Senior Scientist, Cancer Therapeutics, Ottawa Hospital Research Institute
Associate Professor, Department of Medicine, University of Ottawa
Associate Professor, Department of Biochemistry, Microbiology and Immunology, University of Ottawa
Keywords : cancer, epidermal growth factor receptor, experimental therapeutics, atypical protein kinase C, heat shock proteins
Research Interests:
Cancer therapeutics targeting the EGF receptor and its downstream signals
Our lab studies the epidermal growth factor (EGF) receptor, with a focus on the mutated versions of this receptor that are found in some types of cancer. The two basic aims of our research are: (1) to understand how EGF receptors promote tumour growth; (2) to develop and assess strategies for selectively antagonizing EGF receptor function in cancer cells. Specific projects ongoing in the lab are as follows:
Mutant EGF receptor biogenesis: The mutant EGF receptors found in glioblastoma show a number of altered trafficking and signalling properties compared to normal epidermal growth factor receptor. We are carrying out a detailed analysis of these differences using a variety of molecular biology, cell culture and proteomics techniques.
Atypical protein kinase C signaling: Atypical protein kinase C is activated downstream of the EGF receptor and other receptor tyrosine kinases, but its overall contribution to the cancer phenotype is not well understood. We are carrying out a detailed analysis of the role of this enzyme in cancer cell proliferation, apoptosis and loss of polarity. Again we use a variety of techniques including RNA interference and microarray analysis of gene expression
Pharmacodynamic studies of EGF receptor tyrosine kinase inhibitors: In this project we are analysing biopsy samples from patients that have been treated with different EGF receptor tyrosine kinase inhibitors. The goals here are to: (1) assess whether these drugs are working by their intended mechanisms; (2) determine which patients are most likely to respond to these drugs.
Publications:
Lorimer IAJ (2009) Regulation of p27Kip1 by miRNA 221/222 in glioblastoma, Cell Cycle, 8, 2685 (An interview regarding a previous article we'd published in this journal.)
Cemeus C, Zhao TT, Barrett GM, Lorimer IA, Dimitroulakos J (2008) Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status, J. Neuro-Onc., 90, 9-17
Tsirigotis M, Baldwin RM, Tang MY, Lorimer IAJ and Gray D (2008) Critical role of p38MAPK in expanded polyglutamine-induced cytotoxicity, PLoS ONE, 3, e2130
Baldwin RM, Parolin DAE and Lorimer IAJ (2008) Regulation of glioblastoma cell invasion by PKC and RhoB, Oncogene, 27,3587-95
Agulnik M, Cohen EE, Cohen RB, Chen EX, Vokes EE, Hotte SJ, Winquist E, Laurie S, Hayes D.N, Dancey JE, Brown S, Pond GR, Lorimer I, Daneshmand M, Ho J, Tsao MS, Siu LL (2007) A phase II study of lapatinib in recurrent or metastatic EGFR and/or ErbB2 expressing adenoid cystic carcinoma (ACC) and non-ACC malignant tumors of the salivary glands, J. Clin. Oncol. 25, 3978-84
Gillies JK and Lorimer IAJ (2007) Regulation of p27Kip1 by miRNA 221/222 in glioblastoma, Cell Cycle, 6, 2005-9
Dimitroulakos J, Lorimer IA and Goss G (2006) Strategies to Enhance Epidermal Growth Factor Inhibition: Targeting the Mevalonate Pathway, Clin. Cancer Res., 12, 4426s-31s
Baldwin RM, Garratt-Lalonde M, Parolin DAE, Krzyzanowski PM, Andrade MA and Lorimer IAJ (2006) Protection of glioblastoma cells from cisplatin cytotoxicity via protein kinase C -mediated attenuation of p38 MAP kinase signaling, Oncogene, 25, 2909-19
Tsao M-S, Sakurada A, Cutz J-C, Zhu C-Q, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Molecular and clinical predictors of response and survival in patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group trial BR.21, New England Journal of Medicine, 353, 133-44
Mantha AJ, Hanson JEL, Goss G, Lagarde AE, Lorimer IA and Dimitroulakos J (2005) Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor: Synergistic cytotoxicity induced by lovastatin and gefitinib, Clin. Cancer Res.,11, 2398-407
MacKenzie MJ, Hirte HW, Goss G, Maroun J, Goel R, Major PP, Miller WH, Panasci L, Lorimer IAJ, Batist G, Matthews S, Douglas L and Seymour L (2005) A Phase II pharmacodynamic trial of ZD1839 (Iressa*) 750mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer, Invest. New Drugs, 23, 165-70
Goss G, Hirte H, Miller W, Lorimer IAJ, Stewart D, Batist G, Parolin DAE, Hanna P, Stafford S, Friedmann, Walsh W, Mathews S, Douglas L, Seymour L (2005) A phase I study of oral ZD1839 (Iressa) given daily in patients with solid tumours: IND.122, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group, Invest. New Drugs, 23, 147-55
Nakamura T, Peng K-W, Harvey M, Greiner S, Lorimer IAJ, James CD and Russell SJ (2005) Rescue and propagation of fully retargeted oncolytic measles viruses, Nature Biotechnology, 23, 209-14
Bramson JL, Grinshtein N, Meulenbroek RA, Lunde J, Kottachchi D, Lorimer IA, Jasmin BJ, and Parks RJ (2004) Helper-dependent adenoviral vectors containing modified fibre for improved transduction in mature muscle, Human Gene Therapy, 15, 179-88
Gunaratnam L, Morley M, Franovic A, de Paulsen N, Mekhail K, Parolin DAE, Nakamura E Lorimer IAJ and Lee S (2003) HIF activates the TGF- /EGF-R growth stimulatory pathway in VHL-/- renal cell carcinoma cells, J. Biol. Chem., 278, 44966-74
Mantha AJ, McFee KE, Hopkins S, Niknejad N, Goss G, Lorimer IA, Dimitroulakis, J (2003) Epidermal growth factor receptor targeted therapy but not traditional potentiates lovastatin-induced apoptosis in head and neck squamous cell carcinoma cells, J. Cancer Res. Clin. Oncol., 129, 631-41
Daneshmand M, Parolin DAE, Hirte HW, Major P, Goss G, Stewart D, Batist G, Miller WH, Stewart D, Matthews S, Seymour L and Lorimer IAJ (2003) A pharmacodynamic study of the EGF receptor tyrosine kinase inhibitor ZD1839 (IressaTM) in metastatic colorectal cancer patients, Clin. Cancer Res., 9, 2457-2464
Lavictoire SJ, Parolin DAE, Klimowicz AC, Kelly J and Lorimer IAJ (2003) Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII, J. Biol. Chem., 278, 5292-5299
Research Group Members
Technicians:
Sylvie Lavictoire
Doris Parolin
Graduate students:
Michelle Garratt-Lalonde
Mitch Baldwin
Honours student:
Eric Fisher
Postdoctoral fellow:
Manijeh Daneshmand
General Campus
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