Dr. Kerry B. Goralski, PhD
Professor, College of Pharmacy, and Cross Appointment to Department of Pharmacology
Development of new anti-cancer drugs for drug resistant metastatic breast cancer, obesity and endocrine function of fat tissue, preclinical and clinical pharmacology and pharmacokinetics, drug transport and metabolism
Membrane drug pumps and multidrug resistant metastatic breast cancer
Multidrug resistance remains a serious problem in the effective treatment of metastatic breast cancer. One way that breast cancer cells develop resistance is by increasing their number of cell membrane drug pumps (e.g. P-glycoprotein) that remove helpful chemotherapy from the inside of cancer cells. Our research has shown that a class of bacterial-derived natural product molecules called jadomycins escape P-glycoprotein function, allowing them to kill cultured breast cancer cells that are resistant to other chemotherapy drugs. Our current pharmacological research focuses on determining how jadomycins kill breast cancer cells, if jadomycins kill breast cancer cells without harming noncancerous cells and if jadomycins prevent breast cancer growth and metastasis in zebrafish and mouse experimental models. Through this research, we can better understand how jadomycins could be used to treat patients in a clinical setting, and also learn more about metastatic breast cancer as a disease.
Involvement with BHCRI to date:Dr. Goralski is a BHCRI Associate Member
Contact:College of Pharmacy, Dalhousie University, 5968 College Street, Halifax, Nova Scotia, Canada, B3H 4R2
Robertson, A.W., MacLeod, J.M., MacIntyre, L.W., Forget, S.M., Hall, S.R., Bennett, L.G., Correa, H., Kerr, R.G., Goralski, K.B. & Jakeman, D.L. Post Polyketide Synthase Carbon-Carbon Bond Formation in Type-II PKS-Derived Natural Products from Streptomyces venezuelae. J Org Chem 83, 1876-1890 (2018).
Hall, S.R. & Goralski, K.B. ZATT, TDP2, and SUMO2: breaking the tie that binds TOP2 to DNA. Translational Cancer Research 7, S439-S444 (2018).
Forget, S.M., Robertson, A.W., Hall, S.R., MacLeod, J.M., Overy, D.P., Kerr, R.G., Goralski, K.B. & Jakeman, D.L. Isolation of a jadomycin incorporating L-ornithine, analysis of antimicrobial activity and jadomycin reactive oxygen species (ROS) generation in MDA-MB-231 breast cancer cells. J Antibiot (Tokyo) 71, 722-730 (2018).
Hall, S.R., Toulany, J., Bennett, L.G., Martinez-Farina, C.F., Robertson, A.W., Jakeman, D.L. & Goralski, K.B. Jadomycins Inhibit Type II Topoisomerases and Promote DNA Damage and Apoptosis in Multidrug-Resistant Triple-Negative Breast Cancer Cells. J Pharmacol Exp Ther 363, 196-210 (2017).
Hall, S.R., Blundon, H.L., Ladda, M.A., Robertson, A.W., Martinez-Farina, C.F., Jakeman, D.L. & Goralski, K.B. Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism. Pharmacol Res Perspect 3, e00110 (2015).
Issa, M.E., Hall, S.R., Dupuis, S.N., Graham, C.L., Jakeman, D.L. & Goralski, K.B. Jadomycins are cytotoxic to ABCB1-, ABCC1-, and ABCG2-overexpressing MCF7 breast cancer cells. Anticancer Drugs 25, 255-269 (2014).
Dupuis, S.N., Robertson, A.W., Veinot, T., Monro, S.M.A., Douglas, S.E., Syvitski, R.T., Goralski, K.B., McFarland, S.A. & Jakeman, D.L. Synthetic diversification of natural products: semi-synthesis and evaluation of triazole jadomycins. Chemical Science 3, 1640-1644 (2012).