ORCID Profile
0000-0001-8864-8765
Current Organisations
McGill University
,
Rosalind and Morris Goodman Cancer Research Centre
,
University of Tennessee
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Publications
Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 12-2020
DOI: 10.1158/1940-6207.CAPR-20-0186
Abstract: Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Furthermore, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53-dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target toward prevention of prostate cancer.
Data from Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.C.6547697.V1
Abstract: Abstract Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Furthermore, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53-dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target toward prevention of prostate cancer. /
SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation
Publisher: MDPI AG
Date: 31-01-2023
Abstract: SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.
Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.PRP.2019.02.019
Abstract: Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI - encoding Complement Factor I - and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2-3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2-3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17-4.53) and death (adjusted HR: 3.42 95% CI: 1.72-6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.
Supplementary Data from Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.22534898
Abstract: Supplementary Data
Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer
Publisher: Cold Spring Harbor Laboratory
Date: 08-08-2019
DOI: 10.1101/730135
Abstract: Prostate cancers are considered immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models derepresses expression of double-strand RNA (dsRNA), associated with upregulation of genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1. Similarly, application of a novel EZH2 derived gene signature to human prostate s le analysis indicated an inverse correlation between tumor EZH2 activity/expression with T-cell inflamed and IFN gene signatures and PD-L1 expression. EZH2 inhibition combined with PD-1 CPI significantly enhances antitumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.
EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer
Publisher: Springer Science and Business Media LLC
Date: 22-03-2021
DOI: 10.1038/S43018-021-00185-W
Abstract: Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA-STING-ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8
Supplementary Data from Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.22534898.V1
Abstract: Supplementary Data
SOCS3-mediated activation of p53-p21-NRF2 axis and cellular adaptation to oxidative stress in SOCS1-deficient hepatocellular carcinoma
Publisher: Cold Spring Harbor Laboratory
Date: 21-10-2021
DOI: 10.1101/2021.10.21.465149
Abstract: SOCS1 and SOCS3 genes, frequently repressed in hepatocellular carcinoma (HCC), function as tumor suppressors in hepatocytes. However, TCGA transcriptomic data revealed that SOCS1-low/SOCS3-high specimens displayed more aggressive HCC than SOCS1-low/SOCS3-low cases. We show that hepatocyte-specific Socs1- deficient livers upregulate Socs3 expression following genotoxic stress. Whereas deletion of Socs1 or Socs3 increased HCC susceptibility, ablation of both genes attenuated HCC growth. SOCS3 promotes p53 activation in SOCS1-deficient livers, leading to increased expression of CDKN1A (p21 WAF1/CIP1 ), which coincides with elevated expression and transcriptional activity of NRF2. Deleting Cdkn1a in SOCS1-deficient livers diminished NRF2 activation, oxidative stress and HCC progression. Elevated CDKN1A expression and enrichment of antioxidant response genes also characterized SOCS1-low/SOCS3-high HCC. SOCS1 expression in HCC cell lines reduced oxidative stress, p21 expression and NRF2 activation. Our findings demonstrate that SOCS1 controls the oncogenic potential of SOCS3-driven p53-p21-NRF2 axis and suggest that NRF2-mediated antioxidant response represents a drug target in SOCS1-deficient HCC.
RF sheath induced sputtering on Proto-MPEX part 2: Impurity transport modeling and experimental comparison
Publisher: AIP Publishing
Date: 10-2021
DOI: 10.1063/5.0065464
Related Organisations
Dana-Farber Cancer Institute/Harvard Medical School
Location: United States of America
Related Funding Activities
No related grants have been discovered for David Labbé.