Understanding Molecular Cancer Therapeutics

The main goal of our laboratory is to develop effective cancer treatments based on a deeper understanding of the molecular processes occurring in human cancers. Areas of emphasis include the use of xenograft models including primary orthotopic implants from human cancers, and the development of analytical methods for studying complex molecular interactions at the single cell level. We have particular expertise in the development and application of advanced methodology based on the use of flow cytometry and digital fluorescence microscopy. This technology development is done in close collaboration with members of the Physics Division and Department of Pathology. Areas of current interest include the effects of tumour hypoxia on survival signaling in solid tumours; the analysis of complex signaling interactions in hematological malignancies based on multiparametric flow cytometry; and the role of aberrant signaling pathways in the growth of pancreatic cancers. All of these research activities are closely linked to the investigation of novel, molecular targeted therapeutics. In addition to using model systems based on tissue culture and human tumour xenografts, the laboratory also has close links to the Drug Development Program at Princess Margaret Hospital, including the analysis of samples obtained from patients on clinical trials involving molecular cancer therapeutics.

Graduate Students:

• Tina Chen

Selected References:

• Yau,C.Y.F., Wheeler,J., Sutton,K., and Hedley,D.W.  Inhibition of Integrin-Linked Kinase (ILK) by QLT0254 Inhibits Akt-Dependent Signaling Pathways and is Growth Inhibitory in Orthotopic Primary Pancreatic Cancer Xenografts   Cancer Research 65:1497-1504, 2005
  
  
• Chow S, Minden MD, Hedley DW Constitutive phosphorylation of the S6 ribosomal protein via mTOR and ERK signaling in the peripheral blasts of acute leukemia patients.  Experimental Hematology 2006;34:11883-91
  
  
• Birle DC and Hedley DW. Signaling interactions of rapamycin combined with erlotinib in cervical carcinoma xenografts.  Molecular Cancer Therapeutics 2006;5:2494-2502.
  
  
• Birle, D. and Hedley DW.  Suppression of the Hypoxia-Inducible Factor-1 Response in Cervical Carcinoma Xenografts by Proteasome Inhibitors.  Cancer Research 2007;67:1735-43
  
  
• Pham, N-A., Tsao, M-S, Cao, P. and Hedley, DW.  Dissociation of gemcitabine sensitivity and protein kinase B signaling in pancreatic ductal adenocarcinoma models.  Pancreas 2007; 35:e16-26.
  
  
• Schwock, J., Pham, N. A., Cao, M. P., and Hedley, D. W. Efficacy of Hsp90 inhibition for induction of apoptosis and inhibition of growth in cervical carcinoma cells in vitro and in vivo. Cancer Chemother.Pharmacol., 2007 Epub ahead of print.
  
  
• Schwock, J., Ho, J.C.., Luther, E., Hedley, D.W., and Geddie, W. R. Measurement of Signaling Pathway Activities in Solid Tumor Fine-needle Biopsies by Slide-based Cytometry. Diagnostic Molecular Pathology 16:130-140, 2007
  
  
• Hedley, D.W., Chow, S., Goolsby, C.L., and Shankey, T.V. Pharmacodynamic Monitoring of Molecular-Targeted Agents in the Peripheral Blood of Leukemia Patients using Flow Cytometry. Toxicologic Pathology 2007 in press
  
  
• Iakovlev, V., Pintilie, M., Morrison, A., Fyles, A., Hill, R.P., and Hedley, D.W.  Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX. Laboratory Investigation 2007 Oct 1, Epub ahead of print