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Best O.G.,Kolling Institute | Best O.G.,CLL Australian Research Consortium CLLARC | Singh N.,Cytogenetics | Forsyth C.,CLL Australian Research Consortium CLLARC | And 3 more authors.
British Journal of Haematology | Year: 2010

Inhibitors of heat-shockprotein 90 (Hsp90) have been proposed as a novel therapeutic option for Chronic Lymphocytic Leukaemia (CLL), particularly as their mechanism of action appears independent of mutations of ATM or TP53. We investigated the activity of a novel Hsp90 inhibitor, SNX7081, against a panel of eight haematological cell lines and 23 CLL patient samples. SNX7081 displayed significant effects on cell cycle distribution, apoptotic rate and levels of ZAP-70 in the cell lines and in the patient samples, irrespective of TP53 status. Our findings suggest SNX7081 may represent a promising therapeutic option for aggressive CLL. © 2010 Blackwell Publishing Ltd. Source

Best O.G.,Kolling Institute | Best O.G.,CLL Australian Research Consortium CLLARC | Che Y.,University of Sydney | Singh N.,Cytogenetics | And 7 more authors.
Leukemia and Lymphoma | Year: 2012

Drug resistance in chronic lymphocytic leukemia (CLL) associated with lesions in the ATM/TP53 pathway represents a major challenge in clinical management. Evidence suggests that heat shock protein-90 (Hsp90) inhibitors may represent a therapeutic option in combination with more conventional therapies. We explored the effects of combining the Hsp90 inhibitor, SNX-7081, with fludarabine in vitro against CLL cells and hematological cell lines. In seven cell lines and 23 patient samples synergy between SNX-7081 and fludarabine (2-FaraA) was apparent in the three TP53 mutated cell lines and at significantly lower concentrations in TP53 or ATM dysfunctional patient cells. In 11/13 2-FaraA-resistant patient samples, SNX-7081 reduced the 50% inhibitory concentration to within a clinically achievable range. Synergy between SNX-7081 and 2-FaraA was evident in both the cell lines and patient samples as a significant decrease in cell viability. Our data suggest that combining SNX-7081 and fludarabine may be effective in the treatment of fludarabine-refractory CLL. © 2012 Informa UK, Ltd. Source

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