Browsing by Author "Luchman, H. Artee"

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    A Novel Combinatorial Strategy Targeting the EGFR and JAK2/STAT3 Pathways in GBM Brain Tumour Initiating Cells
    (2017) Jensen, Katharine; Weiss, Samuel; Luchman, H. Artee; Grewal, Savraj; Mahoney, Douglas; Narendran, Aru
    Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary adult brain tumour with a median survival of only 15 months. Despite aggressive treatment, long-lasting tumour control cannot be achieved and disease recurrence is inevitable. Brain tumour initiating cells (BTICs) are postulated to be at the root of disease initiation and recurrence, suggesting that BTIC targeting therapies are crucial to establishing tumour control. Resistance of cancer cells to targeted therapies can occur through the activation of compensating signalling pathways. Using a BTIC model of GBM, we identified the activation of signal transducer and activator of transcription (STAT)3 as a compensation mechanism in response to epidermal growth factor receptor (EGFR) inhibition. We showed that concurrent inhibition of EGFR and STAT3 was highly effective in vitro, as it dramatically decreased BTIC viability and neurosphere formation. Combined inhibition of EGFR and STAT3 resulted in the attenuation of both oncogenic signalling pathways. In vivo, systemic administration of the EGFR inhibitor, afatinib, and the JAK2 inhibitor, pacritinib, demonstrated favourable pharmacokinetic and pharmacodynamic properties, displaying blood-brain barrier penetration and on-target activity in orthotopic BTIC xenografts. Overall, these data provide a promising strategy to overcome EGFR inhibitor resistance by targeting two oncogenic pathways in combination.
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    Investigating the Role of the Mediator Complex in Brain Tumour Stem Cells
    (2021-07-27) Cutts, Emilie; Weiss, Samuel; Luchman, H. Artee; Goodarzi, Aaron; Grewal, Savraj
    The regulation of gene transcription is highly controlled and frequently modified in cancer cells. Glioblastoma (GBM) is a fast-growing, malignant grade IV astrocytoma, with a median patient survival of approximately 15 months. Transcriptional dysregulation contributes to the malignant phenotypes of brain tumour stem cells (BTSCs), which are thought to promote GBM initiation and progression. In response to dynamic tumour microenvironment signals, BTSC plasticity has been shown to facilitate adaptive transcriptional programs to enable cellular proliferation and survival. Therefore, there is a growing interest in elucidating the precise mechanisms of transcriptional regulation which promote BTSC plasticity. The Mediator complex acts as a functional bridge between enhancer-bound transcription factors and the basal transcription machinery at core promoters to activate or repress gene transcription. Regulatory transcription factors, involved in cellular response to environmental cues, have been shown to interact with the Mediator tail module. Therefore, the Mediator complex is thought to integrate environmental signals to facilitate context-dependent gene expression. Recently, we identified a role for the Mediator tail module linked to an epigenetic mechanism of gene regulation important for BTSC growth and differentiation, driven by the histone methyltransferase DOT1L. However, the precise contributions of individual tail subunits for transcriptional regulation in BTSCs warrant further investigation. To determine the extent of context-dependent gene transcription regulated by the Mediator complex tail module, I generated single gene knockouts to individually target all 7 tail subunits in BTSCs. Genetic loss of any of the tail subunits had no effect on the viability, proliferation, or self-renewal potential of BTSCs grown in ideal neural stem cell culture conditions. However, orthotopic xenografts of each Mediator tail subunit knockout cell line in SCID mice, a context which more closely recapitulates the GBM tumour microenvironment, resulted in reduced tumour burden and significantly longer overall mouse survival. I further demonstrate that the Mediator tail module regulates transcriptional pathways related to neurogenesis and inflammation. In support of these findings, I identified a role for the Mediator tail module in facilitating cellular response to inflammatory cues, through the regulation of inducible nitric oxide synthase (iNOS) activity. In this study, I describe novel findings to the field of GBM by demonstrating a requirement for the Mediator complex tail module for gliomagenesis. Furthermore, I identify the Mediator complex as an important molecular player in the dynamic interplay between the GBM tumour microenvironment and BTSC gene transcription.
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    The Pace of Prostatic Intraepithelial Neoplasia Development Is Determined by the Timing of Pten Tumor Suppressor Gene Excision
    (Public Library of Science, 2009) Luchman, H. Artee; Benediktsson, Hallgrimur; Villemaire, Michelle L.; Peterson, Alan C.; Jirik, Frank R.