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1.  A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients 
Investigational new drugs  2014;32(5):1005-1016.
Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity.
Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy- Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed.
A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1–12) and 2 in arm B (range 1–9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p=0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9–6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm.
Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC.
PMCID: PMC4281773  PMID: 24788563
Cediranib; Dasatinib; Castration resistant prostate cancer; Quality of life; Bone turnover marker
2.  The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC) 
Agents that have shown improvements in survival in mCRPC now include abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223. Bone supportive agents and palliative radiation continue to play an important role in the overall management of mCRPC. Given the complexity, variety and importance of optimizing the use of these agents, a multidisciplinary team approach is highly recommended.
PMCID: PMC4455631  PMID: 26085865
3.  PD-L1 is highly expressed in Enzalutamide resistant prostate cancer 
Oncotarget  2014;6(1):234-242.
Efficacy of Enzalutamide (ENZ) in castration resistant prostate cancer (CRPC) patients is short-lived. Immunotherapy like T cell checkpoint blockade may improve patient survival. However, when and where checkpoint molecules are expressed in CRPC and whether immune evasion is a mechanism of ENZ resistance remains unclear. Thus, we investigated whether clinically relevant immunotherapy targets, specifically PD-L1/2, PD-1 and CTLA-4, are upregulated in ENZ resistant (ENZR) patients and in a pre-clinical model of ENZ resistance. We show for the first time that patients progressing on ENZ had significantly increased PD-L1/2+ dendritic cells (DC) in blood compared to those naïve or responding to treatment, and a high frequency of PD-1+T cells. These data supported our pre-clinical results, in which we found significantly increased circulating PD-L1/2+ DCs in mice bearing ENZR tumors compared to CRPC, and ENZR tumors expressed significantly increased levels of tumor-intrinsic PD-L1. Importantly, the expression of PD-L1 on ENZR cells, or the ability to modulate PD-L1/2+ DC frequency, was unique to ENZR cell lines and xenografts that did not show classical activation of the androgen receptor. Overall, our results suggest that ENZ resistance is associated with the strong expression of anti-PD-1 therapy targets in circulating immune cells both in patients and in a pre-clinical model that is non-AR driven. Further evaluation of the contribution of tumor vs. immune cell PD-L1 expression in progression of CRPC to anti-androgen resistance and the utility of monitoring circulating cell PD-L1 pathway activity in CRPC patients to predict responsiveness to checkpoint immunotherapy, is warranted.
PMCID: PMC4381591  PMID: 25428917
Enzalutamide resistant CRPC; Immunotherapy; PD-L1
4.  Treatment of muscle-invasive bladder cancer in Canada: A survey of genitourinary medical oncologists and urologists 
Uptake of neoadjuvant chemotherapy (NC) for muscle invasive bladder cancer (MIBC) has been low despite evidence of a survival benefit. The primary aim of this study was to better understand why the rates are low and determine what factors specifically influence the decision to recommend NC for MIBC.
A 31-question survey was emailed between 2009 and 2011 to medical oncologists belonging to the Canadian Association of Genitourinary Medical Oncologists (CAGMO); and to urologists belonging to the Canadian Urologic Oncology Group (CUOG). We gathered data on practice characteristics, referrals for NC, factors influencing NC use, and chemotherapy regimens offered. Responses were summarized using descriptive statistics.
In total, 26/30 (87%) medical oncologists and 25/84 (30%) urologists, who were primarily academic, completed the survey. Most clinicians (medical oncologists 96%, urologists 88%) recommended NC for MIBC, because they considered it to be the standard of care, but most medical oncologists saw ≤6 referrals annually. Performance status, presence of comorbidities and renal function were key considerations in offering NC. NC was not offered if performance status ≥2 (medical oncologists 38%, urologists 44%), age >80 (medical oncologists 46%, urologists 39%), or glomerular filtration rate ≤40 mL/min (medical oncologists 81%, urologists 50%).
Most academic clinicians in Canada believe that cisplatin-based combination NC is the standard of care for MIBC and recommend it for patients with adequate performance status and renal function. Using a multidisciplinary approach to treat this disease may be one strategy to increase referral rates for NC and uptake of NC.
PMCID: PMC4216285  PMID: 25408794
5.  Population-based impact on overall survival after the introduction of docetaxel as standard therapy for metastatic castration resistant prostate cancer 
Utilization of docetaxel in patients with metastatic castration resistant prostate cancer (mCRPC) remains low despite its demonstrated survival benefit. In a population-based cohort, we sought to determine whether the introduction of docetaxel has improved overall survival (OS).
A retrospective review was conducted of mCRPC patients treated with palliative radiotherapy to bone in British Columbia, Canada. Patients in the pre-docetaxel era (pre-DOC, prior to general availability of docetaxel for CRPC) received radiotherapy to bone (RT-B) from 1998 to 2001 and those in the docetaxel era (DOC) received radiotherapy from 2006 to 2009. Time of first radiotherapy to bone was used to select patients at a similar point in their disease state (i.e., onset of bone pain). The primary objective was to determine median OS in the two eras.
Of the 919 patients in the pre-DOC era and the 957 in the DOC era, 7% and 37% received docetaxel, respectively. The median OS from time of first palliative RT was 7.5 months versus 10.3 months (hazard ratio [HR]: 0.79, 95% confidence interval [CI] 0.72–0.87; p < 0.0001) in the pre-DOC and DOC cohorts, respectively. On multivariable analyses, both eras treated (HR 0.84; p = 0.001) and the receipt of docetaxel (HR 0.78; p < 0.001) were significantly associated with OS.
Although docetaxel penetrance was <50%, median OS was significantly improved in the DOC era compared to the pre-DOC era. This is the first study to demonstrate that docetaxel improves OS in mCRPC patients at a population level.
PMCID: PMC4137017  PMID: 25210555
6.  Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer 
Oncotarget  2014;5(3):764-774.
Metastatic prostate cancer (PCa) is still an incurable disease. Long non-coding RNAs (lncRNAs) may be an overlooked source of cancer biomarkers and therapeutic targets. We therefore performed RNA sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The most highly up-regulated transcript was LOC728606, a lncRNA now designated PCAT18. PCAT18 is specifically expressed in the prostate compared to 11 other normal tissues (p<0.05) and up-regulated in PCa compared to 15 other neoplasms (p<0.001). Cancer-specific up-regulation of PCAT18 was confirmed on an independent dataset of PCa and benign prostatic hyperplasia samples (p<0.001). PCAT18 was detectable in plasma samples and increased incrementally from healthy individuals to those with localized and metastatic PCa (p<0.01). We identified a PCAT18-associated expression signature (PES), which is highly PCa-specific and activated in metastatic vs. primary PCa samples (p<1E−4, odds ratio>2). The PES was significantly associated with androgen receptor (AR) signalling. Accordingly, AR activation dramatically up-regulated PCAT18 expression in vitro and in vivo. PCAT18 silencing significantly (p<0.001) inhibited PCa cell proliferation and triggered caspase 3/7 activation, with no effect on non-neoplastic cells. PCAT18 silencing also inhibited PCa cell migration (p<0.01) and invasion (p<0.01). These results position PCAT18 as a potential therapeutic target and biomarker for metastatic PCa.
PMCID: PMC3996663  PMID: 24519926
long non-coding RNA; prostate cancer; metastasis; androgen receptor; cancer biomarkers
7.  Morphological Differences between Circulating Tumor Cells from Prostate Cancer Patients and Cultured Prostate Cancer Cells 
PLoS ONE  2014;9(1):e85264.
Circulating tumor cell (CTC) enumeration promises to be an important predictor of clinical outcome for a range of cancers. Established CTC enumeration methods primarily rely on affinity capture of cell surface antigens, and have been criticized for underestimation of CTC numbers due to antigenic bias. Emerging CTC capture strategies typically distinguish these cells based on their assumed biomechanical characteristics, which are often validated using cultured cancer cells. In this study, we developed a software tool to investigate the morphological properties of CTCs from patients with castrate resistant prostate cancer and cultured prostate cancer cells in order to establish whether the latter is an appropriate model for the former. We isolated both CTCs and cultured cancer cells from whole blood using the CellSearch® system and examined various cytomorphological characteristics. In contrast with cultured cancer cells, CTCs enriched by CellSearch® system were found to have significantly smaller size, larger nuclear-cytoplasmic ratio, and more elongated shape. These CTCs were also found to exhibit significantly more variability than cultured cancer cells in nuclear-cytoplasmic ratio and shape profile.
PMCID: PMC3885705  PMID: 24416373
8.  Reduction in serum clusterin is a potential therapeutic biomarker in patients with castration-resistant prostate cancer treated with custirsen 
Cancer Medicine  2013;2(4):468-477.
Elevated levels of clusterin (CLU), a stress-induced and secreted cytoprotective chaperone, are associated with advanced tumor stage, metastasis, treatment resistance, and adverse outcome in several cancers. Custirsen, a second-generation antisense oligonucleotide, inhibits CLU production in tumor cells and reduces serum CLU levels. A Phase 2 study evaluated custirsen in combination with second-line chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed while on or within 6 months of first-line docetaxel-based chemotherapy. Exploratory analyses evaluated serum CLU levels during custirsen treatment and correlative clinical effects on prostate-specific antigen (PSA) response, overall survival, and any relationship between serum CLU and PSA. Men with mCRPC were treated with mitoxantrone/prednisone/custirsen (MPC, n = 22) or docetaxel retreatment/prednisone/custirsen (DPC plus DPC-Assigned, n = 45) in an open-label, multicenter study. Subject-specific profiles of PSA and serum CLU levels during treatment were characterized using statistical modeling to compute subject-specific summary measures; these measures were analyzed for relationship to survival using proportional hazard regression. Estimated individual serum CLU response profiles were scored as below or at/above the median level for the population through 100 days postrandomization. Median survival was longer for subjects scoring below the median serum CLU level compared with subjects at/above the median level, respectively (MPC: 15.1 months vs. 6.2 months; DPC-Pooled: 17.0 months vs. 12.1 months). Lowered serum CLU levels during custirsen treatment when in combination with either chemotherapy regimen were predictive of longer survival in mCRPC. These results support further evaluation of serum CLU as a therapeutic biomarker.
Aside from PSA, there are currently no other prognostic or predictive biomarkers that can be used to guide treatment response in metastatic castration resistant prostate cancer (mCRPC). In a Phase 2 study, men with mCRPC were treated with prednisone and custirsen plus either mitoxantrone or docetaxel retreatment. Statistical modeling was used to compute subject-specific summary measures of PSA and serum clusterin levels at baseline and at Day 100 of treatment, followed by a regression analysis to evaluate relationship to overall survival. In this analysis, reduced serum clusterin levels during treatment were predictive of longer survival. These results currently support further evaluation of serum clusterin as a therapeutic biomarker in three ongoing Phase 3 clinical trials.
PMCID: PMC3799281  PMID: 24156019
Antisense oligonucleotide; chemotherapy; clusterin; custirsen; mCRPC
10.  Plasma miRNAs as Biomarkers to Identify Patients with Castration-Resistant Metastatic Prostate Cancer 
MicroRNAs (miRNAs) have emerged as key regulators of numerous biological processes, and increasing evidence suggests that circulating miRNAs may be useful biomarkers of clinical disease. In this study, we sought to identify plasma miRNAs that differentiate patients with metastatic castration resistant prostate cancer (mCRPC) from those with localized prostate cancer (PCa). Pooled plasma samples from patients with localized PCa or mCRPC (25 per group) were assayed using the Exiqon miRNA qPCR panel, and the differential expression of selected candidates was validated using qRT-PCR. We identified 63 miRNAs upregulated in mCRPC versus localized PCa, while only four were downregulated. Pearson’s correlation analysis revealed two highly correlated groups: one consisting of miR-141, miR375 and miR-200c and the other including miR151-3p, miR423-3p, miR-126, miR152 and miR-21. A third group, containing miR-16 and miR-205, showed less correlation. One miRNA from each group (miR-141, miR151-3p and miR-16) was used for logistic regression analysis and proved to increase the sensitivity of the prostate-specific antigen (PSA) test alone. While no miRNA alone differentiated localized PCa and mCRPC, combinations had greater sensitivity and specificity. The expression of these 10 candidates was assayed for association with clinical parameters of disease progression through the cBio portal. Our results demonstrate that plasma levels of selected miRNAs are potential biomarkers to differentiate localized PCa and mCRPC.
PMCID: PMC3645714  PMID: 23574937
microRNA; prostate cancer; metastasis; PSA; castration resistant
11.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
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.
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.
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.
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 number, NCT00638690.)
PMCID: PMC3471149  PMID: 21612468
12.  Metastatic signet-ring cell cancer of the bladder responding to chemotherapy with capecitabine: case report and review of literature 
Signet-ring cell cancers deriving from the bladder are rare entities and usually present with advanced incurable disease and associated poor outlook. No standard effective chemotherapeutic option has been described largely due to the rarity of this malignancy. We report a case of a patient with metastatic bladder cancer, signet-ring cell variant. The patient progressed rapidly on standard first-line bladder cancer chemotherapy with gemcitabine and carboplatin. He responded well to second-line capecitabine with a clinically meaningful progression-free survival.
PMCID: PMC2845673  PMID: 20368884
13.  Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions 
An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials, anti-VEGF agents such as sunitinib, sorafenib, bevacizumab-based therapy, and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease. Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.
PMCID: PMC3126007  PMID: 21789125
adjuvant; combination therapy; mammalian target of rapamycin; neo-adjuvant; nonclear cell histologies; renal cell carcinoma; vascular endothelial growth factor

Results 1-13 (13)