M E Gleave

Università degli Studi di Trento, Trient, Trentino-Alto Adige, Italy

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Publications (182)1049.23 Total impact

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    ABSTRACT: Purpose: Clinical evidence suggests an increased CSC in tumor mass may contribute to the failure of conventional therapies since CSCs seem to be more resistant than differentiated tumor cells. Thus, unveiling the mechanism regulating CSCs and candidate target molecules will provide new strategy to cure the patients. Experimental design: The stemness of prostate cancer cells was determined by a prostasphere assay, and dye exclusion assay. To find critical stem cell marker and reveal regulation mechanism, basic biochemical and molecular biological methods such as qRT-PCR, Western blot, reporter gene assay and chromatin immunoprecipitation assay were employed. In addition, to determine the effect of combination therapy targeting both CSCs and its progeny, in vitro MTT assay and in vivo xenograft model was used. Results: We demonstrate immortalized normal human prostate epithelial cells, appeared non-tumorigenic in vivo, become tumorigenic and acquire stem cell phenotype after knocking down a tumor suppressor gene. Also, those stem-like cells increase chemoresistance to conventional anti-cancer reagent. Mechanistically, we unveil that Wnt signaling is a key pathway regulating well-known stem cell marker CD44 by directly interacting to the promoter. Thus, by targeting CSCs using Wnt inhibitors synergistically enhances the efficacy of conventional drugs. Furthermore, the in vivo mice model bearing xenografts showed a robust inhibition of tumor growth after combination therapy. Conclusions: Overall, this study provides strong evidence of CSC in CRPC. This new combination therapy strategy targeting CSC could significantly enhance therapeutic efficacy of current chemotherapy regimen only targeting non-CSC cells.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-0190 · 8.72 Impact Factor
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    ABSTRACT: Tumor microenvironments are characterized by decreased oxygen and nutrition due to the rapid and progressive nature of tumors and also stresses induced by several anti-tumor therapies. These intense cell stressors trigger a protective cell survival mechanism heralded by the unfolded protein response (UPR). The UPR is induced by an accumulation of unfolded proteins in the endoplasmic reticulum (ER) following cell starvation. Although the ER stress response is implicated in cytoprotection, its precise role during anti-angiogenic therapy remains unclear. One of the major proteins involved in ER stress is glucose-regulated protein 78 (GRP78), which binds to unfolded proteins and dissociates from membrane-bound ER stress sensors. To determine the role of ER stress responses during anti-angiogenic therapy and the potential role of GRP78 in combined therapy in renal cell carcinoma (RCC), we used GRP78 overexpressing or knockdown RCC cells under hypoxic or hypoglycemic conditions in vitro and in animal models treated with sunitinib. Here, we report that GRP78 plays a crucial role in protecting RCC cells from hypoxic and hypoglycemic stress induced by anti-angiogenic therapy. Knockdown of GRP78 using siRNA inhibited cancer cell survival and induced apoptosis in RCC cells in vitro and also resulted in ER stress-induced apoptosis and hypoxic/hypoglycemic stress-induced apoptosis by inactivating the PERK/eIF-2α pathway. Finally, GRP78 knockdown showed potent suppression of tumor growth and enhanced the antitumor effect of sunitinib in RCC xenografts. Our findings suggest that GRP78 may serve as a novel therapeutic target in combination with anti-angiogenic therapy for the management of RCC.
    Oncotarget 10/2015; DOI:10.18632/oncotarget.5397 · 6.36 Impact Factor
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    ABSTRACT: Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.
    PLoS ONE 09/2015; 10(9):e0138958. DOI:10.1371/journal.pone.0138958 · 3.23 Impact Factor
  • Yinan Li · Ning Xie · Martin E Gleave · Paul S Rennie · Xuesen Dong ·
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    ABSTRACT: Failure of androgen-targeted therapy and progression of castration-resistant prostate cancer (CRPC) are often attributed to sustained expression of the androgen receptor (AR) and its major splice variant, AR-v7. Although the new generation of anti-androgens such as enzalutamide effectively inhibits AR activity, accumulating pre-clinical and clinical evidence indicates that AR-v7 remains constitutively active in driving CRPC progression. However, molecular mechanisms which control AR-v7 protein expression remain unclear. We apply multiple prostate cancer cell models to demonstrate that enzalutamide induces differential activation of protein phosphatase-1 (PP-1) and Akt kinase depending on the gene context of cancer cells. The balance between PP-1 and Akt activation governs AR phosphorylation status and activation of the Mdm2 ubiquitin ligase. Mdm2 recognizes phosphorylated serine 213 of AR-v7, and induces AR-v7 ubiquitination and protein degradation. These findings highlight the decisive roles of PP-1 and Akt for AR-v7 protein expression and activities when AR is functionally blocked.
    Oncotarget 09/2015; DOI:10.18632/oncotarget.5608 · 6.36 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):731-731. DOI:10.1158/1538-7445.AM2015-731 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):3592-3592. DOI:10.1158/1538-7445.AM2015-3592 · 9.33 Impact Factor
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    ABSTRACT: Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multi-center study of active surveillance. We studied 905 men in the prospective Canary Prostate cancer Active Surveillance Study (PASS) enrolled between 2008 to 2013. We collected clinical data at study entry and at pre-specified intervals and determined associations with adverse reclassification defined as increased Gleason grade or greater cancer volume on follow-up biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance. During a median follow-up of 28 months, 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued active surveillance. Overall, 19% of participants received treatment, 68% with adverse reclassification while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling, percent of biopsy cores with cancer, BMI, and PSA density were associated with adverse reclassification (P = 0.01, 0.04, 0.04). Of 103 participants subsequently treated by radical prostatectomy, 34% had adverse pathology, defined as primary pattern 4-5 or non-organ confined disease, including two with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (P = 0.76). Most men remain on active surveillance at five years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only modest association with disease reclassification, supporting the need for approaches that improve prediction of this outcome. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of urology 08/2015; DOI:10.1016/j.juro.2015.08.087 · 4.47 Impact Factor
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    ABSTRACT: More potent targeting of the androgen receptor (AR) in advanced prostate cancer is driving an increased incidence of neuroendocrine prostate cancer (NEPC), an aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. We modeled the development of NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft and found that the placental gene PEG10 is de-repressed during the adaptive response to AR interference and subsequently highly upregulated in clinical NEPC. We found that the AR and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at distinct stages of NEPC development. In vitro, PEG10 promoted cell-cycle progression from G0/G1 in the context of TP53 loss and regulated Snail expression via TGF-β signaling to promote invasion. Taken together, these findings show the mechanistic relevance of RB1 and TP53 loss in NEPC and suggest PEG10 as a NEPC-specific target. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 12(6). DOI:10.1016/j.celrep.2015.07.012 · 8.36 Impact Factor
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    ABSTRACT: Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer. To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response. Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response. Feasibility, use of WES for decision making, and identification of novel biomarkers. A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.
    07/2015; 1(4):466-474. DOI:10.1001/jamaoncol.2015.1313
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    ABSTRACT: Lipid nanoparticle (LNP) formulations facilitate tumor uptake and intracellular processing through an enhanced permeation and retention effect (EPR), and currently multiple products are undergoing clinical evaluation. Clusterin (CLU) is a cytoprotective chaperone induced by androgen receptor (AR) pathway inhibition to facilitate adaptive survival pathway signalling and treatment resistance. In our study, we investigated the efficacy of siRNA tumor delivery using LNP systems in an enzalutamide-resistant (ENZ-R) castration-resistant prostate cancer (CRPC) model. Gene silencing of a luciferase reporter gene in the PC3-M-luc stable cell line was first assessed in subcutaneous and metastatic PC-3 xenograft tumors. Upon validation, the effect of LNP siRNA targeting CLU in combination with AR antisense oligonucleotides (ASO) was assessed in ENZ-R CRPC LNCaP in vitro and in vivo models. LNP LUC-siRNA silenced luciferase expression in PC-3M-luc subcutaneous xenograft and metastatic models. LNP CLU-siRNA potently suppressed CLU and AR ASO induced CLU and AKT and ERK phosphorylation in ENZ-R LNCaP cells in vitro, more potently inhibiting ENZ-R cell growth rates and increased apoptosis when compared to AR-ASO monotherapy. In subcutaneous ENZ-R LNCaP xenografts, combinatory treatment of LNP CLU-siRNA plus AR-ASO significantly suppressed tumor growth and serum PSA levels compared to LNP Luc-siRNA (control) and AR-ASO. LNP siRNA can silence target genes in vivo and enable inhibition of traditionally non-druggable genes like CLU and other promising co-targeting approaches in ENZ-R CRPC therapeutics. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 06/2015; DOI:10.1158/1078-0432.CCR-15-0866 · 8.72 Impact Factor
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    ABSTRACT: SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation therefore remain largely unknown. Performing a functional genomics screen, we found that downregulation of SRC inhibitory kinase CSK is sufficient to overcome growth arrest induced by depriving human prostate cancer cells of androgen. CSK knockdown led to ectopic SRC activation, increased AR signaling, and resistance to anti-androgens. Consistent with the in vitro observations, stable knockdown of CSK conferred castration resistance in mouse xenograft models, while sensitivity to the tyrosine kinase inhibitor dasatinib was retained. Finally, CSK was found downregulated in a distinct subset of CRPCs marked by AR amplification and ETS2 deletion but lacking PTEN and RB1 mutations. These results identify CSK downregulation as a principal driver of SRC activation and castration resistance and validate SRC as a drug target in a molecularly defined subclass of CRPCs.
    Oncotarget 06/2015; 6(26). DOI:10.18632/oncotarget.4279 · 6.36 Impact Factor
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    ABSTRACT: The first St.Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection.Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with advanced prostate cancer in clinical trials should be encouraged. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 06/2015; 26(8). DOI:10.1093/annonc/mdv257 · 7.04 Impact Factor
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    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 · 13.94 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; 75(15 Supplement). DOI:10.1158/1538-7445.AM2015-1846 · 6.36 Impact Factor
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    ABSTRACT: In this study, we show that the transmembrane glycoprotein Trop-2 is up-regulated in human prostate cancer (PCa) with extracapsular extension (stages pT3/pT4) as compared to organ-confined (stage pT2) PCa. Consistent with this evidence, Trop-2 expression is found to be increased in metastatic prostate tumors of Transgenic Adenocarcinoma of Mouse Prostate mice and to strongly correlate with α5β1 integrin levels. Using PCa cells, we show that Trop-2 specifically associates with the α5 integrin subunit, as binding to α3 is not observed, and that Trop-2 displaces focal adhesion kinase from focal contacts. In support of the role of Trop-2 as a promoter of PCa metastatic phenotype, we observe high expression of this molecule in exosomes purified from Trop-2-positive PCa cells. These vesicles are then found to promote migration of Trop-2-negative PCa cells on fibronectin, an α5β1 integrin/focal adhesion kinase substrate, thus suggesting that the biological function of Trop-2 may be propagated to recipient cells. In summary, our findings show that Trop-2 promotes an α5β1 integrin-dependent pro-metastatic signaling pathway in PCa cells and that the altered expression of Trop-2 may be utilized for early identification of capsule-invading PCa.
    Oncotarget 04/2015; 6(16). DOI:10.18632/oncotarget.3960 · 6.36 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e755. DOI:10.1016/j.juro.2015.02.2239 · 4.47 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; 7(7). DOI:10.15252/emmm.201303701 · 8.67 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(13). DOI:10.18632/oncotarget.3598 · 6.36 Impact Factor

  • Clinical Cancer Research 02/2015; 21(4 Supplement):A12-A12. DOI:10.1158/1557-3265.PMS14-A12 · 8.72 Impact Factor

Publication Stats

6k Citations
1,049.23 Total Impact Points


  • 2015
    • Università degli Studi di Trento
      • CIBIO - Centre for Integrative Biology
      Trient, Trentino-Alto Adige, Italy
  • 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
      • • Faculty of Pharmaceutical Sciences
      • • Division of Endocrinology
      • • Department of Surgery
      Vancouver, British Columbia, Canada
  • 2014
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2013
    • University of Burgundy
      Dijon, Bourgogne, France
  • 1997-2013
    • Vancouver General Hospital
      • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
  • 2010
    • UBC - Universidade BRAZ CUBAS
  • 2001
    • University of Toronto
      Toronto, Ontario, Canada
  • 1998
    • Laval University
      Quebec City, Quebec, Canada
  • 1992-1993
    • University of Houston
      Houston, Texas, United States
  • 1991-1993
    • University of Texas MD Anderson Cancer Center
      • Department of Urology
      Houston, Texas, United States