: Chemotherapy was offered to 17% of patients, while ...