John D. Haley, PhD
Associate Professor of Research, Department of Pathology
Director, Developmental Therapeutics, SBU Cancer Center
Director, SBU Proteomics Center
BST 9-168
Stony Brook Medicine
Stony Brook, NY 11794-8691
Tel: (631) 444-3097
E-mail: John.Haley@stonybrookmedicine.edu
Research Summary:
Over 90% of cancer patient deaths are attributable to metastasis and the majority of patients treated in Phase I and Phase II clinical trials have metastatic cancers. It is clear that metastatic cancers are increasingly heterogeneous, that is many different cell types and states are present within cancer tissues, and importantly metastatic cancers show increased resistance to radiation, chemotherapies and targeted therapies. Cellular plasticity plays a major role in the progression of cancer and the acquisition of mesenchymal cancer stem cell-like phenotypes has been correlated with poor prognosis. Several forms of plasticity have been documented, including epithelial mesenchymal transition (EMT), endothelial-mesenchymal transition and epithelial-neuroendocrine transition. EMT is an important cellular change which allows for metastasis and is associated with poor prognosis and resistance to chemo and targeted therapies in cancer patients. New therapeutics are needed to target the new spectrum of tumor survival signals now present within EMT-derived cells and within related cancer-stem cells. Through the generation and molecular characterization of EMT models, through RNAi-based target validation studies and follow-on pharmacology studies, new targets and compounds which promote death of metastatic cells can be identified and validated in panels of cell lines. Current research interests include defining and exploiting mechanisms for overcoming anti-cancer drug resistance and cancer metastasis.
Education and Experience:
Dr. Haley earned a BA in Chemistry from Tufts University and a Ph.D. in Molecular Endocrinology from the Howard Florey Institute for Experimental Physiology and the University of Melbourne and completed postdoctoral research fellowships at the Howard Florey Institute in Melbourne and at the Imperial Cancer Research Fund and the Ludwig Institute for Cancer Research in London. He returned to the U.S. to join Oncogene Science Inc. as Program Manager for Cancer Therapeutics and was subsequently recruited to OSI Pharmaceutical Inc. in 1992. At OSI, Dr. Haley served as Senior Director for Exploratory Cancer Research, Senior Research Director for Translational and EMT Research, and Senior Research Director for Discovery Research. He has a strong interest in drug discovery and development, most recently in Translational Medicine and Pharmacogenomics at OSI Pharmaceuticals, using biological mass spectrometry as a research tool for the quantitation of signaling networks. He has published on the exploration of cancer drug resistance and cancer biomarkers, and has organized and chaired several AACR symposia and mini-symposia on the subject. Dr. Haley holds numerous patents and has authored over 60 manuscripts related to the development of novel cancer therapeutics. He has presented numerous research seminars at national meetings, and he has served on a number of NCI grant review study sections. Through his experience in the Pharmaceutical industry, he is seeking to foster partnerships with peer institutions and with biotechnology and pharmaceutical companies, with the vision of developing novel approaches to cancer therapies at Stony Brook Medicine.
Selected Peer Reviewed Publications:
Hudson, P., Haley, J., Cronk, M., Shine, J. and Niall, H. (1981) ‘Molecular cloning and characterization of cDNA sequences coding for rat relaxin’ Nature 291, 127-131.
Haley, J., Hudson, H., Scanlon, D., John, M., Cronk, M., Shine, J., Tregear, G., and Niall, H. (1982) ‘Porcine relaxin: Molecular cloning and cDNA structure’ DNA 1, 155-162.
Hudson, P., Haley, J., John, M., Cronk, M., Crawford, R., Haralambidis, J., Tregear, G., Shine, J., and Niall, H. (1983) ‘Structure of a genomic clone encoding biologically active human relaxin’ Nature 30l, 628-631.
Haley, J., Crawford, W., Hudson, P., Scanlon, D., Tregear, G., Shine, J. and H. Niall. (1987) ‘Porcine relaxin: Gene structure and expression’. J. Biol. Chem. 262, 11940- 11946.
Haley, J., Hsuan, J. and Waterfield, M. (1989). ‘Analysis of mammalian fibroblast transformation by normal and mutated human EGF receptors’. Oncogene 4, 273-283.
Haley, J. and Waterfield, M. (1991). ‘Contributory effects of de novo transcription and premature transcript termination in the regulation of human epidermal growth factor receptor proto-oncogene RNA synthesis’. J. Biol. Chem. 266, 1746-1753.
Strife, A., Lambek, C., Perez, A., Darzynkiewicz, Z., Skierski, J., Gulati, S., Haley, J.D., ten Dijke, P., Iwata, K. and Clarkson, B. (1991). ‘The effects of TGF-beta3 on the growth of highly enriched hematopoietic progenitor cells derived from normal human bone marrow and peripheral blood’. Cancer Res. 51: 4828-4836.
Lemoli, R.M., Strife, A., Clarkson, B.D., Haley, J.D. and Gulati, S. (1992). ‘TGF-beta3 protects normal human hematopoietic progenitor cells treated with 4-hydroperoxycyclophosphamide in vitro’. Exp. Hematol. 20, 1252-1256.
Sonis, S., Lindquist, L., Van Vugt, A., Stewart, A., Stam, K., Qu, G-Y., Iwata, K. and Haley, J.D. (1994). ‘Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta3’. Cancer Res. 54, 1135-1138.
Molineux, G., Migdalska, A., Haley, J.D., Evans, G. and Dexter, T.M. (1994). ‘Total bone marrow failure induced by pegylated stem cell factor administered prior to 5-fluorouracil’. Blood 83, 3491-3499.
Stewart, A. A., Haley, J.D., Qu, G Y., Stam, K., Fenyö, D., Chait, B. T., Marshak, D. R. and Iwata, K. (1996) ‘Umbilical cord transforming growth factor beta-3: Isolation, comparison with recombinant TGF-beta3 and cellular localization’ Growth Factors 13, 87-98.
Potten, C.S., Booth, D. and Haley, J.D. (1997) ‘Pretreatment with transforming growth factor beta-3 protect small intestinal stem cells against radiation damage in vivo‘ Brit. J. Cancer 75, 1454-1459.
E.S. McCormack, G. Borzillo, C. Ambrosino, G. Mak, G-Y. Qu, L. Hamablett and Haley, J. (1997) ‘Protection of epithelial cells from cycle-selective chemotherapy by TGF-beta3 in vitro’ Biochem. Pharmacol. 53, 1149-1159.
C.A. Squier, M.Kremer, A. Bruskin, A. Rose and J.D. Haley (1999) ‘Oral mucosal permeability and stability of transforming growth factor beta-3 in vitro’ Pharm. Res. 16, 1557-1563.
Booth, D., Haley, J.D., Bruskin, A. and Potten, C.S. (2000) ‘TGF-beta3 protects murine small intestinal crypt stem cells and animal survival after irradiation by reducing stem cell cycling’ Int. J. Cancer 86, 53-59.
Thomson, S., Buck, E., Petti, F., Griffin, G., Brown, E., Ramnarine N., Iwata, K., Gibson, N. and Haley, J.D. (2005) ‘Epithelial-mesenchymal transition is a determinant of sensitivity of non-small cell lung carcinoma cell lines and xenografts to EGF receptor inhibition’ Cancer Res. 65, 9455-9462.
Iwata, K., Beard, S. and Haley, J.D. (2006) ‘Epidemal growth factor receptor (EGFR) inhibitor for oncology: Discovery and development of erlotinib’ In: Target Validation in Drug Discovery, Eds. B. Metcalf and S. Dillon, pp. 155 – 178. Academic Press, London, UK.
Carey, K.D., Garton, A., Romero, M., Kahler, J., Eberhard, D., Thomson, S., Ross, S., Park, F., Haley, J., Gibson, N. and Sliwkowski, M.X. (2006) ‘Kinetic analysis of EGFR somatic mutant proteins demonstrates increased sensitivity to the EGFR tyrosine kinase inhibitor, erlotinib’ Cancer Res. 66, 8163-8171.
Buck, E., Eyzaguirre, A., Brown, E., Petti, F., McCormack, S., Haley, J.D, Iwata, K.K., Gibson, N.W. and Griffin, G. (2006) ‘Rapamycin Synergizes with the EGFR Inhibitor Erlotinib in NSCLC, Pancreatic, Colon, and Breast Cancers’ Mol. Cancer Ther. 5, 2676-84.
Buck, E., Eyzaguirre, A., Thomson, S., Iwata, K., Gibson, N., Cagnoni, P. and Haley, J.D. (2007). Loss of homotypic cell adhesion by epithelial-mesenchymal-transition or mutation limits sensitivity to EGF receptor inhibition. Mol. Cancer Ther. 6, 532-41.
‘EGFR Signaling Networks in Cancer Therapy’ 2008. Eds. J.D. Haley and W. Gullick, pp1-393. Springer-Verlag, Berlin.
Barr, S., Thomson, S., Buck, E., Russo, S., Petti, F., Sujka, I., Ezyguirre, A., Franklin, M., Gibson, N., Miglarese, M., Epstein, D., Iwata, K.K. and Haley, J.D. (2008) ‘Bypassing cellular EGF receptor dependence through epithelial mesenchymal-like transitions’ Clin. Exp. Metastasis 25, 685-93.
Thomson, S., Petti, F., Sujka-Kwok, I., Epstein, D. and Haley, J.D. (2008) ‘Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy’. Clin. Exp. Metastasis 25, 843-854.
Buck, E., Eyzaguirre, A., Barr, S., Thomson, S. Franklin, M., Brown, E., O’Connor, M., Yao, Y., Pachter, J., Iwata, K.K., Haley, J.D., Gibson, N.W. and Ji, Q-S. (2008). ‘Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors’ Cancer Res. 68, 8322-8332.
Thomson, S., Petti, F., Sujka-Kwok, I., Mercado, P., Bean, J., Monaghan, M., Seymour, S.L., Argast, G., Epstein, D. and Haley, J.D. (2011) ‘A systems view of epithelial - mesenchymal transition signaling states’ Clin. Exp. Metastasis 28, 137-55.
White, F. and Haley, J.D. (2014) ‘Adaptive protein and phosphoprotein networks which promote therapeutic sensitivity or acquired resistance’ Biochem. Soc. Trans., in press.
