Hypoxia is arguably the most well established characteristic of solid tumors that has yet to be effectively targeted therapeutically, and it is a significant obstacle to the successful treatment of cancer. Hypoxia is a reduction in the normal level of tissue oxygen that occurs in tumors due to poor blood flow and the aberrant development of new blood vessels. In response to hypoxia, cancer cells take particular advantage of their ability to activate the hypoxia-inducible factor 1 (HIF-1) transcription factor. HIF-1 increases the expression of genes that promote survival and angiogenesis, and it is associated with poor prognosis and resistance to therapy in various types of cancer. As a result, inhibiting the activity of hypoxia-inducible factors that stimulate tumor growth is currently a major objective of anticancer therapy; most notably the use of antibodies and tyrosine kinase inhibitors to block VEGF activity. While these agents display antitumor activity, they do not markedly inhibit tumor growth or induce massive tumor regression. Therefore, new strategies are needed to inhibit the expression of hypoxia-inducible genes that stimulate tumor growth. The current focus of my lab is to develop novel approaches to target the hypoxic tumor microenvironment. Our goal is to understand the complex signaling networks that control hypoxia-mediated therapeutic resistance in solid tumors and translate these basic concepts to clinical applications that will directly impact patient care.
Noel Warfel, PhD
Associate Professor, Cellular and Molecular Medicine
Vice Chair, Cancer Biology GIDP
Associate Professor, Cancer Biology GIDP
Co-Director, Experimental Mouse Shared Resource
Research Interests:
Molecular Medicine Grad Program:
Yes
Bibliography
2023
Jensen, C. C., A. N. Clements, H. Liou, L. E. Ball, J. R. Bethard, P. R. Langlais, R. K. Toth, S. S. Chauhan, A. L. Casillas, S. R. Daulat, et al., "PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion.", J Cell Biol, vol. 222, issue 6, 2023 Jun 05.
PMCID: PMC10103708 PMID: 37042842
Torres-Ayuso, P., M. Katerji, D. Mehlich, S. A. Lookingbill, V. R. Sabbasani, H. Liou, A. L. Casillas, S. S. Chauhan, R. Serwa, M. R. Rubin, et al., "PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer.", Cell Chem Biol, 2023 Nov 16.
PMID: 38016478
Chauhan, S. S., A. L. Casillas, A. D. Vizzerra, H. Liou, A. N. Clements, C. E. Flores, C. T. Prevost, D. F. Kashatus, A. J. Snider, J. M. Snider, et al., "PIM1 drives lipid droplet accumulation to promote proliferation and survival in prostate cancer.", Oncogene, 2023 Dec 14.
PMCID: 6986389 PMID: 38097734
2022
Ryniawec, J. M., M. R. Coope, E. Loertscher, V. Bageerathan, D. de Oliveir Pessoa, N. A. Warfel, A. E. Cress, M. Padi, and G. C. Rogers, "GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors.", Diagnostics (Basel), vol. 12, issue 3, 2022 Mar 10.
PMCID: PMC8946944 PMID: 35328229
Toth, R. K., R. Solomon, and N. A. Warfel, "Stabilization of PIM Kinases in Hypoxia Is Mediated by the Deubiquitinase USP28.", Cells, vol. 11, issue 6, 2022 Mar 16.
PMCID: PMC8947361 PMID: 35326457
2021
Casillas, A. L., S. S. Chauhan, R. K. Toth, A. G. Sainz, A. N. Clements, C. C. Jensen, P. R. Langlais, C. K. Miranti, A. E. Cress, and N. A. Warfel, "Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors.", Oncogene, 2021 Jul 02.
PMID: 34211090
Singh, N., V. R. Ramnarine, J. H. Song, R. Pandey, S. K. R. Padi, M. Nouri, V. Olive, M. Kobelev, K. Okumura, D. McCarthy, et al., "The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer.", Nat Commun, vol. 12, issue 1, pp. 7349, 2021 Dec 21.
PMID: 34934057
2020
Chauhan, S. S., R. K. Toth, C. C. Jensen, A. L. Casillas, D. F. Kashatus, and N. A. Warfel, "PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer.", Oncogene, 2020 01 28.
PMID: 31992853
2019
Rubenstein, C. S., J. M. C. Gard, M. Wang, J. E. McGrath, N. Ingabire, J. P. Hinton, K. D. Marr, S. J. Simpson, R. B. Nagle, C. K. Miranti, et al., "Gene editing of α6 integrin inhibits muscle invasive networks and increases cell-cell biophysical properties in prostate cancer.", Cancer Res, 07/2019.
PMID: 31337652
Toth, R. K., J. D. Tran, M. T. Muldong, E. A. Nollet, V. V. Schulz, C. C. Jensen, L. A. Hazlehurst, E. Corey, D. Durden, C. Jamieson, et al., "Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC.", Am J Clin Exp Urol, vol. 7, issue 4, pp. 297-312, 08/2019.
PMCID: PMC6734039 PMID: 31511835
Harryman, W. L., N. A. Warfel, R. B. Nagle, and A. E. Cress, "The Tumor Microenvironments of Lethal Prostate Cancer.", Adv Exp Med Biol, vol. 1210, pp. 149-170, 2019 01 01.
PMID: 31900909
2018
Song, J. H., N. Singh, L. A. Luevano, S. K. R. Padi, K. Okumura, V. Olive, S. M. Black, N. A. Warfel, D. W. Goodrich, and A. S. Kraft, "Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase.", Mol Cancer Ther, vol. 17, issue 12, pp. 2710-2721, 2018 12.
PMCID: PMC6279580 PMID: 30190422
Chauhan, S. S., and N. A. Warfel, "Targeting PIM kinases to oppose hypoxia-mediated therapeutic resistance.", Oncoscience, vol. 5, issue 9-10, pp. 254-255, 2018 Sep.
PMCID: PMC6231444 PMID: 30460324
2017
Toth, R. K., and N. A. Warfel, "Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia.", Antioxidants (Basel), vol. 6, issue 2, 2017 Apr 06.
PMCID: PMC5488007 PMID: 28383481
Warfel, N. A., "Targeting CDK4/6 to oppose hypoxia-mediated therapeutic resistance.", Cell Cycle, vol. 16, issue 13, pp. 1241-1242, 2017 Jul 03.
PMCID: PMC5531619 PMID: 28594259
Casillas, A. L., R. K. Toth, A. G. Sainz, N. Singh, A. A. Desai, A. S. Kraft, and N. A. Warfel, "Hypoxia-Inducible PIM Kinase Expression Promotes Resistance to Antiangiogenic Agents.", Clin Cancer Res, 2017 Oct 30.
PMID: 29084916
2016
Warfel, N. A., A. G. Sainz, J. H. Song, and A. S. Kraft, "PIM kinase inhibitors kill hypoxic tumor cells by reducing Nrf2 signaling and increasing reactive oxygen species.", Mol Cancer Ther, 2016 May 16.
PMID: 27196781
2015
Zhang, S., L. Zhou, B. Hong, P. J. A van den Heuvel, V. V. Prabhu, N. A. Warfel, C. Leah B. Kline, D. T. Dicker, L. Kopelovich, and W. S. El-Deiry, "Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53.", Cancer Res, vol. 75, issue 18, pp. 3842-52, 2015 Sep 15.
PMCID: PMC4573895 PMID: 26294215
Warfel, N. A., and A. S. Kraft, "PIM kinase (and Akt) biology and signaling in tumors.", Pharmacol Ther, vol. 151, pp. 41-9, 2015 Jul.
PMID: 25749412
2014
Warfel, N. A., and W. S. El-Deiry, "HIF-1 signaling in drug resistance to chemotherapy.", Curr Med Chem, vol. 21, issue 26, pp. 3021-8, 2014.
PMID: 24735366
2013
Warfel, N. A., N. G. Dolloff, D. T. Dicker, J. Malysz, and W. S. El-Deiry, "CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth.", Cell Cycle, vol. 12, issue 23, pp. 3689-701, 2013 Dec 1.
PMCID: PMC3903720 PMID: 24189531
Warfel, N. A., and W. S. El-Deiry, "p21WAF1 and tumourigenesis: 20 years after.", Curr Opin Oncol, vol. 25, issue 1, pp. 52-8, 2013 Jan.
PMID: 23159848
2012
Warfel, N. A., and A. C. Newton, "Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP): a new player in cell signaling.", J Biol Chem, vol. 287, issue 6, pp. 3610-6, 2012 Feb 3.
PMCID: PMC3281723 PMID: 22144674
Prabhu, V. V., N. A. Warfel, and W. S. El-Deiry, "CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis.", Cell Cycle, vol. 11, issue 14, pp. 2592-3, 2012 Jul 15.
PMCID: PMC3409005 PMID: 22751431
2011
Warfel, N. A., M. Niederst, and A. C. Newton, "Disruption of the interface between the pleckstrin homology (PH) and kinase domains of Akt protein is sufficient for hydrophobic motif site phosphorylation in the absence of mTORC2.", J Biol Chem, vol. 286, issue 45, pp. 39122-9, 2011 Nov 11.
PMCID: PMC3234737 PMID: 21908613
Warfel, N. A., M. Niederst, M. W. Stevens, P. M. Brennan, M. C. Frame, and A. C. Newton, "Mislocalization of the E3 ligase, β-transducin repeat-containing protein 1 (β-TrCP1), in glioblastoma uncouples negative feedback between the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt.", J Biol Chem, vol. 286, issue 22, pp. 19777-88, 2011 Jun 3.
PMCID: PMC3103356 PMID: 21454620
2009
Brognard, J., M. Niederst, G. Reyes, N. Warfel, and A. C. Newton, "Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C.", J Biol Chem, vol. 284, issue 22, pp. 15215-23, 2009 May 29.
PMCID: PMC2685702 PMID: 19324870
2007
Granville, C. A., N. Warfel, J. Tsurutani, C. M Hollander, M. Robertson, S. D. Fox, T. D. Veenstra, H. J. Issaq, I. R Linnoila, and P. A. Dennis, "Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors.", Clin Cancer Res, vol. 13, issue 7, pp. 2281-9, 2007 Apr 1.
PMID: 17404113
Gills, J. J., S. S Castillo, C. Zhang, P. A. Petukhov, R. M. Memmott, M. Hollingshead, N. Warfel, J. Han, A. P. Kozikowski, and P. A. Dennis, "Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms.", J Biol Chem, vol. 282, issue 37, pp. 27020-9, 2007 Sep 14.
PMID: 17631503
Gills, J. J., J. Lopiccolo, J. Tsurutani, R. H. Shoemaker, C. J. M. Best, M. S. Abu-Asab, J. Borojerdi, N. A. Warfel, E. R. Gardner, M. Danish, et al., "Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo.", Clin Cancer Res, vol. 13, issue 17, pp. 5183-94, 2007 Sep 1.
PMID: 17785575
2006
Warfel, N. A., E. R. Lepper, C. Zhang, W. D. Figg, and P. A. Dennis, "Importance of the stress kinase p38alpha in mediating the direct cytotoxic effects of the thalidomide analogue, CPS49, in cancer cells and endothelial cells.", Clin Cancer Res, vol. 12, issue 11 Pt 1, pp. 3502-9, 2006 Jun 1.
PMID: 16740776