Warfel Lab

Hypoxia (low oxygen) is arguably the most well characterized aspect of tumor biology that has yet to be exploited therapeutically. The Warfel lab strives to identify and understand the signal transduction pathways that promote therapeutic resistance and the aggressive phenotype associated with tumor hypoxia. We are particularly interested in elucidating HIF-1-independent mechanisms that control survival, angiogenesis, and cell migration in hypoxia. Our long-term goal is to identify new targets and translate new therapeutic strategies to oppose tumor hypoxia and improve patient care. Using a combination of biochemistry, live cell imaging, and in vivo models, we are understanding how to exploit hypoxia as a target for cancer therapy.

1. Toth RK, Solomon R, Warfel NA. Stabilization of PIM kinases in hypoxia is mediated by the deubiquitinase USP28. Cells (2022) PMID: 35326457.
2. Ryniawec JM, Coope MR, Loertscher E, Bageerathan V, de Oliveira Pessoa D, Warfel NA, Cress AE, Padi M, Rogers GC. GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors. Diagnostics 2022 PMID: 35328229.
3. Singh N, Ramnarine VR, Song JH, Pandey R, Padi SKR, Nouri M, Olive V, Kobelev M, Okumura K, McCarthy D, Hanna MM, Mukherjee P, Sun B, Lee BR, Parker JB, Chakravarti D, Warfel NA, Zhou M, Bearss JJ, Gibb EA, Alshalalfa M, Karnes RJ, Small EJ, Aggarwal R, Feng F, Wang Y, Buttyan R, Zoubeidi A, Rubin M, Gleave M, Slack FJ, Davicioni E, Beltran H, Collins C, Kraft AS. The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer. Nat Commun. (2021) PMID: 34934057.
4. Casillas AL, Chauhan SS, Toth RK, Sainz AG, Clements AN, Jensen CC, Langlais PR, Miranti CK, Cress AE, Warfel NA. Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors. Oncogene. (2021) PMID: 34211090.
5. Chauhan SS, Toth RK, Jensen CC, Casillas AL, Kashatus DF, Warfel NA. PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer. Oncogene (2020) PMID: 31992853.
6. Rubenstein CS, Gard JMC, Wang M, McGrath JE, Ingabire N, Hinton JP, Marr KD, Simpson SJ, Nagle RB, Miranti CK, Warfel NA, Garcia JGN, Arif-Tiwari H, Cress AE. Gene Editing of α6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in Prostate Cancer. Cancer Res 79(18):4703-4714 (2019) PMID: 31337652
7. Toth RK, Tran JD, Muldong MT, Nollet EA, Schulz VV, Jensen CC, Hazlehurst LA, Corey E, Durden D, Jamieson C, Miranti CK, Warfel NA. Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC. Am J Clin Exp Urol 7(4):297-312 (2019) PMID: 31511835
8. Song JH, Singh N, Luevano L, Padi S, Okumura K, Olive V, Black SM, Warfel NA, Goodrich DW, and Kraft AS. Mechanisms behind resistance to PI3K Inhibitor treatment induced by the PIM kinase. Molecular Cancer Therapeutics (2018). PMID: 30190422
9. Casillas AL, Toth RK, Singh N, Desai AA, Kraft AS, and Warfel NA. Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents. Clinical Cancer Research (2018). PMID: 29084916
10. Warfel NA*, Sainz AG, Song JH, Kraft AS*. PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species. Molecular Cancer Therapeutics. (2016). *co-corresponding authors. PMID: 27196781
11. Song JH, Padi SK, Luevano LA, Minden MD, DeAngelo DJ, Hardiman G, Ball LE, Warfel NA, Kraft A.S. Insulin receptor substrate 1 is a substrate of the Pim protein kinases. Oncotarget. (2016). PMID: 26956053
12. Zhang S, Zhou L, Hong B., van den Heuvel AP., Prabhu VV, Warfel NA, Kline CL, Dicker DT, Kopelovich L, El-Deiry WS. Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer research, (2015). PMID: 26294215
13. Warfel NA, Dolloff N, Dicker DT., Malysz J, El-Diery WS, CDK1-mediated phosphorylation of Ser668 stabilizes HIF-1a to promote tumor growth. Cell Cycle (2013). PMID: 24189531
14. Warfel NA, Niederst M, Stevens MW, Brennan PM, Frame MC, Newton AC. Mislocalization of the E3 ligase, beta-transducin repeat-containing protein 1 (beta-TrCP1), in the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt. J Biol Chem 286, 19777 (2011). PMID: 21454620
15. Warfel NA, Niederst M, Newton AC. Disruption of the interface between the PH and kinase domains of Akt is sufficient for hydrophobic motif site phosphorylation in the absence of mTORC2. J Biol Chem,  (2011). PMID: 21908613
16. Brognard J, Niederst M, Reyes G, Warfel NA, Newton AC. Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C. J Biol Chem 284, 15215 (2009). PMID: 19324870
17. Gills JJ, Lopiccolo J, Tsurutani J, Shoemaker RH, Best CJ, Abu-Asab MS, Borojerdi J, Warfel NA, Gardner ER, Danish M, Hollander MC, Kawabata S, Tsokos M, Figg WD, Steeg PS, Dennis PA. 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 13, 5183 (2007). PMID: 17785575
18. Gills JJ, Castillo SS, Zhang C, Petukhov PA, Memmott RM, Hollingshead M, Warfel NA, Han J, Kozikowski AP, Dennis PA. Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. J Biol Chem 282, 27020 (2007). PMID: 17631503
19. Granville CA, Warfel N, Tsurutani J, Hollander MC, Robertson M, Fox SD, Veenstra TD, Issaq TJ, Linnoila RI, Dennis PA. 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 13, 2281 (2007). PMID: 17404113
20. Warfel NA, Lepper ER, Zhang C, Figg WD, Dennis PA. 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 12, 3502 (2006). PMID: 16740776

Invited review articles and commentaries

1. Warfel NA. Defining the mechanisms underlying cyclin dependent kinase control of HIF-1a. Oncotarget. (2022). PMID: 35251493.
2. Toth RK, Warfel NA. Targeting PIM Kinases to Overcome Therapeutic Resistance in Cancer. Mol Cancer Ther. (2021) 2020 Dec 10. Review. PubMed PMID: 33303645.
3. Harryman WL, Warfel NA, Nagle RB, Cress AE. The Tumor Microenvironments of Lethal Prostate Cancer. Adv Exp Med Biol 1210:149-170 (2019) PMID: 31900909
4. Chauhan SS and Warfel NA. Targeting PIM kinase to Oppose Hypoxia-mediated Therapeutic Resistance. Oncoscience (2018). PMID: 30460324
5. Warfel NA. Targeting CDK4/6 to Oppose Hypoxia-Mediated Therapeutic Resistance. Cell Cycle. (2017). PMID: 28594259
6. Toth RK and Warfel NA. Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-inducible Factor 1 (HIF-1) in Tumor Hypoxia. Antioxidants, (2017). PMID: 28383481
7. Warfel NA and Kraft AS. PIM Kinase (and Akt) Biology and Signaling in Tumors. Pharmacology and Therapeutics, (2015). PMID: 25749412 
8. Warfel NA and El-Deiry WS. HIF-1 Signaling in Drug Resistance to Chemotherapy. Curr Med Chem, (2014). PMID: 24735366
9. Warfel NA and El-Deiry WS. p21WAF1 and tumourigenesis: 20 years after. Curr Opin Oncol 25, 52 (Jan, 2013). PMID: 23159848 
10. Prabhu VV, Warfel NA, El-Deiry WS. CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis. Cell Cycle, (2012). PMID: 22751431 
11. Warfel NA and Newton AC. PH domain Leucine-rich Repeat Protein Phosphatase, PHLPP: a New Player in Cell Signaling. J Biol Chem,  (2011). PMID: 22144674 

Noel received his B.S. in 2004 from James Madison University, with a dual concentration in Engineering and Biotechnology. Following undergrad, he was awarded the Molecular Targets and Drug Discovery Fellowship, a joint program sponsored by Johns Hopkins University and the NIH, where he earned an M.S. in Biotechnology. During this time, he trained at the NCI in the lab of Dr. Phil Dennis studying PI3K signaling in lung cancer. Noel received his Ph.D. in Biomedical Sciences in 2011 from UC San Diego in the lab of Dr. Alexandra Newton, where he studied mechanisms responsible for Akt activation in cancer. His postdoctoral research was conducted as a NCI Ruth L. Kirschstein postdoctoral fellow at the Penn State Hershey Cancer Center in the lab of Dr. Wafik El-Deiry. There, he gained experience in translational medicine studying novel mechanisms of HIF-1 regulation. In 2015, Noel joined the Department of Cellular and Molecular Medicine at the University of Arizona as an Assistant Professor. He is also a member of the UA cancer center and is funded by the American Cancer Society and Department of Defense PCRP.

Shailender received his M.S. (2005) and Ph.D. (2013) from the Panjab University, Chandigarh, India where he studied biochemistry and experimental toxicology. After graduating, he worked numerous research jobs including Senior Research Fellow and Senior Research Officer at Post Graduate Institute of Medical Education and Research, Chandigarh, India. In 2015, he moved to Omaha, Nebraska to become a postdoctoral researcher at University of Nebraska Medical Center studying colon cancer progression. He joined the Warfel Lab at the University of Arizona Cancer Center in 2018. He is currently studying reactive oxygen species and mitochondrial dynamics in lung cancer.

Amber received her B.S. in Molecular and Cell Biology from Western Washington University in 2014. After a few years working as a laboratory technician in a clinical pathology lab, Amber returned to school and received her master’s degree in Biomedical Sciences from Midwestern University in Phoenix Arizona. Her master’s thesis focused on the effects of altered cadherin expression on cell survival signaling in basal-like breast cancer. Her interest in cancer cell signaling led her to the University of Arizona. She matriculated into the Cancer Biology Graduate Interdisciplinary Program and the Warfel Lab in 2020. Her current research focus is determining the role of hypoxia-induced PIM expression in regulating an immunosuppressive tumor microenvironment via alterations in macrophage recruitment and survival.

Hope received her B.S in Biology from the University of Oregon in 2017. Upon graduating, she worked on developing drugs-of-abuse immunoassays at Thermo Fisher, gaining experience working on 510k FDA clearances. After a year at Thermo Fisher, deciding to challenge herself, she hopped onboard a start-up proteomics company, SEER Inc. She helped get it off the ground and launched the Proteograph™, an automated rapid unbiased instrument to sample the proteome. Here she gained experience working with automation engineering, assay development, and developing production processes. Her interest in proteomics and pathways led her to the University of Arizona in 2021 where she rotated and eventually entered the Cancer Biology Graduate Interdisciplinary Program and the Warfel lab in 2022. Currently, she’s working on kinase-independent pathways and the regulation of PIM1.

Caitlyn received her B.S. in Microbiology from the University of Arizona where she studied the life cycle of high-risk human papillomaviruses in the Van Doorslaer lab. She became particularly interested in HPV-associated cancers and decided to pursue her PhD in Cancer Biology at the University of Arizona. Caitlyn’s interest in cancer therapeutics led her to join the Warfel lab where her research is focused on developing a targeted hypoxia drug in pancreatic ductal adenocarcinoma.

Former Lab Members

Adi Gunderia, MS 2021 Adi gunderiaadi@gmail.com

Andrea Casillas, PhD 2020 alcasillas@wisc.edu

Corbin Jensen, PhD 2022 jensencc@unc.edu

Email: warfelna@email.arizona.edu

Office: (520) 626-7756      

Fax: (520) 626-4230