M E Gleave

Vancouver Prostate Centre, Vancouver, British Columbia, Canada

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Publications (154)755.71 Total impact

  • Arun A Azad, Amina Zoubeidi, Martin E Gleave, Kim N Chi
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    ABSTRACT: The survival of malignant cells is constantly threatened by a myriad of cellular insults. In the context of such proteotoxic stress, cancer cells activate cytoprotective adaptive pathways. Heat shock proteins (HSPs) are highly conserved molecular chaperones that are expressed at low levels under normal conditions, but upregulated by cellular stress. As molecular chaperones, HSPs control the stability and function of client proteins, preventing aggregation of misfolded proteins, facilitating intracellular protein trafficking, maintaining protein conformation to enable ligand binding, phosphorylating proteins in signalling complexes and degrading severely damaged proteins via the ubiquitin-proteasome pathway. A key client protein of several HSPs is the androgen receptor (AR). HSPs facilitate binding of dihydrotestosterone to the AR, and enhance AR-mediated transcriptional activity. The integral role of HSPs in AR function speaks to their potential utility as therapeutic targets in castration-resistant prostate cancer (CRPC), a disease state characterized by persistent activation of the androgen-AR axis. Inhibition of HSPs has the additional benefit of potentially modulating signalling and transcriptional networks that are associated with HSP client proteins in CRPC cells. As a consequence, HSPs represent highly attractive targets in the development of treatments for CRPC.
    Nature Reviews Urology 12/2014; · 4.52 Impact Factor
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    ABSTRACT: The glucocorticoid and androgen receptors (GR and AR) can commonly regulate up to 50% of their target genes in prostate cancer (PCa) cells. GR expression is stimulated by castration therapy, which has been proposed to be one mechanism that compensates for AR signaling blockade and promotes castration-resistant PCa (CRPC) progression. However, whether GR functions as a driver for CRPC or a marker reflecting AR activity remains unclear. Here, we applied PCa tissue microarrays to show that GR protein levels were elevated by castration therapy, but reduced to pre-castration levels when tumors were at the CRPC stage. Using subrenal capsule xenograft models, we showed that GR expression was inversely correlated with AR and PSA expressions. GR expression levels are not associated with tumor invasion and metastasis phenotypes. In castration-resistant C4-2 xenografts expressing AR shRNA, regressing tumors induced by AR knockdown expressed higher levels of GR and lower levels of PSA than non-regressing tumors. Immunoblotting and real-time PCR assays further showed that AR knockdown or AR antagonists increased GR expression at both mRNA and protein levels. ChIP combined with DNA sequencing techniques identified a negative androgen responsive element (nARE) 160K base pairs upstream of the GR gene. Gel shift assays confirmed that AR directly interacted with the nARE and luciferase assays demonstrated that the nARE could mediate transcription repression by ligand-activated AR. In conclusion, GR expression is negatively regulated by AR signaling and may serve as a marker for AR signaling in prostate tumors. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 08/2014; · 6.20 Impact Factor
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    ABSTRACT: Treatment resistance, the major challenge in the management of advanced prostate cancer, is in part based on resistance to apoptosis. The Inhibitor of Apoptosis (IAP) family is thought to play key roles in survival and drug resistance of cancer via inhibition of apoptosis. Of the IAP family members, cIAP1, cIAP2, XIAP and survivin are known to be up-regulated in prostate cancer. BIRC6, a much less studied IAP member, was recently shown to be elevated in castration-resistant prostate cancer (CRPC). In the present study, we showed a correlation between elevated BIRC6 expression in clinical prostate cancer specimens and poor patient prognostic factors, as well as co-upregulation of certain IAP members. In view of this, we designed antisense oligonucleotides that simultaneously target BIRC6 and another co-upregulated IAP member (dASOs). Two dASOs, targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cells proliferation, exceeding that obtained with single BIRC6 targeting. The growth inhibition was associated with increased apoptosis, cell cycle arrest and suppression of NFkB activation. Moreover, treatment with both dASOs led to significantly lower viable tumor volume in vivo, without major host toxicity. This study shows that BIRC6-based dual IAP-targeting ASOs represent potential novel therapeutic agents against advanced prostate cancer.
    Oncotarget 07/2014; · 6.63 Impact Factor
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    ABSTRACT: Exosomes are emerging as a source of biomarkers with putative prognostic and diagnostic value. However, little is known about the efficiency, reproducibility and reliability of the protocols routinely used to quantify exosomes in human serum.
    Clinical Biochemistry 06/2014; · 2.23 Impact Factor
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    ABSTRACT: Cabazitaxel, abiraterone acetate (AA), and enzalutamide have been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel chemotherapy. Whether taxanes and next-generation androgen receptor (AR) axis inhibitors are cross-resistant or not is a subject of debate.
    European Urology 05/2014; · 12.48 Impact Factor
  • European Urology Supplements 04/2014; 13(1):e30. · 3.37 Impact Factor
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    ABSTRACT: The transcription factor E-twenty-six related gene (ERG), which is overexpressed through gene fusion with the androgen-responsive gene transmembrane protease, serine 2 (TMPRSS2) in ∼40% of prostate tumors, is a key driver of prostate carcinogenesis. Ablation of ERG would disrupt a key oncogenic transcriptional circuit and could be a promising therapeutic strategy for prostate cancer treatment. Here, we show that ubiquitin-specific peptidase 9, X-linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro. USP9X knockdown resulted in increased levels of ubiquitinated ERG and was coupled with depletion of ERG. Treatment with the USP9X inhibitor WP1130 resulted in ERG degradation both in vivo and in vitro, impaired the expression of genes enriched in ERG and prostate cancer relevant gene signatures in microarray analyses, and inhibited growth of ERG-positive tumors in three mouse xenograft models. Thus, we identified USP9X as a potential therapeutic target in prostate cancer cells and established WP1130 as a lead compound for the development of ERG-depleting drugs.
    Proceedings of the National Academy of Sciences 03/2014; · 9.81 Impact Factor
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    ABSTRACT: Context Until recently, the only approved agent for metastatic castration-resistant prostate cancer (mCRPC) was docetaxel chemotherapy. But over the last 5 years, significant advances in the field have led to the approval of five new agents, each with different mechanisms of action and demonstrating improved overall survival in separate randomized phase 3 trials. Many of these novel agents are now also being evaluated in earlier stages of the disease, which may ultimately lead to even better outcomes. Objective To summarize the current literature on the management of mCRPC with a particular focus on novel chemotherapy approaches, hormonal approaches, immunotherapy, and radiopharmaceuticals showing survival benefits in phase 3 clinical trials. Emerging therapies in late stages of development are also discussed briefly. Evidence acquisition A comprehensive search of PubMed, identified studies pertaining to novel therapies evaluated in mCRPC since the initial approval of docetaxel in 2004. Abstracts from major international meetings were hand searched to identify studies of novel agents in late stage development in mCRPC. The Clinical Trials.gov database was used to find ongoing clinical trials in the area of mCRPC. A detailed search of each new agent was also performed to ensure that additional trials of these agents in other stages of the disease were included where relevant. Evidence synthesis The main agents discussed are the androgen synthesis inhibitor abiraterone acetate, the androgen receptor inhibitor enzalutamide, the novel taxane chemotherapy cabazitaxel, the immunotherapy sipuleucel-T, and the radiopharmaceutical radium 223. Other emerging agents and a brief discussion of negative phase 3 results are also included. Conclusions It is a very exciting time in the field of mCRPC, where therapeutic advances have improved outcomes in this disease, although once metastatic overall median survival remains a dismal 2–3 years. The key now will be to understand how best to use these new agents, understand the mechanisms of resistance to them, continue to develop novel treatment strategies, and ultimately test these agents earlier in the disease when cure may be possible.
    European Urology 02/2014; 65(2):289–299. · 12.48 Impact Factor
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    ABSTRACT: Various conflicting guidelines and recommendations about prostate cancer screening and early detection have left both clinicians and their patients quite confused. At the Prostate Cancer World Congress held in Melbourne in August 2013, a multidisciplinary group of the world's leading experts in this area gathered together and generated this set of consensus statements to bring some clarity to this confusion.The five consensus statements provide clear guidance for clinicians counselling their patients about the early detection of prostate cancer.
    BJU International 11/2013; · 3.13 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4062-4062. · 9.28 Impact Factor
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    ABSTRACT: Background:Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth.Methods:The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (lit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN-/-) mice. How suppressed GH/IGF-I levels impacted growth of PTEN-/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum.Results:Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN-/- littermates. While the anterior lobes of lit/+ PTEN-/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20-week-old lit/lit and lit/+ PTEN-/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N-cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH.Conclusions:These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed.Prostate Cancer and Prostatic Disease advance online publication, 21 May 2013; doi:10.1038/pcan.2013.14.
    Prostate cancer and prostatic diseases 05/2013; · 2.10 Impact Factor
  • Cancer Research 05/2013; 72(4 Supplement):C25-C25. · 9.28 Impact Factor
  • B J Eigl, M E Gleave, K N Chi
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    ABSTRACT: In the last decade, many systemic therapies have become available to improve survival in the setting of castration-resistant prostate cancer. Once effective treatments for advanced and incurable disease have been established, these agents are generally explored in the adjuvant and neoadjuvant settings to evaluate their role in increasing the chance of cure for localised disease. Clinical trials evaluating new therapies in high-risk prostate cancer can broadly be divided into two categories. Phase III (and some phase II) trials generally evaluate treatments that have already been shown to provide clinical benefit in the advanced disease setting; whereas smaller phase I (and some phase II) trials often serve as proof-of-principle assessments in the development of novel agents. The goal of this review is to provide an overview of present and ongoing clinical trials of both of these categories, evaluating the promise of systemic therapies in the setting of high-risk localised prostate cancer. We undertook a search of Ovid Medline, Embase and clinicaltrials.gov for prospective clinical studies assessing systemic therapy for early stage prostate cancer, either before or after definitive local treatment (surgery or radiation) from 2000 onwards. This resulted in 53 studies, of which 29 were deemed worthy of this overview and are presented herein, broadly divided by mechanism of action. Clearly, the arena evaluating the future of systemic therapies for localised prostate cancer will be a very active one.
    Clinical Oncology 05/2013; · 2.83 Impact Factor
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    ABSTRACT: Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.Oncogene advance online publication, 22 April 2013; doi:10.1038/onc.2013.143.
    Oncogene 04/2013; · 8.56 Impact Factor
  • Paul J Toren, Martin E Gleave
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    ABSTRACT: Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease. Further understanding of the biology of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.Journal of Andrology advance online publication, 15 April 2013; doi:10.1038/aja.2013.38.
    Asian Journal of Andrology 04/2013; · 2.14 Impact Factor
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    ABSTRACT: PURPOSEAs part of the ENTHUSE (Endothelin A Use) program, the efficacy and safety of zibotentan (ZD4054), an oral specific endothelin A receptor antagonist, has been investigated in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (CRPC).Patients And methodsIn this randomized, double-blind, placebo-controlled, phase III study, patients received intravenous docetaxel 75 mg/m(2) on day 1 of 21-day cycles plus oral zibotentan 10 mg or placebo once daily. The primary end point was overall survival (OS). Secondary end points included time to pain and prostate-specific antigen (PSA) progression, pain and PSA response, progression-free survival, health-related quality of life, and safety.ResultsA total of 1,052 patients received study treatment (docetaxel-zibotentan, n = 524; docetaxel-placebo, n = 528). At the time of data cutoff, there had been 277 and 280 deaths, respectively. There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P = .963). No significant differences were observed on secondary end points, including time to pain progression (median 9.3 v 10.0 months, respectively) or pain response (odds ratio, 0.84; 95% CI, 0.61 to 1.16; P = .283). The median time to death was 20.0 and 19.2 months for the zibotentan and placebo groups, respectively. The most commonly reported adverse events in zibotentan-treated patients were peripheral edema (52.7%), diarrhea (35.4%), alopecia (33.9%), and nausea (33.3%). CONCLUSION Docetaxel plus zibotentan 10 mg/d did not result in a significant improvement in OS compared with docetaxel plus placebo in patients with metastatic CRPC.
    Journal of Clinical Oncology 04/2013; · 17.88 Impact Factor
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    ABSTRACT: PURPOSE: Active surveillance is used to manage low risk prostate cancer. Both PCA3 and TMRPSS2-ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort. EXPERIMENTAL DESIGN: Post-DRE urine was collected prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2-ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables. RESULTS: In 387 men, both PCA3 and TMPRSS2-ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1-10%, 11-33%, ≥34% positive cores, median PCA3 and TMPRSS2-ERG scores increased incrementally (P < 0.005). Both PCA3 and TMPRSS2-ERG scores were also significantly associated with presence of high grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3 and TMPRSS2-ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as a continuous variables, the odds ratio for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI 1.07-1.85), P = 0.01 for PCA3 and 1.28 (95% CI 1.10-1.49), P = 0.001 for TMPRSS2-ERG. CONCLUSIONS: For men on active surveillance both PCA3 and TMPRSS2-ERG appear to stratify risk of having aggressive cancer as defined by tumor volume or Gleason score.
    Clinical Cancer Research 03/2013; · 8.19 Impact Factor
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    ABSTRACT: Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.
    Cancer cell 03/2013; 23(3):332-46. · 25.29 Impact Factor
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    ABSTRACT: Resistance to anti-androgen drugs, like MDV3100, occurs in patients with castration resistant prostate cancer (CRPC). Thus, preventing or treating anti-androgen resistance is a major clinical challenge. We identified a novel anti-androgen, Compound 30, and compared its efficacy to MDV3100. We found that Compound 30 inhibits AR activity in LNCaP cells, C4-2 cells, as well as MDV3100 resistant cell lines. Compared to MDV3100, Compound 30 treatment induces greater reduction in AR, PSA, and AR transcriptional activity, and prevents AR nuclear translocation, in AR-sensitive LNCaP cells. Compound 30 has anti-proliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100 resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100 resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a pre-clinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of anti-androgens resistant tumors.
    Molecular Cancer Therapeutics 03/2013; · 5.60 Impact Factor
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    ABSTRACT: Background:Standard treatment options are limited for the management of non-metastatic castration-resistant prostate cancer (CRPC). This study, part of the ENTHUSE (EndoTHelin A USE) phase III programme, evaluated the efficacy and safety of the oral specific endothelin (ET)(A) receptor antagonist zibotentan vs placebo in patients with non-metastatic CRPC (non-mCRPC).Methods:This was a multicentre, randomized, double-blind, phase III study. Patients (n=1421) with non-mCRPC and biochemical progression (determined by rising serum PSA levels) were randomized to receive zibotentan 10 mg or placebo once daily. Based on the lack of efficacy signal in another ENTHUSE phase III study, an interim analysis was performed to determine whether the study was likely to achieve the co-primary objectives of improved overall survival (OS) and progression-free survival (PFS).Results:Criteria for continuation of this study were not met. A total of 79 deaths and 293 progression events were recorded at final data cutoff. Zibotentan-treated patients did not significantly differ from placebo-treated patients for OS (hazard ratio (HR): 1.13; 95% confidence interval (CI): 0.73-1.76, P=0.589) or PFS (HR: 0.89; 95% CI: 0.71-1.12, P=0.330). The most commonly reported adverse events in zibotentan-treated patients were peripheral oedema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with >15% higher incidence than in the placebo group.Conclusions:This trial was terminated early because of failure at interim analysis of the efficacy data to meet the defined criteria for continuation. Owing to the absence of demonstrable survival benefits in the ENTHUSE clinical studies, zibotentan is no longer under investigation as a potential treatment for prostate cancer.Prostate Cancer and Prostatic Disease advance online publication, 5 February 2013; doi:10.1038/pcan.2013.2.
    Prostate cancer and prostatic diseases 02/2013; · 2.10 Impact Factor

Publication Stats

5k Citations
755.71 Total Impact Points


  • 2005–2014
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
  • 2000–2014
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
    • University of Toronto
      • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 1995–2014
    • University of British Columbia - Vancouver
      • • Vancouver Prostate Centre
      • • Department of Urologic Sciences
      • • Division of Neurology
      • • Division of Endocrinology
      • • Department of Surgery
      Vancouver, British Columbia, Canada
  • 2013
    • Université de Montréal
      Montréal, Quebec, Canada
  • 2012
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2006–2012
    • University of California, Los Angeles
      • Department of Molecular and Medical Pharmacology
      Los Angeles, California, United States
  • 1998–2012
    • Vancouver General Hospital
      • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
  • 1992–1994
    • University of Texas MD Anderson Cancer Center
      • Department of Urology
      Houston, TX, United States