Plenary Lecture
Novel Combination Therapeutic Strategies to Enhance Epidermal Growth Factor Inhibitor Efficacy: Mevalonate Pathway Inhibitors and Activators of Cellular Stress as Potential Enhancers
Professor Jim Dimitroulakos
Ottawa Hospital Research Institute
University of Ottawa
Canada
E-mail: jdimitroulakos@ohri.ca
Abstract: Combination therapies incorporating various treatment modalities are standard therapies for the majority of advanced cancer patients. Generally these combinations have been developed empirically and required improvements in outcomes will require rationally designed strategies. Our laboratory has incorporated a re-iterative process-utilizing bench to bedside evaluations and back to identify such a therapeutic approach. We initially demonstrated that high dose statins, inhibitors of HMG-CoA reductase the rate-limiting enzyme of the mevalonate pathway, induced tumour specific apoptosis in a subset of cancers, including squamous cell carcinomas (SCC). The completed Phase I trial in recurrent SCC by our group suggested the most effective use of statins as part of a combined modality approach. To this end, we demonstrated through laboratory studies and data mining of patients prescribed statins that they enhanced the efficacy of epidermal growth factor receptor (EGFR) inhibitors. Targeting the activity of the EGFR, particularly in non-small cell lung carcinomas (NSCLC) and SCC has demonstrated its importance as a relevant and viable therapeutic target. However, EGFR-tyrosine kinase inhibitors (TKIs) have shown activity in only a limited subset of NSCLC patients that harbour point mutations in its tyrosine kinase domain. Currently, EGFR-TKIs have limited activity as single agents in wild-type EGFR patients and will also require combination based therapeutic approaches to increase their efficacy. Our results directly led to a Phase I trial (rosuvastatin+EGFR-TKI erlotinib; NCT00966472) demonstrating the feasibility of this approach in wild-type EGFR patients, however while demonstrating efficacy, statin-induced myopathies limited this regimen. This trial has led to further bench studies to refine this therapeutic strategy. (1) We are evaluating the potential of targeting downstream mevalonate pathway enzyme as a means to maintain the efficacy of statins while circumventing the toxicities associated with these agents. (2) To identify key regulators of statin-induced apoptosis as potential therapeutic targets. We have demonstrated that statin-induced apoptosis was regulated by the induction of a common cellular stress pathway modulated by activating transcription factor 3 (ATF3). ATF3 represents a hub of signalling pathways that drive cellular apoptosis. We demonstrated that ATF3 is a key regulator of the statins and EGFR-TKIs synergistic response. We have demonstrated that ATF3 is an anti-cancer therapeutic target and that combining agents that target ATF3 through different mechanisms inducing its elevated and sustained expression drives cellular apoptosis and represent a novel combination-based therapeutic strategy.
Brief Biography of the Speaker: Dr. Jim Dimitroulakos is currently a Senior Scientist at the Ottawa Hospital Research Institute, Centre for Cancer Therapeutics and an Associate Professor, Faculty of Medicine at the University of Ottawa since 2002. He was a Canadian Institute of Health Research Postdoctoral Fellow in the Conacher Research Laboratory and held an Amgen Postdoctoral Fellowship, Division of Cellular and Molecular Biology both at the Ontario Cancer Institute at the Princess Margaret Hospital in Toronto. He obtained his PhD in the Department of Pathology at the University of Toronto at the Hospital for Sick Children. His laboratory work is focused on the development of novel combination therapeutic approaches targeting cellular stress pathways with receptor tyrosine kinase inhibitors.