Anatomy and Neuroscience - Research Publications

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Start date: 2020 × End date: 2022 × Author: Williams, David ×

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    Potential biomarkers and challenges in glioma diagnosis, therapy and prognosis
    Kan, LK ; Drummond, K ; Hunn, M ; Williams, D ; O'Brien, TJ ; Monif, M (BMJ PUBLISHING GROUP, 2020-08)
    Gliomas are the most common central nervous system malignancies and present with significant morbidity and mortality. Treatment modalities are currently limited to surgical resection, chemotherapy and radiotherapy. Increases in survival rate over the previous decades are negligible, further pinpointing an unmet clinical need in this field. There is a continual struggle with the development of effective glioma diagnostics and therapeutics, largely due to a multitude of factors, including the presence of the blood-brain barrier and significant intertumoural and intratumoural heterogeneity. Importantly, there is a lack of reliable biomarkers for glioma, particularly in aiding tumour subtyping and measuring response to therapy. There is a need for biomarkers that would both overcome the complexity of the disease and allow for a minimally invasive means of detection and analysis. This is a comprehensive review evaluating the potential of current cellular, proteomic and molecular biomarker candidates for glioma. Significant hurdles faced in glioma diagnostics and therapy are also discussed here.
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    BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
    Arulananda, S ; O'Brien, M ; Evangelista, M ; Harris, TJ ; Steinohrt, NS ; Jenkins, LJ ; Walkiewicz, M ; O'Donoghue, RJJ ; Poh, AR ; Thapa, B ; Williams, DS ; Leong, T ; Mariadason, JM ; Li, X ; Cebon, J ; Lee, EF ; John, T ; Douglas Fairlie, W (SPRINGERNATURE, 2020-10-31)
    Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.