Dr. Barry Nelkin
Molecular Mechanisms of Thyroid and Lung Cancers
Molecular Mechanisms of Thyroid and Lung Cancers
Ph.D., George Washington University, Washington, D.C.
Postdoctoral Fellow, Johns Hopkins Kimmel Cancer Center
For the past two decades, this laboratory has explored the control of growth and differentiation of MTC cells. The initial impetus for this research was the finding by Dr. Stephen Baylin that loss of expression of a well-known differentiation marker for MTC, calcitonin, was correlated with poor disease prognosis. This laboratory isolated the human calcitonin gene and, using a cell culture model of MTC, showed that a coordinated program of cell differentiation and growth arrest could be induced by several signal transduction pathways. Subsequent research has focused on the ability of the ras/raf signal transduction pathway to induce irreversible growth arrest and differentiation in these cells. This has resulted in the identification of two ras/raf-responsive transcription factors, RREB and BARX2, and the demonstration that the RET oncogene is silenced during raf-mediated MTC cell differentiation. Raf activation also induces growth arrest and differentiation in small cell lung cancer (SCLC) cells.
Recently, this laboratory has shown that ras/raf-induced differentiation and cell arrest in MTC cells involves two parallel signal transduction pathways, either of which is sufficient to elicit the cell response. One of these pathways is intracellular. The other pathway involves ras/raf-induced expression and autocrine/paracrine signaling by a cytokine, leukemia inhibitory factor (LIF). Thus, in these cells, the ras/raf signal transduction pathway can activate the JAK/STAT signal transduction pathway. SCLC cells are also induced by ras/raf to activate LIF expression and JAK/STAT signaling; however, ras/raf activation arrests SCLC only by the intracellular pathway but not by the autocrine/paracrine LIF-mediated pathway. The significance of these findings is that neuroendocrine cancers, which rarely, if ever, have ras mutations, are actually arrested by such activation of the ras/raf signal transduction pathway. This cell arrest in response to ras/raf activation has been described previously in normal cells, where it may serve as a defense mechanism against ras/raf-mediated growth dysregulation. For ras-associated carcinogenesis, these mechanisms must be inactivated. The findings indicate that, in neuroendocrine cancer cells, some of these growth inhibitory mechanisms are still intact, suggesting that activation of these growth regulatory mechanisms, e.g., by LIF in MTC, may be a potential approach for therapy in neuroendocrine cancers.
Sommer, M.; Poliak, N.; Upadhyay, S.; Ratovitski, E.; Nelkin, B.D.; Donehower, L.A.; Sidransky, D. DeltaNp63alpha overexpression induces downregulation of Sirt1 and an accelerated aging phenotype in the mouse. Cell Cycle. 2006 Sep;5(17):2005-2011.
Strock, C.J.; Park, J.I.; Nakakura, E.K.; Bova, G.S.; Isaacs, J.T.; Ball, D.W.; Nelkin, B.D. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res. 2006 Aug 1;66(15):7509-7515.
Strock, C.J.; Park, J.I.; Rosen, D.M.; Ruggeri, B.; Denmeade, S.R.; Ball, D.W.; Nelkin, B.D. Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. J Clin Endocrinol Metab. 2006 Jan;91(1):79-84.
Ball, D.W.; Jin, N.; Rosen, D.M.; Dackiw, A.; Sidransky, D.; Xing, M.; Nelkin, B.D. Selective Growth Inhibition in BRAF Mutant Thyroid Cancer by the Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244. J Clin Endocrinol Metab. 2007 Dec;92(12):4712-4718.
Madar, I.; Ravert, H.; Nelkin, B.; Abro, M.; Pomper, M.; Dannals, R.; Frost, J.J. Characterization of membrane potential-dependent uptake of the novel PET tracer (18)F-fluorobenzyl triphenylphosphonium cation. Eur J Nucl Med Mol Imaging. 2007 Dec;34(12):2057-2065.
Jiang, T.; Collins, B.J.; Jin, N.; Watkins, D.N.; Brock, M.V.; Matsui, W.; Nelkin, B.D.; Ball, D.W. Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res. 2009 Feb 1;69(3):845-854.
Jin, N.; Jiang, T.; Rosen, D.M.; Nelkin, B.D.; Ball, D.W. Dual inhibition of mitogen-activated protein kinase kinase and mammalian target of rapamycin in differentiated and anaplastic thyroid cancer. J Clin Endocrinol Metab. 2009 Oct;94(10):4107-4112.
Tjiang, T.; B.J., C.; Jin, N.; Brock, M.V.; Watkins, D.N.; Matsui, W.; Nelkin, B.D.; Ball, D.W. ASCL1 regulates CD133 and tumor-initiating capacity of SCLC. Cancer Research. 2009 (In Press).
Feldmann, G.; Mishra, A.; Hong, S.M.; Bisht, S.; Strock, C.J.; Ball, D.W.; Goggins, M.; Maitra, A.; Nelkin, B.D. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res. 2010 Jun 1;70(11):4460-4469.
Hector, A.; Montgomery, E.A.; Karikari, C.; Canto, M.; Dunbar, K.B.; Wang, J.S.; Feldmann, G.; Hong, S.M.; Haffner, M.C.; Meeker, A.K.; Holland, S.J.; Yu, J.; Heckrodt, T.J.; Zhang, J.; Ding, P.; Goff, D.; Singh, R.; Roa, J.C.; Marimuthu, A.; Riggins, G.J.; Eshleman, J.R.; Nelkin, B.D.; Pandey, A.; Maitra, A. The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biol Ther. 2010 Nov 29;10(10):1009-1018.