Molecular chaperones and telomerase expression profiles and inhibition: Clinical implications for Glioma

Glioma, an infrequent form of cancer, continues to confer poor prognosis despite advances in current therapeutic techniques. This research identified the presence of hsp90a in glioma and investigated its potential as a diagnostic or therapeutic marker. l-Isp90ct is emerging as an encouraging target for cancer therapy attributed to the integral role it plays in the stabilisation and folding of proteins crucial for normal cellular homeostasis and its subsequent involvement in tumorigenesis. Modulation of Hsp90 as a drug target offers the possibility of simultaneously impeding numerous signaling pathways implicated in the development and progression of glioma and has thus far shown evidence of clinical activity in patients with melanoma, breast and prostate cancer. With this in mind, the primary focus of this thesis was to evaluate the association between hsp90a expression in glioma versus the normal brain cell lines and tissues. Results from this study showed that hsp90a was transcribed at a higher level in glioma cell lines and tissues and absent in normal brain cell lines and tissues. This suggests that the expression level of hsp90a may be a distinguishing marker between glioma and normal brain tissue and furthermore, in the subset of glioma cell lines examined, an increase in expression of hsp90cz appeared to correlate with a decrease in malignancy. As modulation of a single target is likely to be insufficient due to the development of resistance, emphasis of research has focused on a combinational attack for optimal therapy. Simultaneous silencing of hsp90a, at transcriptional (siRNA) or post-translational level (RA), and subsequent subjection to a chemotherapeutic drug appeared to be more effective than chemotherapy alone. This increase in chemosensitivity could be attributed to the downregulation of hTERT caused by inhibition of l-Isp90c&. The research has led to two novel findings; 1) The identification of hsp90a in glioma 2) Silencing hsp90a led to approximately 13-fold reduction of TMZ in tissues for the achievement of the same effect with TMZ alone 3) Has led to the following two publications: a). Shervington, A., Cruickshanks, N., Wright, H., Atkinson-Dell, R., Lea, R., Roberts, (3 and Shervington, L. (2006) Glioma: What is the role of c-Myc, Hsp90 and telomerase? MoL celL Biochem. 283, 1-9. b). Shervington, A., Cruickshanks, N., Lea, R., Roberts, (3., Dawson, T and Shervington, L. (2008) Can the lack of Hsp90a protein in brain normal tissue and cell lines, rationalise it as a possible therapeutic target for gtiomas. Cancer Invest. 16, 900-904. As silencing of hsp90a and the subsequent downregulation of /ITERT exhibited a correlation with chemosensitivity, it has further emphasised the need for individual characterisation of tumours to highlight the most effective therapeutic option and improve patient survival rates for glioma