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.
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.
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
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
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
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
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
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
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
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.
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
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
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
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
91. Williams, J.L., Greer, P.A., and Squire, J.A. 2014. Recurrent copy number alterations in prostate cancer: an in silico meta-analysis of publicly available genomic data. Cancer Genetics 207:474-488
90. Sangrar, W. Shi, C., Mullins, G.S., LeBrun, D., Ingalls, B., and Greer, P.A. 2014. Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems. Oncogene 34:4109-17
89. Redpath, G.M., Woolger, N., Piper, A.K., Lemckert, F.A., Lek, A., Greer, P.A., North, K.N., Cooper, S.T. 2014. Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair. Mol. Biol. Cell. 25:3037-3048
88. Kumar, V., Everingham, S., Hall, C., Greer, P.A. and Craig, A.W.B. 2014. Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model. European Journal of Immunology 44:831
87. Elagib, K.E., Rubinstein, J.D., Delehanty, L.L., Ngoh, V., Greer, P.A., Li, S., Lee, J.K., Orkin, S.H., Mihaylov, I.S. and Goldfarb, A.N. 2013 Calpain 2 Activation of P-TEFb Drives Megakaryocyte Morphogenesis and Is Disrupted by Leukemogenic GATA1 Mutation. Developmental Cell 27:607
86. Nagaria, T., Williams, J.L., Leduc, C., Squire, J.A., Greer, P.A, and Sangrar, W. 2013 Flavopiridol synergizes with Sorafenib to induce cytotoxicity and potentiate anti-tumorigenic activity in EGFR/HER-2 and mutant RAS/RAF breast cancer model systems. Neoplasia 15:939-51
85. Miyata, Y., Kanda, S., Sakai, H., and Greer, P.A. 2013. Feline sarcoma-related protein expression correlates with malignant aggressiveness and poor prognosis in renal cell carcinoma. Cancer Science 104:681
84. Amini, M., Ma, C. Farazifard, R., Zhang, Y.H., Vanderluit, J., Zoltewicz, J.S., Hage, F., Savitt, J.M., Lagace, D., Slack, R.S., Beique, J.C., Greer, P.A., Richard Bergeron, R., Park, D.S. 2013. Conditional disruption of calpain in CNS alters dendrite morphology, impairs LTP, and promotes neuronal survival following injury. J. Neuroscience 33:5773-84
83. Khajah, M., Andonegui, G., Chan, R., Craig, A.W., Greer, P.A. and McCafferty, D.M. 2013. Fer Kinase Limits Neutrophil Chemotaxis towards End Target Chemoattractants. J. Immunol. 190:2208-16
82. Ma, J., Wie, M., Wang, Q., Li, J., Wang, H., Liu, W., Liu, W., Lacefield, J.C., Greer, P.A., Karmazyn, M., Fan, G., and Peng, T. 2012. Deficiency of Capn4 inhibits NF-kB signaling/inflammation and reduces remodeling after myocardial infarction. J. Biol. Chem. 287:27480
81. Kwok, E., Everingham, S., Zhang, S., Greer, P.A., Allingham, J.S. and Craig, A.W.B. 2012.
FES kinase promotes mast cell recruitment to mammary tumors via the stem cell factor/KIT receptor signaling axis. Molecular Cancer Research 10:881-91
80. Ho., W.C., Pikor, L, Gao, Y., Elliott, B.E., and Greer, P.A. 2012. Calpain 2 regulates the Akt-FoxO-p27Kip1signaling pathway in mammary carcinoma. J. Biol. Chem. 287:15458-15465
79. Greer, P.A., Kanda, S., and Smithgall, T.E. 2012. The contrasting oncogenic and tumor suppressor roles of FES. Frontiers in Bioscience 4:489-501
78. Ma, W., Han, W., Greer, P.A., Tuder, R., Toque, H.F., Wang, K.K.W. Caldwell, R.W. and Su, Y. 2011. Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuated pathologic features of disease. J. Clinical Invest. 121:4548-66
77. Li, Y., Ma, J., Zhu, H., Singh, M., Hill, D., Greer, P.A., Arnold, J. A., Abel, E.D. and Peng, T., 2011. Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type-I diabetes. Diabetes 60:2985-94
76. Miyata, Y., Watanabe, S., Matsuo, T., Maruta, S., Hayashi, T., Sakai, H., Xuan, J.W., Greer, P.A. and Kanda, S. 2011. Pathological significance and predictive value for biochemical recurrence of c-Fes expression in prostate cancer. Prostate 72:201-8
75. Zhang, S., Chitu, V., Stanley, R., Elliott, B., and Greer, P.A. 2011. Fes tyrosine kinase expression in the tumor niche correlates with enhanced tumor growth, angiogenesis, circulating tumor cells, metastasis and infiltrating macrophages. Cancer Research 71:1465-1473