Dimitroulakos, Jim - University of Ottawa - Department of Biochemistry, Microbiology and Immunology

研究领域

My laboratory has two main research themes revolving around the identification of novel therapeutic approaches in the treatment of epithelial cancers including lung, head and neck and prostate carcinomas. (1) The first research theme stems from my initial discovery that inhibiting the mevalonate pathway, involved in de novo cholesterol synthesis, can induce tumour specific killing. Targeting HMG-CoA reductase, the rate-limiting enzyme of this pathway, with the statin family of drugs induces a potent apoptotic response in a specific subset of human cancers including lung, head and neck and prostate carcinomas. My laboratory is actively pursuing the identification of potential mediators that regulate the apoptotic response elicited by targeting the mevalonate pathway in these responsive tumor types. We have demonstrated that statins in combination with epidermal growth factor receptor inhibitors that are relatively novel anti-cancer therapeutics induce synergistic tumour cell killing in these tumour types. This has led to the first human clinical trial evaluating this novel therapeutic approach being performed at our Institute. We are further evaluating the mechanism of this synergy and devising more refined and efficacious therapies based on these findings. This program has led to a re-iterative bench to bedside approach that has resulted in a number of clinical trials that had led to the refinement of this approach and further clinical studies. 1. Phase I/II Study of Lovastatin Alone in the Treatment of AML. Co-Investigator, Principal Investigator: Mark D. Minden. Single Institute Study at the Princess Margaret Hospital. 2. A Phase I/II Trial of Prolonged Administration of Lovastatin in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or of the Cervix. Co-Investigator, Principal Investigators: Ahmit Oza, Lillian Sui. Single Institute Study at the Princess Margaret Hospital. 3. A Phase I trial to examine the addition of Rosuvastatin (Crestor) to Erlotinib (Tarceva) Treatment in advanced cancer patients. Sponsor: Hoffmann-La Roche. Lead Scientist, Principal Investigator: Glenwood Goss. Single Institute Study at the Ottawa Hospital Regional Cancer Centre. ClinicalTrials.gov Identifier: NCT00966472. 4. Phase II Trial of Rosuvastatin Combined with Standard Chemoradiation Therapy in the Treatment of High-Risk Locally Advanced Rectal Cancer. Lead Scientist, Principal Investigator: Monzon Jose. Multiple Institute Study at the Tom Baker Cancer Centre, Princess Margaret Hospital, Ottawa Hospital Regional Cancer Centre. ClinicalTrials.gov Identifier: NCT02569645. (2) In collaboration with our clinical colleagues, we are also interested in identifying novel mechanisms of action to common chemotherapies particularly the platin family of drugs. Although platins demonstrate activity in the above tumour types, acquired or intrinsic resistance mechanisms limit their efficacy. In this study, we are evaluating a cellular stress pathway regulated by the activating transcription factor 3 (ATF3) as a key regulator of platin cytotoxicity. Understanding the role of this pathway in regulating platin-induced tumour cell killing and developing drugs that target this pathway to enhance platin efficacy will have therapeutic benefit.

近期论文

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1. A Phase I Study of the Combination of High-Dose Rosuvastatin with Erlotinib in Patients with Advanced Solid Malignancies. Glenwood D. Goss, Derek J. Jonkers, Scott A. Laurie, Amit M.Oza, Michael M. Vickers, Charles la Porte and Jim Dimitroulakos. (Under Review, J Transl Med) 2. Dayekh K, Johnson-Obaseki S, Corsten M, Villeneuve PJ, Sekhon HS, Weberpals JI, Dimitroulakos J. Monensin Inhibits Epidermal Growth Factor Receptor Trafficking and Activation: Synergistic Cytotoxicity in Combination with EGFR Inhibitors. Mol Cancer Ther, 13(11):2559-71, 2015. 3. Zhao TT, LeFrancois BG, Goss G, Ding K, Bradbury PA, Dimitroulakos J. Lovastatin inhibits EGFR dimerization and AKT activation in squamous cell carcinoma cells: Potential regulation through targeting rho proteins. Oncogene. 29(33):4682-92, 2010. ATF3 as a Regulator of Platin-Induced Cytotoxicity 1. Induction of Activating Transcription Factor 3 is associated with cisplatin responsiveness in NSCLC: A potential predictive biomarker of response. Jair Bar, Ivan Gorn-Hondermann, Mohammed S. Hasim, Theodore Perkins, Michael Rudnicki, David Stewart, Glenwood D. Goss, Harmon Sekhon, James Villeneuve and Jim Dimitroulakos. (Under Review, Cancer Research) 2. O’Brien A, Barber JEL, Reid S, Niknejad N, Dimitroulakos J. Enhancement of cisplatin cytotoxicity by disulfiram involves Activating Transcription Factor 3. O’Brien A, Barber JEL, Reid S, Niknejad N, Dimitroulakos J. Anticancer Research. 32(7):2679-88, 2012. 3. St. Germain C, Niknejad N, Ma L, Garbuio K, Hai T, Dimitroulakos J. Cisplatin induces cytotoxicity via the mitogen-activated protein kinase pathways and Activating Transcription Factor 3. Neoplasia 12(7): 527-38, 2010.