Yuzhuo Wang

Professor

Research Classification

Prostate Cancer

Research Interests

Modeling and Targeting the Development of Castration-Resistant Prostate Cancer

Relevant Degree Programs

 

Biography

Dr. Yuzhuo Wang, Ph.D. FCAHS (王玉琢院士) has a dual appointment as a Distinguished Scientist at the BC Cancer Research Centre and Senior Research Scientist at the Vancouver Prostate Centre. He is also the Founder of the Living Tumor Laboratory (www.livingtumorlab.com) and a Professor in Department of Urologic Sciences at UBC. Dr. Wang did his Ph.D. at the University of Hong Kong, and joined Dr. Gerald R. Cunha at University of California, San Francisco (UCSF) as a postdoctoral fellow in 1997. Since then, He has authored/co-authored over 150 peer reviewed articles, many in top-tier journals such as Cancer Research, Cancer Cell, Nature Medicine, Nature, Clinical Cancer Research, and European Urology. He has published 13 book chapters and edited two books (i.e. PDX Model of Human Cancers and Tumor Dormancy). As a principal investigator, he is well funded by a number of agencies (e.g., the Canadian Institutes of Health Research).
Dr. Wang’s academic contributions can be highlighted by a number of novel hypotheses he has proposed, such as hypotheses on “prostate stem cells”, “epithelial-immune cell transition (EIT)”, “cancer-generated lactic acid is critical, immunosuppressive metabolite rather than a ‘waste product’ (which has been believed for more than 90 years)” and “tumour dormancy is a non-genetic disease”. Dr. Wang is recognized for his pioneering work in the field of prostate cancer modeling. He was the first to establish tissue recombination model of hormonal prostatic carcinogenesis. He also developed the first model of hormonal carcinogenesis in human prostatic epithelium. Moreover, he is responsible for a novel method for establishing transplantable, patient-derived xenograft models that closely resemble patients’ malignancies. Using the methodology, his group has developed over 300 transplantable patient-derived xenograft models in the Living Tumor Laboratory. Importantly such “next generation” xenograft models have been effectively applied in a number of research areas, such as (i) preclinical drug efficacy studies in anti-cancer therapeutics development, (ii) discovery and validation of potential biomarkers and/or therapeutic targets, and (iii) personalized cancer therapy.
Dr. Wang has received numerous awards for his academic achievements in cancer research, such as a Prostate Cancer Foundation Research Award (2007), the Translation Research Award from Roche (2009), an Overseas Chinese Scholars Award from the National Natural Science Foundation of China (2009), the Innovative Scholar Award from the International Cancer Alliance for Research and Education (ICARE), US (2010), an UBC Faculty of Medicine Distinguished Achievement Award (2011), an UBC Department of Urologic Sciences Outstanding Academic Performance Award (2013) and a Department of Urologic Sciences Research Teaching Excellence Award (2015), and an UBC Department of Urologic Sciences Outstanding Academic Performance Award (2017). Notably, he has been inducted as a Fellow of the Canadian Academy of Health Sciences (FCAHS) (加拿大健康科学院院士) in 2018.

Research Methodology

PDX models
Target discovery
Drug development

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Doctoral students
Postdoctoral Fellows
Any time / year round
I support public scholarship, e.g. through the Public Scholars Initiative, and am available to supervise students and Postdocs interested in collaborating with external partners as part of their research.
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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
Potential use of Aneustat for improvement of docetaxel-based therapy of advanced prostate cancer (2018)

Metastatic prostate cancer (mPCa) is currently incurable. Docetaxel-based chemotherapy, used as first-line treatment for advanced PCa, is marginally effective. As PCa is a heterogeneous disease, use of therapeutics targeting multiple pathways may improve its treatment outcome. Aneustat is first-of-a-class of multivalent immuno-oncology drug candidates; a Phase-I trial has shown it is well-tolerated by patients and has immunomodulatory activity. The main goal of this PhD project is to determine whether Aneustat can be used to improve docetaxel-based therapy of advanced PCa. In vitro, Aneustat markedly inhibited human metastatic C4-2 PCa cell proliferation/migration in a dose-dependent manner and, combined with docetaxel, showed synergistic growth inhibition. In vivo, a combination of Aneustat and docetaxel synergistically enhanced anticancer activity in a clinically relevant, patient-derived xenograft (PDX) metastatic PCa model without inducing major host toxicity (inhibition of tumor growth, lung micro-metastasis, kidney invasion). Gene expression analysis of microarray data obtained from xenografts, using Ingenuity Pathway Analysis (IPA) and Oncomine software, indicated that Aneustat+docetaxel, as distinct from the single drugs, targeted multiple pathways and cancer-driving genes. Aneustat alone significantly inhibited growth of human LNCaP cells/xenografts; glucose consumption, lactic acid secretion and glycolysis-related gene expressions of LNCaP cells were markedly reduced, indicating it inhibited aerobic glycolysis. Treatment of LNCaP xenografts and first-generation PCa PDX with Aneustat led to marked changes in host immune cell levels (mouse/human), i.e. a higher ratio of CD8⁺T/Treg cells, higher Natural Killer (NK) cell numbers, lower Treg cell and MDSC numbers – changes favoring the host anticancer immune response. This study shows that combined use of Aneustat and docetaxel can lead to marked, synergistically increased anticancer activity, both in vitro and in vivo. As indicated by IPA and Oncomine analyses, this is due to the combination-induced expansion of the targeting of pathways and cancer-driving genes. Furthermore, as found with first-generation PDX PCa model, Aneustat has immunomodulatory properties, likely stemming from its inhibition of aerobic glycolysis, that may lead to stimulation of the anticancer immune response in immunocompetent hosts. Since a clinically relevant PDX metastatic PCa model was used in this study, treatment with Aneustat+docetaxel is likely valuable for clinical management of advanced PCa.

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Targeting MCT4 for treatment of advanced prostate cancers : inhibiting cell proliferation and enhancing anticancer immunity through suppressing lactic acid secretion and elevated glycolysis (2018)

Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in North American males and a leading cause of cancer deaths. The lack of effective treatment options for advanced PCa such as AR-positive castration-resistant PCa (CRPC-AD) and the highly aggressive AR-negative CRPC, e.g. neuroendocrine PCa (CRPC-NE) presents a critical, unmet need for the development of novel therapeutics. Altered metabolism in the form of elevated aerobic glycolysis is a common cancer characteristic. Here we propose a novel conceptual understanding for the central, functional role of excessive cancer-generated lactic acid. In particular, the acidification of the tumor microenvironment via increased MCT4-mediated lactic acid secretion can facilitate multiple crucial cancer-promoting processes, including proliferation, tissue invasion/metastasis, angiogenesis, and suppression of local anticancer immunity. As such, the inhibition of MCT4 could be an effective therapeutic strategy broadly impacting multiple downstream lactate-associated tumour-promoting processes. Experimentally, we were able to confirm the clinical relevance of elevated glycolysis and increased lactic acid production in various advanced PCa patient-derived xenograft (PDX) models and patient tumours using a novel metabolic pathway score. In particular, NEPC tumours appear to rely much more heavily on elevated aerobic glycolysis and MCT4-mediated lactic acid secretion. In a proof-of-concept study using MCT4-specific antisense oligonucleotides (ASOs), reduced MCT4 expression is able to reduce proliferation, invasion/migration, and glucose metabolism of advanced PCa cells in vitro. More importantly, we demonstrated in two distinct in vivo models containing residual functional immune cells that MCT4 inhibition enhanced anticancer immunity. Finally, a state-of-the-art in silico drug discovery pipeline was employed in the first steps towards developing a potent and specific MCT4 small molecule inhibitor. Computer modeling of MCT4 structure, virtual molecular docking, and downstream experimental validation identified a promising hit series based on the chemical scaffold of VPC-25009 as a potential second therapeutic modality for MCT4 inhibition. Taken together, we were able to provide experimental support for our novel hypothesis regarding the central tumour-promoting and immunosuppressive role of cancer-generated lactic acid. A therapeutic approach blocking lactic acid secretion by targeting MCT4 function could thus inhibit multiple downstream lactate-associated processes for effective treatment of advanced PCa and other highly glycolytic cancers.

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BIRC6 as novel therapeutic target in advanced prostate cancer : clinical relevance, development of potential therapeutic agents & preclinical drug efficacy (2016)

The lack of effective therapy for advanced prostate cancer (PCa) remains a major unmet clinical need. Recently approved therapeutics, such as enzalutamide (ENZ), have only delayed the inevitable progression of castration-resistant PCa (CRPC), as resistance will typically emerge following treatment. Although increased apoptosis-resisting ability of cancer cells represents a fundamental mechanism for the onset of treatment resistance, no relevant agents have yet been developed. Preliminary work in our laboratory has revealed an association between elevated expression of BIRC6, an Inhibitor of Apoptosis (IAP) protein, and advanced PCa. The overall objective of this doctoral study is to investigate the roles of BIRC6 in advanced PCa, and to assess the therapeutic efficacy of a novel anti-BIRC6 agent. Firstly, I evaluated the clinical relevance of BIRC6 using patients’ PCa specimens, and the functional importance of BIRC6 using cell line-based PCa models. A significant correlation was found between elevated BIRC6 protein expression in clinical PCa and poor patient prognostic factors. Functional assays validated the importance of BIRC6 in PCa cell proliferation and apoptosis suppression. Next, I designed BIRC6-based, dual IAP-targeting antisense oligonucleotides (dASOs) to inhibit BIRC6 and an additional IAP. Two dASOs, 6w2 and 6w5 targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cell proliferation in vitro and in vivo. Functional studies showed that both dASOs significantly induced apoptosis, cell cycle arrest and suppression of NFκB activation in CRPC cells. Finally, I assessed the growth-inhibitory efficacy of dASO-6w2 in ENZ-resistant CRPC, which has become an increasingly prominent problem in the clinic. The efficacy of dASO-6w2 was studied using both ENZ-resistant PCa cell lines and a clinically relevant, transplantable patient-derived xenograft PCa tissue model, designated LTL-313BR, which exhibits primary ENZ resistance. Importantly, I showed that treatment with dASO-6w2 markedly suppressed the growth of LTL-313BR xenografts. The dASO-6w2 was also found to increase tumour apoptosis and inhibit the expression of several pro-survival genes that were up-regulated in the LTL-313BR line. In conclusion, this doctoral study has established the clinical relevance and functional importance of BIRC6 in advanced PCa, and has also presented new BIRC6-targeting agents that markedly suppress the growth of advanced PCa.

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Identification of metastasis-driving genes as potential therapeutic targets/ biomarkers for metastatic prostate cancer (2015)

Metastatic prostate cancer is currently incurable. Metastasis is thought to result from changes in the expression of specific metastasis-driving genes, leading to a cascade of activated downstream genes setting the metastatic process in motion. As such, metastasis-driving genes could provide effective therapeutic targets and prognostic biomarkers for improved disease management. In search of potential metastasis-driving genes, genes with elevated expression in patient-derived metastatic LTL-313H prostate cancer tissues, as distinct from non-metastatic LTL-313B tissues, were identified. Among these genes, TIMELESS and DLX1 were promising. Unfortunately, their silencing and overexpression in prostate cancer cells did not lead to inhibition of metastatic properties, indicating that they were not metastasis-driving genes. A different, novel approach was used based on the notion that metastasis-driving genes can activate genes in an amplification cascade fashion. Accordingly, I used the IPA’s Upstream Regulator Analysis tool to analyze the differential gene expression profile of the metastatic and non-metastatic tissues to predict the upstream master regulatory (metastasis-driving) genes accountable for the differential expression. Six candidate genes were identified, including GATA2, a pioneer factor-encoding gene. Elevated GATA2 expression in clinical metastatic prostate cancer specimens correlated with poor patient prognosis. Furthermore, GATA2 gene silencing in human prostate cancer LNCaP cells led to marked reduction in cell proliferation, cell migration, tissue invasion, focal adhesion disassembly and a dramatic change in transcriptional activity, indicating that GATA2 plays a critical role in prostate cancer metastasis. As such, GATA2 could represent a metastasis-driving gene and a potential therapeutic target for inhibiting the growth and metastasis development in prostate cancer. Further analysis of GATA2-regulated genes led to the development of a GATA2-based metastatic gene signature. Its prognostic value was confirmed using two prostate cancer patient cohorts. In addition, it was shown to be a prognostic factor for risk assessment of metastasis development, independent of the widely used D’Amico prognostic classification system. However, a thorough validation is critical and, if successful, the GATA2-based gene signature could lead to a paradigm shift in the management of early prostate cancer. In conclusion, the findings of this study appear to be potentially useful for improved management of metastatic prostate cancer.

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Tumor-promoting effects on Genistein and ER beta prostate cancer (2012)

No abstract available.

 
 

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