Greer, Peter A - Queen's University - Department of Biomedical and Molecular Sciences

个人简介

Our research explores several potential therapeutic targets, but it considers these in the context of the larger picture of mitogenic and survival signalling pathways available to the cancer cell.We reason that targeted inhibition of one pathway will select for cancer cells that have evolved to bypass that first pathway, perhaps by engaging alternative parallel or interacting pathways.It follows that we must anticipate this plasticity in the signalling apparatus of the surviving cancer cells and use an appropriate combination of targeted small molecule inhibitors which collectively prevent survival of all cancer cells. Current projects in the lab explore the functions of Fps/Fes and Fer protein-tyrosine kinases and the calpain protease system in cellular signalling.We also investigate the effects of single or combinations of small molecule kinase inhibitors on the signalling apparatus of cancer cells. This work involves biochemistry, molecular biology, cell biology, transgenic and gene knock-out mice and animal physiology, and translational cancer research using clinical materials.

研究领域

The discovery of retroviral oncogenes in the 1970’s lead to the identification of their corresponding normal cellular proto-oncogene homologs. Their encoded proteins were subsequently found to play important signalling functions controlling cellular survival, growth, proliferation and differentiation.It seemed that mutations leading to over exuberant or altered activity of these oncoproteins could be at the root of cancer, and perhaps many other diseases. The pharmaceutical industry descended on these oncoproteins with drug discovery programs aimed at developing targeted small molecule inhibitor based therapeutics. We appeared on the verge of cures or clinical management of several major cancers and other diseases.However, with a few exceptions, essentially all targeted small molecule inhibitors have failed cancer clinical trials when used as single agents.Much like the organisms in which they develop, cancer cells are willey creatures capable of evolving to survive in face of seemingly insurmountable challenges. This often leads to cancer relapse after what often appears to be a successful clinical intervention. It is clear that we need to devise more ingenious multipronged attacks to prevent cancer relapse. Our research explores several potential therapeutic targets, but it considers these in the context of the larger picture of mitogenic and survival signalling pathways available to the cancer cell.We reason that targeted inhibition of one pathway will select for cancer cells that have evolved to bypass that first pathway, perhaps by engaging alternative parallel or interacting pathways.It follows that we must anticipate this plasticity in the signalling apparatus of the surviving cancer cells and use an appropriate combination of targeted small molecule inhibitors which collectively prevent survival of all cancer cells. Current projects in the lab explore the functions of Fps/Fes and Fer protein-tyrosine kinases and the calpain protease system in cellular signalling.We also investigate the effects of single or combinations of small molecule kinase inhibitors on the signalling apparatus of cancer cells. This work involves biochemistry, molecular biology, cell biology, transgenic and gene knock-out mice and animal physiology, and translational cancer research using clinical materials.

近期论文

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104. Rao, S.-.S., Mu, Q., Zeng, Y., Cai, P.-.C., Yang, J., Xia, Y., Zhang, Q., Song, L.-.J., Zhou, L.-.L., Li, F.-.Z., Lin, Y.-.L., Fang, J., Greer, P.A., Shi, H.-.Z., Ma, W.-.L., Su, Y., and Ye, H. 2016. Calpain-activated mTORC2/Akt pathway mediates airway smooth muscle remodeling in asthma. Clinical & Experimental Allergy (In press) Epub Sept 20, 2016 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27649066 103. Li, S., Zhang, Zhang, L., Xiong, S, Greer, P.A., Fan, G.-G., and Peng, T. 2016. Disruption of calpain reduces lipotoxcity-induced cardiac injury by preventing endoplasmic reticulum stress. BBA – Molecular Basis of Disease 1862:2023-33 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27523632 102. Fan, G., Zhang, S., Gao, Y., Greer, P.A. and Tonks, N.K. 2016. HGF-independent regulation of MET and GAB1 by non-receptor tyrosine kinase FER potentiates metastasis in ovarian cancer. Genes and Development 30: 1542-57 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27401557 101. Yang, J., Xiang, F., Cai, P.-C., Lu, Y.-Z., Xu, X.-X., Yu, F., Li, F.-Z., Greer, P.A., Shi, H.-Z., Zhou, Q., Xin, J.-B., Ye, H., Su, Y., and Ma, W.-L. 2016. Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis. American Journal of Physiology Lung Cellular and Molecular Physiology 311:L145 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27261452 100. Alvau, A., Battistone, M.A., Gervasi, M.G., Salicioni, A.M., Navarrete, F.A., Sanchez, C., De la Vega-Beltran, J.L., Greer, P.A., Darszon, A., Cuasnicu, P., Visconti, P.E. 2016. The tyrosine kinase Fer is responsible for the capacitation-associated increase in tyrosine phosphorylation. Development 143: 2325-33 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27226326 99. Grieve, S., Gao, Y., Hu, J., Hall, C., and Greer, P.A. 2016. Calpain genetic disruption and HSP90 inhibition combine to attenuate mammary tumorigenesis. Molecular & Cellular Biology 36:2078-88 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27215381 98. Ni, R., Zheng, D., Xiong, S., Hill, D., Sun, T., Gardnier, R., Fan, G.-C., Lu, Y., Abel, D., Greer, P.A., Peng, T. 2015. Mitochondrial calpain-1 disrupts ATP synthase and induces superoxide generation in type-1 diabetic hearts: a novel mechanism contributing to diabetic cardiomyopathy. Diabetes 65:255-68 http://diabetes.diabetesjournals.org/content/early/2015/10/08/db15-0963.long 97. Ni, R, Zheng, D., Wang, Q., Yu, Y., Chen, R., Sun, T., Wang, W., Zhang, H., Fan, G.-C., Greer, P.A. Gardiner, R., and Peng, T. 2015. Deletion of capn4 protects the heart against endotoxemic injury by preventing ATP synthase disruption and inhibiting mitochondrial superoxide generation. Circulation: Heart Failure 8:988-996. http://www.ncbi.nlm.nih.gov/pubmed/26246018?dopt=Citation 96. Hoskin, V., Szeto, V., Ghaffari, A., Greer, P.A., Côté, G.P., and Elliott, B.E., 2015. Ezrin regulates focal adhesion and invadopodia dynamics by altering calpain activity to promote breast cancer cell invasion. Molecular Biology of the Cell. 26:3464-79 http://www.ncbi.nlm.nih.gov/pubmed/26246600?dopt=Citation 95. Zhang, S., Kim, H., Mullins, G.S., LeBrun, D., Elliott, B.E., and Greer, P. A. 2015. Interleukin-4 Expressed By Neoplastic Cells Provokes an Anti-Metastatic Myeloid Immune Response. Journal of Clinical & Cellular Immunology 6:329-47 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27563494 94. Li, F.-Z., Cai, P.-C., Song, L.-J., Zhou, L.-L., Zhang, Q., Xiang, F., Zhang, J.-C., Rao, S.-S., Xia, Y., Xiang, F., Xin, J.-B., Greer, P.A., Shi, H.-Z., Su, Y., Ma, W.-L., Ye, H. 2015. Crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in pulmonary fibrosis. BBA-Molecular Basis of Disease 1852:1796 http://www.sciencedirect.com/science/article/pii/S092544391500174X 93. Yang, J., Wu, Z., Renier, N., Simon, D.J., Uryu, K., Park D.S., Greer, P.A., Tournier, C., Davis, R.J., and Tessier-Lavigne, M. 2015. Pathological axonal death through a MAPK cascade that triggers local energy deficit. Cell 160:161-176 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=25594179 92. Lu, S., Kanekura, K., Hara, T., Mahadevan, J., Spears, L.D., Oslowski, C.M., Marinez, R., Yamazaki-Inoue, M., Toyoda, M., Neilson, A., Blanner, P.M., Brown, C., Semenkovich, C.F., Marshall, B.A., Hershey, T., Umezawa, A., Greer, P.A., and Urano, F. 2014. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. PNAS 111: E5292-301 http://www.pnas.org/content/early/2014/11/20/1421055111.full.pdf+html