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Christopher J. Ong, Ph.D.

Research Scientist, The Prostate Centre at VGH
Assistant Professor, Department of Surgery, Faculty of Medicine, UBC

B.Sc. - University of British Columbia, 1988
Ph.D.- University of British Columbia, 1996

Jack Bell Research Centre
2660 Oak St.
Vancouver, BC
Canada V6H 3Z6
Office: 604-875-5555 ext 63120
Fax: 604-875-5654
E-mail: chriso@interchange.ubc.ca

   

Research Interest

Prostate cancer is presently the second leading cause of cancer-related deaths and the most commonly diagnosed non-skin cancer in men. While frequently curable in its early stage, approximately one third of patients present with advanced disease that requires development of novel therapeutic approaches for its control and to improve patient survival. The primary focus of my research program is to understand the molecular mechanism(s) that govern the progression of prostate cancer from a state of androgen sensitivity to hormone independence with the hopes of developing novel therapeutic strategies to prevent or delay the progression of prostate cancer to androgen independence. The PTEN tumour suppressor gene is inactivated in ~50% of prostate tumours and is correlated with advanced disease and a poor prognosis. Mutations in the PTEN phosphoinositol phosphatase gene result in deregulated signaling through the phosphoinositide 3-kinase (PI3K) dependent cell survival pathway. Continuous signaling through the PI3K pathway as a result of PTEN deficiency confers protection of prostate cancer cells from cell death and resistance to chemotherapy.

Despite cell surface expression of both the Fas receptor and its ligand (FasL), prostate cancer cells are resistant to autocrine Fas mediated apoptosis. We have found that constitutive PI3K activity as a result of PTEN deficiency may be responsible for mediating resistance of prostate tumour cells from undergoing autocrine Fas mediated apoptosis. Therefore, progression of prostate cancer to androgen independence may, in part, be due to genetic alterations that confer protection from autocrine Fas mediated death. Implications from this research may lead to new multimodality combination therapeutic strategies designed to prevent or delay progression to androgen independence. Novel therapeutic drugs that target genes/proteins involved in the PI3K signal transduction pathway may be used in combination with androgen withdrawal therapy to prevent or delay the progression of prostate cancer to a state of androgen independence; thus, representing a new approach toward treatment of advanced prostate cancer.

Based on the observation that loss of PTEN and consequent over-activation of the PI3K/ Akt cell survival pathway is a common event in prostate cancer, we set out to identify novel potential therapeutic points of intervention to down modulate the PI3K dependent cell survival signalling pathways in prostate tumours. To this end, we are currently testing the potential utility of two novel classes of small molecule drugs that act to down modulate the PI3K survival pathway in the treatment of prostate cancer. The first class of compounds includes antagonists of the Integrin Linked Kinase, ILK. ILK is a serine threonine kinse which has been shown to be a key upstream mediator of the PI3K dependent Akt survival pathway. Our initial findings in collaboration with Dr. Shoukat Dedhar have demonstrated that small molecule ILK inhibitors can efficiently down modulate Akt activity and effectively induce autocrine Fas mediated apoptosis of the PTEN deficient LNCaP human prostate cancer model. We are currently examining the in vitro activity of ILK antagonists in regulating prostate cancer survival and its in vivo efficacy in xenograft prostate tumour models. Small molecule drugs that target ILK activity represent an entirely new class of compounds for the treatment of prostate cancer and have the potential to revolutionize the treatment of prostate cancer in humans. These novel compounds have tremendous promise as lead compounds for development of therapeutics that target a primary defect associated with prostate cancer and other malignancies.

My laboratory is also involved in the production of transgenic and gene knock out mice to characterize the function of a number of genes including ILK, and clusterin in normal prostate biology and androgen withdrawal induced prostate involution. Finally, with the aim of identifying and validating new therapeutic targets in the treatment of prostate cancer. We have developed a functional genomics strategy using mouse models to characterize the critical genes that regulate androgen withdrawal induced apoptotic involution of the normal prostate. This approach entails the use of large scale gene trap mutagenesis of murine embryonic stem cells and high density gene array technology for generating knock-out mice to determine the identity and function of genes critical to tumour regression upon androgen withdrawal.

 

   

Publications

Chen Y, McKenna GJ, Ong C, Mui AL, Chung SW. Liver nonparenchymal cells involved in hyporesponsiveness induced by portal vein injection of alloantigen. Immunol Lett 81 (1) : 1 - 11. 2002

McKenna GJ, Chen Y, Smith RM, Meneghetti A, Ong C, McMaster R, Scudamore CH, Chung SW. A role for matrix metalloproteinases and tumor host interaction in hepatocellular carcinomas. Am J Surg 183 (5) : 588 - 594. 2002

Chen Y, Ong CR, McKenna GJ, Mui AL, Smith RM, Chung SW. Induction of immune hyporesponsiveness after portal vein immunization with ovalbumin. Surgery. 129 (1) : 66 - 75. 2001

Smith RM, Chen Y, McKenna GJ, Ong C, Zhang R, Chung SW. Prolongation of heterotopic heart allograft survival by portal venous injection of alloantigen: the role of hepatic nonparenchymal cells. J Invest Surg 13 (5) : 241 - 246. 2000

Ong CJ, Ip S, Teh SJ, Wong C, Jirik FR, Grusby MJ, Teh HS. A role for T helper 2 cells in mediating skin fibrosis in tight-skin mice. Cell Immunol. 196 (1) : 60 - 68. 1999

Ong, CJ, Wong, C, Roberts, C, Teh, HS, FR Jirik. Anti-IL4 treatment prevents dermal collagen deposition in the tight skin mouse model of scleroderma. Eur J Immunol 28 (9) : 2619 - 2629. 1998

Boyd R, Kozieradzki I, Chidgey A, Mittrucker HW, Bouchard D, Timms E, Kishihara K, Ong CJ, Chui D, Marth JD, Mak TW, Penninger JM. Receptor-specific allelic exclusion of TCRV alpha-chains during development. J Immunol. 161 (4) : 1718 - 1727. 1998

Kozieradzki I, Kundig T, Kishihara K, Ong CJ, Chiu D, Wallace VA, Kawai K, Timms E, Ionescu J, Ohashi P, Marth JD, Mak TW, Penninger JM. T cell development in mice expressing splice variants of the protein tyrosine phosphatase CD45. J Immunol. 158 (7) : 3130 - 3139. 1997

Ong CJ, Lim AS, Teh HS. CD28-induced cytokine production and proliferation by thymocytes are differentially regulated by the p59fyn tyrosine kinase. J Immunol. 159 (5) : 2169 - 2176. 1997

Ong CJ, Dutz JP, Chui D, Teh HS, Marth JD. CD45 enhances positive selection and is expressed at a high level in large, cycling, positively selected CD4+CD8+ thymocytes. Immunology. 91 (1) : 95 - 103. 1997

   
   

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