Dr. Sandra Dunn is a molecular biologist who holds joint appointments in the Departments of Pediatrics, Experimental Medicine and Medical Genetics at the University of British Columbia.  Her laboratory is located at the Child & Family Research Institute where she coordinates the High Content Screening Program.  She is also the Course Coordinator for Medical Genetics 521/ Molecular Biology of Cancer.

Since 2001, Dr. Dunn, whose expertise is in molecular biology, has focused her research on discovering new treatments for cancers affecting children and women such as childhood brain tumors, sarcomas (soft tissue tumours), and breast cancer.  She is investigating the common links between child and adult cancers to develop better therapies with reduced side effects that can help all cancer patients.

As part of her research, Dr. Dunn has been investigating new molecular targets for cancer therapies. Specifically, she has focused on interfering with signal patterns of cancer molecules.  Despite conventional beliefs, not all cancers are the same. In fact, every cancer is unique, and so broad-based treatments such as chemotherapy are not always effective and often cause much suffering in cancer patients.

Because of this unique nature of cancer cells, Dr. Dunn has been searching for extremely targeted therapies that would be specific to individual cancers. In her research, she discovered a protein in breast cancer that allows cancer cells to grow and at the same time makes them resistant to treatment.  Her projects include the following:

1. Phosphoprotein profiling of primary tumors to identify patients that would benefit from inhibitors to the IGF-1R/Akt/mTOR pathway.  This is being done by screening tumor tissue microarrays and quantifying the profiles with patient outcome.   In addition, they are testing inhibitors to this pathway to find which might be the most beneficial in the clinic.

2. Another project involves studying the molecular events downstream of Akt because its activation renders cancer cells resistant to traditional therapies.  As such, they identified a novel Akt substrate referred to as the Y-box binding protein-1 (YB-1); which they subsequently determined is essential for the growth of aggressive forms of cancer.  With this information, they have begun to identify novel ways of inhibiting YB-1 either directly using small interfering RNA's, antisense, cell permeable peptides or small molecules.

3. While she develops direct inhibitors to YB-1, a second approach is to inhibit this target indirectly using signal transduction inhibitors that would block the activation of YB-1 by perturbing upstream signals coming from Akt.  For example, they recently found that the small molecule OSU-03012 developed to inhibit PDK-1 suppresses Akt activation and therefore YB-1 action.

4. Because YB-1 is a transcription factor, they are interested in understanding how YB-1 promotes tumor growth using chromatin immunoprecipitation (ChIP) leading to the discovery that it directly regulates EGFR, Her-2 and the Met receptor.  Global YB-1 gene targets are being elucidated using ChIP coupled to promoter arrays also known as ChIP-on-Chip.  These studies have led to a curious link between YB-1 and cancer stem cells. This is of particular interest because YB-1 is highly associated with cancer recurrence suggesting that it could impart stem cell properties.

5. Her team searches for other potential therapeutic leads using small interfering RNA and small molecule screens enabled by their new ArrayScan VIT (Cellomics) a high content screening instrument.  For example, they are using the ArrayScan to evaluate which kinases and phosphatases are needed for cancer cells to survive.  It is a revolutionary approach in that it allows cancer researchers to visualize up to six different cellular events at one time.  Once potential molecular targets have been identified using the screen, the molecules of interest will be validated using in vitro and in vivo models that address tumor growth, invasion, and metastasis.

Dr. Dunn has trained over 45 students in the past five years and published more than 30 papers. She holds three patents for novel anticancer agents. Her research is supported by the B.C. Children's Hospital Foundation, the Michael Cuccione Foundation, the U.S. National Institute of Health, the National Cancer Institute of Canada, Canadian Institute for Health Research, Hannah's Heroes Foundation, and Summits of Hope.

Lee C, Fotovati A, Triscott J, Chen J, Venugopal C, Singhal A, Dunham C, Kerr JM, Verreault M, Yip S, Wakimoto H, Jones C, Jayanthan A, Narendran A, Singh SK, Dunn SE. Polo-Like Kinase 1 (PLK1) Inhibition Kills Glioblastoma Multiforme Brain Tumour Cells in Part Through Loss of SOX2 and Delays Tumour Progression in Mice. Stem Cells. Accepted. 2012. PMID: 22415968

Hu K, Law J, Fotovati A, Dunn SE. Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumour-initiating cells. Breast Cancer Research 14:R22. 2012. PMID: 22309939

Astanehe A, Finkbeiner MR, Krzywinski M, Fotovati A, Dhillon J, Berquin IM, Mills GB, Marra MA, Dunn SE. MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition. Oncogene. 2012 Jan 16. PMID: 22249268

Fotovati A, Abu-Ali S, Wang PS, Deleyrolle LP, Lee C, Triscott J, Chen JY, Franciosi S, Nakamura Y, Sugita Y, Uchiumi T, Kuwano M, Leavitt BR, Singh SK, Jury A, Jones C, Wakimoto H, Reynolds BA, Pallen CJ, Dunn SE.YB-1 bridges neural stem cells and brain tumor-initiating cells via its roles in differentiation and cell growth. Cancer Res. 71(16):5569-78. 2011. PMID: 21730024

Law JH, Li Y, To K, Wang M, Astanehe A, Lambie K, Dhillon J, Jones SJ, Gleave ME, Eaves CJ, Dunn SE. Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. PLoS One. 2010. 5 (9). 2010. PMID: 20844753

To K, Fotovati A, Reipas KM, Law JH, Hu K, Wang J, Astanehe A, Davies AH, Lee L, Stratford AL, Raouf A, Johnson P, Berquin IM, Royer HD, Eaves CJ, Dunn SE. Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere growth, and drug resistance. Cancer Res. 70(7): 2840-51. 2010. PMID: 20332234

Gao Y, Fotovati A, Lee C, Wang M, Cote G, Guns E, Toyota B, Faury D, Jabado N, Dunn SE. Inhibition of Y-box binding protein-1 slows the growth of glioblastoma multiforme and sensitizes to temozolomide independent O6-methylguanine-DNA methyltransferase. Mol Cancer Ther. 8(12):3276-84. 2009. PMID: 19996271

Hu K, Lee C, Qiu D, Fotovati A, Davies A, Abu-Ali S, Wai D, Lawlor ER, Triche TJ, Pallen CJ, Dunn SE. Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas. Mol Cancer Ther. 8(11):3024-35. 2009. PMID: 19887553

Habibi, G, Leung S, Law JH, Gelmon K, Masoudi H, Turbin D, Pollak MN, Nielsen TO, Huntsman D, and Sandra E. Dunn. Re-defining prognostic factors for breast cancer: YB-1 is a stronger predictor of relapse and disease specific survival than estrogen receptor or HER-2 across all tumor subtypes. Highly accessed, Breast Cancer Research 10:R86, 1-9, 2008 (IF 4.37). PMID: 18925950

Finkbeiner M*, Astanehe A*, To K, Fotovati A, Zhao L, Jiang H, Stratford AL, Boccaccio C, Eirew P, Comoglio P, Eaves CJ and Dunn SE. Exploiting the repertoire of YB-1 responsive genes through promoter array analyses reveals putative cancer stem cell markers: Validation of the met receptor. In press, Oncogene (IF 6.4). *equal contributions

Law J, Habibi G, Hu K, Park E, Masouldi H, Wang M, Gee JMW, Finlay P, Jones HE, Nicholson RI, Pollak M, and Dunn SE, Phosphorylation of insulin-like growth factor-1 receptor/insulin receptor is present amongst all breast cancer subtypes and is related to poor survival. Dec 15;68(24);10238-10246 2008, Cancer Research (IF 8.2). PMID: 19074892

Stratford AL, Michelle Wang, Berquin IM, Fry CJ, Roux P and Dunn SE. Y-box binding protein-1 (YB-1) serine 102 is a downstream target of p90 ribosomal S6 kinase (RSK) in breast cancer cells, Breast Cancer Research 10:99 Nov 2008 (IF 4.37). PMID: 19036157

Lee L, Dhillon J, Wang M, Gao Y, Zhao Y, Leung S, Park E, Hu K, Masoudi H, Turbin D, To K, Stratford AL, Hung MC, Eirew P, Eaves CJ, and Dunn SE, Targeting YB-1 in HER-2 over-expressing breast cancer cells induces apoptosis via the mTOR/STAT3 pathway and suppresses tumor growth in mice. Priority Report Cancer Research, 68: (221) Nov 1 2008 (IF 8.2). PMID: 18974106

Astanehe A, Dunn SE, Wasserman WW, Arenillas D, Davies BR, Mills GB, and N Auersperg. Mechanisms underlying p53 regulation of PIK3CA transcription in Ovarian Surface Epithelium and Ovarian Cancer. J. Cell Science Accepted. PMID: 18270270

Stratford AL, Habibi G, Astanehe A, Jiang H, Hu K, Park E, Shadeo A, Buys TP, Lam W, Pugh T, Marra M, Nielsen TO, Klinge U, Mertens PR, Aparicio S, Dunn SE. Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer providing a potential target for therapy. Breast Cancer Res. Sept 17;9(5):R61 [Epub ahead of print], 2007. PMID: 17875215

Dos Santos N, Habibi G, Wang M, Law JH, Andrews HN, Wei D, TricheT, Dedhar S, Dunn SE. Urokinase-type Plasminogen Activator (uPA) is inhibited with QLT0267 a small molecule targeting integrin-linked kinase (ILK). Translational Oncogenomics 2: 67-79, 2007. PMID: 19409087

Wu J, Stratford AL, Astanehe A and Dunn SE, YB-1 is a transcription/translation factor that orchestrates the oncogenome by hardwiring signal transduction to gene expression. Translational Oncogenomics, 2; 49-65, 2007.

Badve S, Turbin D, Thorat MA, Morimiya A,, Nielsen TO, Perou CM, Dunn SE, Huntsman DG and H. Nakshatri. FOXA1Expression in Breast Cancer Correlation with Luminal SubtypeA and Survival. Clinical Cancer Research, Aug 1;13(15 Pt 1):4415-21. 2007. PMID: 17671124

To K, Zhao Y, Jiang H, Yokom DW, Hu K, Wang M, Wu J, Stratford AL, Lee C, Chen CS, Yapp D, Bally M, Klinge u, Mertens PR, Dunn SE. The phosphoinositide-dependent kinase-1 inhibitor, OSU-03012, prevents Y-box binding protein-1 (YB-1) from inducing epidermal growth factor receptor (EGFR). Mol Pharmacol. 2007 Jun 26. 2007. PMID: 17595327

Faury D, Nantel A, Dunn SE, et al. 2007. Molecular profiling identifies prognostic subgroups of pediatric glioblastoma. J Clin Oncol Vol 25, no 10 1196-1208. PMID: 17401009

Tsent, P., Weng, S., Brueggemeier, R. W., Shapiro, C. L., Dunn, S. E., Pollak, M., Chen, C. S. Overcoming Trastuzumab Resistance in HER-2-overexpressing Breast Cancer Cells. Molecular Pharmacology Vol. 70, No. 5 1534–1541, 2006. PMID: 16887935

Wu, J., Lee, C., Yokom, D., Jiang, H., Cheang, M. C. U., Yorida, E., Turbin, D., Berquin, I. M., Mertens, P., Iftner, T., Gilks, C. B., Dunn, S. E. Disruption of the Y-Box Binding Protein-1 results in suppression of the epidermal growth factor receptor and Her-2. Cancer Research May 1, 66:(9) 2006. PMID: 16651443

Waterhouse, D. N., Gelmon, K. A., Klasa, R., Chi, K., Huntsman, D., Ramsay, E., Wasan, E., Edwards, L., Tucker, C., Zastere, J., Zhang, Y.Z., Yapp, D., Dragowska, V., Dunn, S. E., Dedhar, S., Bally, M. B. Development and assessment of conventional and targeted drug combinations for the use in the treatment of aggressive breast cancer. Current Cancer Drug Targets Sep 6 (6) 455-489, 2006. PMID: 17017873

McDonald, P., Troussard, A. A., Mawji, M. N., Dunn, S. E., Kucab, J. E., Bally, M., Gelmon, K., Dedhar, S. Preferential dependence of Cancer Cells versus normal cells for integrin-linked kinase induced PKB/AKT activation and cell survival. Cancer Research Jan 1; 66(1), 393-403. 2006. PMID: 16397254

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