M E Gleave

Vancouver Prostate Centre, Vancouver, British Columbia, Canada

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Publications (154)854.42 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Multimodal treatment for men with locally advanced prostate cancer (PCa) using neoadjuvant/adjuvant systemic therapy, surgery, and radiation therapy is being increasingly explored. There is also interest in the oncologic benefit of treating the primary tumor in the setting of metastatic PCa (mPCa). To perform a review of the literature regarding the treatment of the primary tumor in the setting of mPCa. Medline, PubMed, and Scopus electronic databases were queried for English language articles from January 1990 to September 2014. Prospective and retrospective studies were included. There is no published randomized controlled trial (RCT) comparing local therapy and systemic therapy to systemic therapy alone in the treatment of mPCa. Prospective studies of men with locally advanced PCa and retrospective studies of occult node-positive PCa have consistently shown the addition of local therapy to a multimodal treatment regimen improves outcomes. Molecular and genomic evidence further suggests the primary tumor may have an active role in mPCa. Treatment of the primary tumor in mPCa is being increasingly explored. While preclinical, translational, and retrospective evidence supports local therapy in advanced disease, further prospective studies are under way to evaluate this multimodal approach and identify the patients most likely to benefit from the inclusion of local therapy in the setting of metastatic disease. In this review we explored preclinical and clinical evidence for treatment of the primary tumor in metastatic prostate cancer (mPCa). We found evidence to support clinical trials investigating mPCa therapy that includes local treatment of the primary tumor. Currently, treating the primary tumor in mPCa is controversial and lacks high-level evidence sufficient for routine recommendation. Copyright © 2015. Published by Elsevier B.V.
    European Urology 05/2015; DOI:10.1016/j.eururo.2015.04.036 · 12.48 Impact Factor
  • Haolong Li, Ning Xie, Martin E Gleave, Xuesen Dong
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    ABSTRACT: Although the new generation of androgen receptor (AR) antagonists like enzalutamide (ENZ) prolong survival of metastatic castration-resistant prostate cancer (CRPC), AR-driven tumors eventually recur indicating that additional therapies are required to fully block AR function. Since DNA topoisomerase II (Topo II) was demonstrated to be essential for AR to initiate gene transcription, this study tested whether catalytic inhibitors of Topo II can block AR signaling and suppress ENZ-resistant CRPC growth. Using multiple prostate cancer cell lines, we showed that catalytic Topo II inhibitors, ICRF187 and ICRF193 inhibited transcription activities of the wild-type AR, mutant ARs (F876L and W741C) and the AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 also inhibited cell proliferation and delayed cell cycling at the G2/M phase. ICRF187 inhibited tumor growth of castration-resistant LNCaP and 22RV1 xenografts as well as ENZ-resistant MR49F xenografts. We conclude that catalytic Topo II inhibitors can block AR signaling and inhibit tumor growth of CRPC xenografts, identifying a potential co-targeting approach using these inhibitors in combination with AR pathway inhibitors in CRPC.
    Oncotarget 05/2015; · 6.63 Impact Factor
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    Alexander W Wyatt, Martin E Gleave
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    ABSTRACT: Castration and androgen receptor (AR) pathway inhibitors induce profound and sustained responses in advanced prostate cancer. However, the inevitable recurrence is associated with reactivation of the AR and progression to a more aggressive phenotype termed castration-resistant prostate cancer (CRPC). AR reactivation can occur directly through genomic modification of the AR gene, or indirectly via co-factor and co-chaperone deregulation. This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways. In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways. We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC.
    EMBO Molecular Medicine 04/2015; DOI:10.15252/emmm.201303701 · 8.25 Impact Factor
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    ABSTRACT: Large oncosomes (LO) are atypically large (1-10µm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrepTM) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.
    Oncotarget 03/2015; · 6.63 Impact Factor
  • Clinical Cancer Research 02/2015; 21(4 Supplement):A12-A12. DOI:10.1158/1557-3265.PMS14-A12 · 8.19 Impact Factor
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    Journal of Clinical Oncology 01/2015; 33:(suppl 7; abstr 157). · 17.88 Impact Factor
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    ABSTRACT: Background: ENZ is a potent androgen receptor (AR) antagonist that prolongs survival in mCRPC patients (pts). However, factors driving resistance to ENZ are incompletely understood. Genomic analysis of cfDNA is a promising, minimally invasive approach for interrogating mechanisms of therapeutic resistance in mCRPC. Methods: Baseline plasma samples were collected from 57 mCRPC pts commencing ENZ. In 37 pts, additional samples at 12-weeks +/- end-of-treatment were obtained. DNA was extracted and subjected to array Comparative Genomic Hybridization (aCGH) for chromosome copy number (CN) analysis and AR gene (exon 2-8) sequencing (MiSeq) for mutation analysis. Endpoints were i) PSA50 or PSA30 response rates (RR) (PSA decline ≥ 50% or 30% for ≥ 3 weeks); and ii) radiographic/clinical progression-free survival (PFS). Results: On aCGH, the most frequent CN changes in baseline samples (n = 57) were 8p loss (25%), 8q gain (35%), MYC gain (26%) and AR gain/amp (33%). Compared to pts with no AR gain/amp, pts with pre-treatment AR gain/amp had lower PSA50 (39% vs. 21%, P= 0.16; Χ2) and PSA30 RR (44% vs. 25%, P= 0.059; Χ2) and shorter median PFS (4.5 vs. 2.2 months, P= 0.002; log-rank). On multivariate analysis, pre-treatment AR gain/amp (HR 2.56 P= 0.01) was confirmed as an independent prognostic factor for PFS. In pts with 12-week +/- end-of-treatment samples, 14% (5/37) had a change in AR CN status from baseline with 3 pts converting from no AR gain to AR gain and 2 pts from AR gain to AR amp. Median PFS in these 5 pts was 2.8 months. AR gene sequencing was performed on a subset of 4 pts with 4 high-frequency mutations detected in 3 pts including H874Y (n = 2) and L702H (n = 2), the latter of which converts glucocorticoids to AR agonists. Notably, both L702H mutations were found in end-of-treatment samples from pts who progressed rapidly on ENZ (2.9 months PFS each). Neither of these pts was on glucocorticoids at progression, potentially implicating L702H in ENZ resistance. Conclusions: Our data indicate that AR gene aberrations may be key biomarkers of primary and acquired resistance to ENZ in mCRPC. Complete AR gene sequencing data will be presented.
    Journal of Clinical Oncology 01/2015; 33:suppl; abstr 5015. · 17.88 Impact Factor
  • 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; 12(1). DOI:10.1038/nrurol.2014.320 · 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; 136(4). DOI:10.1002/ijc.29147 · 5.01 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: Objectives: 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 the human serum. Design and methods: We used increasing amounts of the same serum sample to isolate exosomes using two different methods: ultracentrifugation onto a sucrose cushion and ExoQuick (TM). Quantitative analysis of serum-derived exosomes was performed by determining protein concentration (BCA assay) and the number of nanoparticles (Nanosight (TM) technology). Exosome quality was assessed by Coomassie staining and Western blotting for CD9, LAMP2 exosomal markers and a negative marker Grp94. Results: Correlation between serum volume and the number of isolated exosomes is significant for both methods when exosomes are quantified using protein concentration. However, when the number of nanoparticles is used to quantify exosomes, ExoQuick (TM) is the only reproducible and efficient method. CD9, LAMP2 and Grp94 exosomal markers are equivalently expressed in both methods. However, exosomes isolated using ultracentrifuge method are strongly contaminated with albumin and IgG. Conclusion: ExoQuick (TM) is an efficient and reproducible method to isolate exosomes for quantitative studies, whereas ultracentrifugation is not. Moreover, high albumin contamination of ultracentrifuged-derived exosomes impairs the use of protein concentration as a mean to quantify serum-derived exosomes.
    Clinical Biochemistry 06/2014; 47(13-14). DOI:10.1016/j.clinbiochem.2014.06.011 · 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; DOI:10.1016/j.eururo.2014.04.015 · 12.48 Impact Factor
  • European Urology Supplements 04/2014; 13(1):e30. DOI:10.1016/S1569-9056(14)60032-4 · 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; DOI:10.1073/pnas.1322198111 · 9.81 Impact Factor
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    ABSTRACT: Most small renal masses (SRMs) are diagnosed incidentally and have a low malignant potential. As more elderly patients and infirm patients are diagnosed with SRMs, there is an increased interest in active surveillance (AS) with delayed intervention. Patient and tumour characteristics relating to aggressive disease have not been well-studied. The objective was to determine predictors of growth of SRMs treated with AS. A multicentre prospective phase 2 clinical trial was conducted on 207 SRMs in 169 patients in 8 institutions in Canada from 2004 to 2009; in these patients treatment was delayed until disease progression. Patient and tumour characteristics were evaluated to determine predictors of growth of SRMs by measuring rates of change in growth (on imaging) over time. All patients underwent AS for presumed renal cell carcinoma (RCC) based on diagnostic imaging. We used the following factors to develop a predictive model of tumour growth with binary recursive partitioning analysis: patient characteristics (age, symptoms at diagnosis) and tumour characteristics (consistency [solid vs. cystic] and maximum diameter at diagnosis. With a median follow-up of 603 days, 169 patients (with 207 SRMs) were followed prospectively. Age, symptoms at diagnosis, tumour consistency and maximum diameter of the renal mass were not predictors of growth. This cohort was limited by lack of availability of patient and tumour characteristics, such as sex, degree of endophytic component and tumour location. Slow growth rates and the low malignant potential of SRMs have led to AS as a treatment option in the elderly and infirm population. In a large prospective cohort, we have shown that age, symptoms, tumour consistency and maximum diameter of the mass at diagnosis are not predictors of growth of T1a lesions. More knowledge on predictors of growth of SRMs is needed.
    Canadian Urological Association journal = Journal de l'Association des urologues du Canada 02/2014; 8(1-2):24-7. DOI:10.5489/cuaj.1483 · 1.92 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. DOI:10.1016/j.eururo.2013.08.008 · 12.48 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):C89-C89. DOI:10.1158/1535-7163.TARG-13-C89 · 6.11 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; 113(2). DOI:10.1111/bju.12556 · 3.13 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):5359-5359. DOI:10.1158/1538-7445.AM2013-5359 · 9.28 Impact Factor

Publication Stats

5k Citations
854.42 Total Impact Points


  • 2005–2015
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
  • 1995–2015
    • 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
  • 2000–2014
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2013
    • University of Burgundy
      Dijon, Bourgogne, France
  • 1998–2013
    • Vancouver General Hospital
      • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
    • Laval University
      Quebec City, Quebec, Canada
  • 2000–2001
    • University of Toronto
      • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 1997
    • University of Washington Seattle
      Seattle, Washington, United States
  • 1992–1994
    • University of Texas MD Anderson Cancer Center
      • Department of Urology
      Houston, TX, United States