Matthew Hebb – Research Grant – 2012
Matthew Hebb, Western University, London, Ontario
Project Title: “HSP27 as a New Molecular Target in Glioblastoma”
What does the title mean?
The study is looking at heat shock proteins as a potential new therapeutic target in glioblastoma multiforme tumours.
Glioblastoma multiforme (GBM) is a deadly brain cancer that remains without effective treatment. There is a critical need to identify new molecular targets in order to advance our understanding and treatment ofGBM.
Heat shock protein 27 (HSP27) is overexpressed in systemic cancers and in brain tumours and provides unwanted protection to tumour cells that promotes their replication, spread and resistance to treatment. Numerous studies are ongoing to evaluate drugs that inhibit this protein in systemic cancers but little advancement has been made in the brain.
We have recently shown that HSP27 inhibitors markedly increase the sensitivity of GBM cell lines to chemotherapy, similar to that which has been reported in pancreatic, lung, breast, colon and other cancers.
The objective of this study is to now test these agents in fresh GBM cells obtained directly from neurosurgical patients. These efforts have important implications as an essential next step in determining the potential of HSP27 as a new therapeutic target in GBM.
This proof-of-concept study evaluated the antitumor impact of a direct electrical stimulation technique, termed intratumoral modulation therapy (IMT) on glioblastoma (GBM) cells. Materials and Methods: An in vitro IMT model comprised of a calibrated electrode to deliver continuous, low-intensity stimulation within GBM preparations. Viability and apoptosis assays were performed in treated immortalized and patient-derived GBM cells, and postmitotic neurons. IMT was delivered alone and with temozolomide, or gene silencing of the tumour-promoting chaperone, heat-shock protein 27 (HSP27). Results: GBM cells, but not neurons, exhibited >40% loss of viability, caspase-3 activation and apoptosis with IMT. Cell death was modest with temozolomide alone (30%) but increased significantly with concomitant IMT (70%). HSP27 silencing alone produced 30% viability loss, with significant enhancement of target knockdown and GBM cell death (65%), when combined with IMT. Conclusion: These findings warrant further evaluation of IMT as a potential novel therapeutic strategy for GBM.
In Vitro Validation of Intratumoral Modulation Therapy for Glioblastoma
Xu HU, Bihari F, Whitehead S, Wong E, Schmid S, Hebb MO.