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Kevin L. Bennewith

Department of Integrative Oncology - Radiation Biology Unit

Scientist

kbennewi@bccrc.ca    Rm. 9-107 • 675 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3    Tel.  604 675 8042    Lab. 604 675 8000 x7041 

Current Appointments

Scientist, Department of Integrative Oncology, Radiation Biology Unit, BC Cancer Agency

Assistant Professor, Department of Pathology and Laboratory Medicine, University of British Columbia

Faculty Associate Member, Interdisciplinary Oncology Program, College of Interdisciplinary Studies, University of British Columbia

Previous Appointments

Clinical Assistant Professor, Department of Pathology and Laboratory Medicine, UBC (2009-2011)

Research Scientist, Department of Integrative Oncology, BC Cancer Agency (2008-2011)

Post-Doctoral Scholar, Division of Radiation and Cancer Biology, Stanford University (2004-2008)

PhD, Department of Pathology and Laboratory Medicine, UBC (1999-2004)

GROUP MEMBERS

Kevin L. Bennewith, PhD - Principal Investigator

Staff

Nancy E. LePard - Research Assistant

Trainees

Melisa J. Hamilton, PhD - Post-Doctoral Fellow

Momir Bosiljcic - MSc Student

Liz C. Halvorsen - MSc Student

Bryant T. Harbourne - MSc Student

Ada Kim - Undergraduate Student

Alumni

Maria Ashley, MD - Internal Medicine Resident

Judit P. Banath, PhD - Research Assistant

Jessica X. Jia - Technician

Martin Koehler - MSc Student

Rose Shumiatcher - Undergraduate Student; BC Cancer Studentship Award recipient

G.R. Tom Walton - Medical Student; UBC Faculty of Medicine Summer Student Research Program Award recipient

RESEARCH INTERESTS

Most solid tumours contain cells that are poorly oxygenated, and these hypoxic tumour cells are refractory to a variety of cancer treatments including radiation therapy and chemotherapy.  Not only are hypoxic cells the most difficult tumour cells to kill with conventional therapies, but hypoxia also promotes a more aggressive tumour phenotype. In the clinic, patients with primary tumours that contain large fractions of hypoxic cells have poor outcome, due in large part to limited treatment response and the presence of distant metastatic disease. My lab is interested in the role of tumour hypoxia (and the tumour microenvironment) in cancer therapy and in the development of tumour metastases.

Quantification of Tumour Hypoxia

The extent of hypoxia in solid tumours can be measured by exogenous hypoxia markers (drugs that are bound and retained in hypoxic cells) and/or endogenous hypoxia markers (proteins that are increased in hypoxic cells).  The oxygenation level of tumour cells can change as a function of time, and this transient (or cyclic) hypoxia is poorly understood.  We use immunohistochemistry and flow cytometry to identify and quantify transiently hypoxic tumour cells with the goal of designing more effective therapeutic strategies to target (or exploit) tumour hypoxia.

Multicellular Spheroids to Model Tumour Response to Therapy

Three-dimensional multicellular spheroids contain a natural diffusion gradient of oxygen and nutrients, and are an excellent in vitro model of solid tumours.  Using a fluorescent DNA perfusion dye and fluorescence-activated cell sorting, tumour cells can be isolated from different regions of the spheroids for subsequent analysis of hypoxia-induced proteins, proliferation, response to therapy, etc.  We are currently using spheroids to investigate the inhibition of prostate tumour cell proliferation with a small molecule inhibitor of the androgen receptor, and to study the efficacy of pro-drugs that are converted to toxic chemotherapeutic agents in hypoxic cells. 

TumSph

Bone marrow-derived cells in solid tumour metastasis

The metastatic spread of cancer is associated with over 90% of cancer-related deaths.  We have found that selected proteins secreted by tumours can stimulate the accumulation of bone marrow-derived cells (BMDCs) in tissues prior to the arrival of metastatic tumour cells.  BMDC accumulation may enhance the survival and growth of metastatic tumour cells, and predict future sites of metastatic tumour growth.  We are interested in the therapeutic and/or prophylactic modification of tumour-secreted proteins to affect BMDC accumulation in metastatic-target organs and influence metastatic tumour growth.

FUNDING

We gratefully acknowledge funding from:

The British Columbia Cancer Foundation (http://www.bccancerfoundation.com/)

The Canadian Institutes of Health Research: Institute of Cancer Research (http://www.cihr-irsc.gc.ca)

The Terry Fox Foundation (http://www.terryfox.org) via The Canadian Cancer Society Research Institute

Kevin Bennewith is a Michael Smith Foundation for Health Research Biomedical Research Scholar (http://www.msfhr.org/)

Melisa Hamilton is funded by a Canadian Breast Cancer Foundation BC/Yukon Division Post-Doctoral Fellowship (http://www.cbcf.org/bc)

Ada Kim is funded by a Summer Studentship from the Canadian Breast Cancer Foundation BC/Yukon Division(http://www.cbcf.org/bc)

SELECTED PUBLICATIONS

  1. Hamilton MJ, Banath JP, Lam V, LePard NE, Krystal G, Bennewith KL. Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice. Cancer Immunol Immunother. 61(5): 643-54, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22021068

  2. Bennewith KL, Dedhar S. Targeting hypoxic tumour cells to overcome metastasis. BMC Cancer. 11: 504-9, 2011. http://www.ncbi.nlm.nih.gov/pubmed/22128892

  3. Bosiljcic M, Hamilton MJ, Banath JP, LePard NE, McDougal DC, Jia JX, Krystal G, Bennewith KL. Myeloid suppressor cells regulate the lung environment - letter. Cancer Res. 71(14): 5050-1, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21750177

  4. Bennewith KL, Erler JT, Giaccia AJ. Pre-metastatic niches, in Tumor Microenvironment, Siemann DW ed., Chichester, West Sussex, UK, John Wiley & Sons Ltd., 2011.

  5. Hamilton MJ, Antignano F, von Rossum A, Boucher JL, Bennewith KL, Krystal G. TLR agonists that induce IFN-beta abrogate resident macrophage suppression of T cells. J Immunol. 185(8): 4545-53, 2010. http://www.ncbi.nlm.nih.gov/pubmed/20844190

  6. Ho AS, Huang X, Cao H, Christman-Skieller C, Bennewith K, Le QT, Koong AC. Circulating miR-210 as a novel hypoxia marker in pancreatic cancer. Trans Oncol. 3(2): 109-13, 2010. http://www.ncbi.nlm.nih.gov/pubmed/20360935

  7. Cairns RA, Bennewith KL, Graves EE, Giaccia AJ, Chang DT, Denko NC. Pharmacologically increased tumor hypoxia can be measured by (18)F-fluoroazomycin arabinoside positron emission tomography and enhances tumor response to the hypoxic cytotoxin PR-104.  Clin Cancer Res. 15(23): 7170-4, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19920111

  8. Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, Story M, Le QT, Giaccia AJ.  Hypoxia inducible miR-210 regulates normoxic gene expression involved in tumor initiation.  Mol Cell. 35(6): 856-67, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19782034

  9. Bennewith KL, Huang X, Ham CM, Graves EE, Erler JT, Kambham N, Feazell J, Yang GP, Koong A, Giaccia AJ. The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res. 69(3): 775-84, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19179545

  10. Erler* JT, Bennewith* KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the pre-metastatic niche. Cancer Cell. 15(1): 35-44, 2009. [*equal contributions] http://www.ncbi.nlm.nih.gov/pubmed/19111879

  11. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JTA, Jeffrey SS, Giaccia AJ. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 440(7088): 1222-6, 2006. http://www.ncbi.nlm.nih.gov/pubmed/16642001

  12. Dornhofer N, Spong S, Bennewith K, Salim A, Klaus S, Kambham N, Wong C, Kaper F, Sutphin P, Nacamuli R, Hockel M, Le Q, Longaker M, Yang G, Koong A, Giaccia A. Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 66(11): 5816-27, 2006. http://www.ncbi.nlm.nih.gov/pubmed/16740721

  13. Bennewith KL, Durand RE. Quantifying transient hypoxia in human tumor xenografts by flow cytometry. Cancer Res. 64(17): 6183-9, 2004. http://www.ncbi.nlm.nih.gov/pubmed/15342403

  14. Bennewith KL, Raleigh JA, Durand RE. Orally administered pimonidazole to label hypoxic tumor cells. Cancer Res. 62(23): 6827-30, 2002. http://www.ncbi.nlm.nih.gov/pubmed/12460894

  15. Bennewith KL, Durand RE. Drug-induced alterations in tumour perfusion yield increases in tumour cell radiosensitivity. Br J Cancer. 85(10): 1577-84, 2001. http://www.ncbi.nlm.nih.gov/pubmed/11720448