Scientist, Cancer Therapeutics, Ottawa Hospital Research Institute
Keywords: Cancer therapeutics, receptor tyrosine kinases, mevalonate pathway, drug development
Research Interests
My laboratory has two main research themes revolving around my initial discovery that the mevalonate pathway, involved in de novo cholesterol synthesis, regulates some of the biological properties of retinoids. HMG-CoA reductase is the rate-limiting enzyme of this pathway, whose targeting with a number of inhibitors of the statin family of drugs is effective treatments for elevated serum cholesterol. Targeting the rate-limiting enzyme of this pathway with lovastatin induces a potent apoptotic response in a specific subset of human cancers that are also sensitive to the differentiative effects of retinoids. My laboratory is actively pursuing the identification of potential mediators that regulate the apoptotic response elicited by targeting the mevalonate pathway in responsive tumor types and obtaining pre-clinical data to potentially exploit this novel finding in the clinic. Our most recent work has demonstrated the lovastatin targets the function of the epidermal growth factor receptor (EGFR) in a novel and as yet recognized mechanism. Furthermore, lovastatin in combination with EGFR tyrosine kinase inhibitors demonstrated synergistic cytotoxic activity in a number of tumour types that may warrant future clinical evaluation.
Selected Publications
Mantha AJ, Hanson JEL, Glenwood G, Legarde AE, Lorimer IA , Dimitroulakos J . Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor. Clinical Cancer Research 11: 2398-2407 , 2005.
Knox JJ, Siu LL, Chen E, Dimitroulakos J , Kamel-Reid S, Moore MJ, Chin S, Irish J, LaFramboise S, Oza AM. A Phase I Trial of Prolonged Administration of Lovastatin in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or of the Cervix. Eur J Cancer 41:523-530, 2005.
Mantha AJ, McFee K, Niknejad N, Glenwood G, Lorimer IA , Dimitroulakos J. Epidermal Growth Factor Receptor Targeted Therapy Potentiates Lovastatin-Induced Apoptosis in Head and Neck Squamous Cell Carcinoma Cells. J Cancer Res Clin Oncol 129(11): 631-41, 2003.
Dimitroulakos J , Marhin WH, Tokunaga J, Irish J, Gullane P, Penn LZ, Kamel-Reid S. Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. Neoplasia 4(4): 337-46, 2002.
Dimitroulakos J , Ye YL, Benzaquen MJ, Moore MJ, Kamel-Reid S, Freedman MH, Yeger H, Penn LZ. Differential Sensitivity of Various Pediatric Cancers and Squamous Cell Carcinomas to Lovastatin Induced Apoptosis: Therapeutic Implications. Clinical Cancer Research 7: 158-167, 2001.
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