Noel Andrew Warfel
- Research Assistant Professor
2004 James Madison University
- BSc., Department of Integrated Science and Technology
2004 Johns Hopkins University
- MSc., Zanvyl Kreiger School of Arts and Science
2011 University of California, San Diego
- PhD., Biomedical Sciences graduate program
2015 – present Research Assistant Professor, University of Arizona
- Department of Cellular and Molecular Medicine
2013 – 2015 Research Assistant Professor, Medical University of South Carolina
- Joint appointment in the Hollings Cancer Center and Department of Biochemistry and Molecular Biology
2011 – 2013 Postdoctoral Fellow, Penn State University, HMC Cancer Institute
- Mentor: Dr. Wafik El-Deiry
2006 – 2011 Graduate Student, University of California, San Diego
- Mentor: Dr. Alexandra C. Newton
2004 – 2006 Graduate Research Fellow, National Cancer Insititute
- Mentor: Dr. Phillip Dennis
2016 American Cancer Society Research Scholar Grant
2012 - 2014 Ruth L. Kirschstein National Research Service Award
- National Cancer Institute (1F32CA174138-01)
2009 – 2011 Predoctoral Traineeship Award
- DoD Breast Cancer Research Program (BC093021)
2009 Dissertation Award, CBCRP (Declined in favor of DoD award)
2006 – 2008 Pharmacology training grant, UCSD
- NIH (5 T32 GM07752-28)
2004 – 2006 Molecular Targets and Drug Discovery Fellowship
- Joint program - NIH/Johns Hopkins University
2013 AACR-Aflac Scholar in Training Award, AACR Annual Meeting
2012 Roland K. Robins Pharmacology Dissertation Award for best thesis, UCSD
2011 AACR Scholar in Training Award, Targeting PI3K/mTOR Signalling in Cancer
2004 Honors senior project in the department of ISAT, James Madison University
2015 – present University of Arizona Cancer Biology GIDP
2008 - present American Association for Cancer Research
2002 – 2006 Golden Key International Honor Society
SUPERVISION OF STUDENTS (2015-2016)
Supervision of 2 undergraduate students: Ms. Alva Sainz (entered Yale graduate program in biology fall of 2016) and Ms. Isabella Brody-Calixito
Supervision of 1 MSc student: Ms. Ashley Suiter
Supervision of 1 PhD student: Ms. Andrea Casillas
2012 - present Peer reviewer for Cancer Biology and Therapy and Oncotarget
2009 Reviewer for Journal of Experimental & Clinical Cancer Research
2016 Poster presentation at 2016 AACR Annual Meeting
2016 Utilizing PIM Kinase inhibitors to target Nrf2-driven cancers. Invited Speaker, Pharmacology seminar series, Univ. of Arizona
2015 Targeting PIM Kinases to Overcome hypoxia-mediated therapeutic resistance. Invited Speaker, Cancer Biology seminar series, Univ. of Arizona Cancer Center
2014 Poster presentation at the 2014 Hollings Cancer Center Prostate Cancer Research Retreat
2013 Poster presentation at the 2013 AACR Annual Meeting
2013 Poster presentation at the 11th PSU postdoctoral society annual event
2012 Poster presentation at the 2012 AACR Annual Meeting
2011 Poster presentation at AACR PI3K/mTOR Signaling in Cancer meeting
2010 Invited Speaker at UCSD Biomedical Sciences annual graduate retreat
2010 Poster presentation at Salk Institute meeting on Protein Phosphorylation and Cell Signaling
2010 Poster presentation at CSHL PTEN and Pathways Meeting
2009 Poster presentation at 2009 AACR Annual Meeting
2008 Poster presentation at Salk meeting on protein phosphorylation
2008 Poster presentation at Experimental Biology Annual Meeting
2007 Invited Speaker at UCSD Biomedical Sciences annual graduate retreat
2006 Poster presentation at AACR Annual Meeting
PEER REVIEWED PUBLICATIONS
- N. A. Warfel, E. R. Lepper, C. Zhang, W. D. Figg, 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 12, 3502 (2006).
- C. A. Granville, N. Warfel, J. Tsurutani, M. C. Hollander, M. Robertson, S. D. Fox, T. D. Veenstra, H. J. Issaq, R. I. Linnoila, 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 13, 2281 (2007).
- J. J. Gills, S. S. Castillo, C. Zhang, P. A. Petukhov, R. M. Memmott, M. Hollingshead, N. Warfel, J. Han, A. P. Kozikowski, 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 282, 27020 (2007).
- J. J. Gills, J. Lopiccolo, J. Tsurutani, R. H. Shoemaker, C. J. Best, M. S. Abu-Asab, J. Borojerdi, N. A. Warfel, E. R. Gardner, M. Danish, M. C. Hollander, S. Kawabata, M. Tsokos, W. D. Figg, P. S. Steeg, P. A. Dennis, 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).
- J. Brognard, M. Niederst, G. Reyes, N. Warfel, A. C. Newton, Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C. J Biol Chem 284, 15215 (2009).
- N. A. Warfel, M. Niederst, M. W. Stevens, P. M. Brennan, M. C. Frame, A. C. Newton, 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).
- N. A. Warfel, M. Niederst, A. C. Newton, 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).
- N. A. Warfel, A. C. Newton, PH domain Leucine-rich Repeat Protein Phosphatase, PHLPP: a New Player in Cell Signaling. J Biol Chem, (2011).
- V.V. Prabhu, N.A. Warfel, W.S. El-Deiry, CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis. Cell Cycle, (2012).
- N. A. Warfel, W. S. El-Deiry, p21WAF1 and tumourigenesis: 20 years after. Curr Opin Oncol 25, 52 (Jan, 2013).
- N.A. Warfel, N. Dolloff, Dicker D.T., J. Malysz, W. S. El-Diery, CDK1-mediated phosphorylation of Ser668 stabalizes HIF-1a to promote tumor growth. Cell Cycle (2013).
- N.A. Warfel and W.S. El-Deiry, HIF-1 Signaling in Drug Resistance to Chemotherapy. Curr Med Chem, (2014).
- N.A. Warfel and A.S. Kraft, PIM Kinase (and Akt) Biology and Signaling in Tumors. Pharmacology and Therapeutics, (2015).
- Zhang S., Zhou L., Hong B., van den Heuvel A.P., Prabhu V.V., Warfel N.A., Kline C.L., Dicker D.T., Kopelovich L., El-Deiry W.S. Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer research, (2015)
- Song J.H., Padi S.K., Luevano L.A., Minden M.D., DeAngelo D.J., Hardiman G., Ball L.E., Warfel N.A., Kraft A.S. Insulin receptor substrate 1 is a substrate of the Pim protein kinases. Oncotarget. (2016).
- Warfel N.A*., Sainz A.G., Song J.H., Kraft A.S*. PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species. Molecular Cancer Therapeutics. (2016). *co-corresponding authors.
- Gupta G., Gupta A., Tang H., DesaiS., Larsen B., Rafikov R., Rafikova O., Nair V., Mitra S., Mathew B., Jacobson J., Warfel N.A., Black S.M., Yuan J., Garcia J., Desai A.A. Gadd45α deficiency attenuates pulmonary hypertension: A novel role for the deubiqtuitnase UCHL1. American Journal of Respiratory and Critical Care Medicine. (2016, currently in review).
- Casillas A., Sainz, A.G., Toth, R., Cardenas-Rodriguez, J., Desai, A., Singh, N., Kraft, A., Warfel N.A. PIM kinases inhibitors reduce HIF-1 signaling and sensitize solid tumors to anti-angiogenic agents. (Submitted to Cancer Research, Dec. 2016).
- Ph.D. Biomedical Sciences
- University of California, San Diego, La Jolla, California, United States
- Regulation of the PHLPP Phosphatases and Akt Signaling
- M.S. Biotechnology
- Johns Hopkins University, Baltimore, Maryland, United States
- Research Assistant Professor, Medical University of South Carolina (2013 - 2015)
- Postdoctoral Fellow, Penn State Hershey Cancer Institute (2011 - 2013)
In addition to my passion for research, I have taken advantage of the opportunity to serve as a mentor to clinical fellows, undergraduate, and graduate students. Since arriving at Univ. of Arizona, I have served as a mentor to Alva Sainz, a talented undergraduate in the UROC program. Her work will be included in two manuscripts, and she has recently been accepted into several graduate programs to study cancer biology. In addition, I had my first ABBS student, Andrea Casillas, rotate in my lab this winter. Her rotation project was to generate and characterize a somatic mutation in HIF-1 that is widely observed in clinical samples. In addition to my training, I have learned from mentoring students in my own lab. As a result, I have confidence in my ability to effectively train students in both the conceptual and technical aspects of how to study cancer biology through hypothesis driven science. I am extremely interested in serving as a mentor to train the next generation of scientist in cancer biology. In the coming year I hope to recruit a graduate student into my lab and train another undergraduate.
My laboratory concentrates on understanding the complex biological mechanisms that allow cancer cells to thrive in the hypoxic tumor microenvironment, with a focus on understanding how we can exploit such pathways to oppose the oncogenic properties of tumor hypoxia. In particular, we are currently focused on understanding how the Proviral Integration site for Moloney murine leukemia virus (PIM) kinases regulation of tumor angiogenesis and response to therapy. This research will be the first to describe a novel signaling pathway discovered in our lab in which PIM kinases control the amplitude of hypoxia-inducible factor-1 (HIF-1) signaling. Our working model places PIM kinases upstream of HIF-1 in the cellular response to hypoxia, making it a promising target for hypoxia-targeted therapy. We have developed innovative biochemical and imaging techniques to understand how aberrant PIM expression/activity impacts tumor angiogenesis and resistance to therapy in vitro and in vivo. Of particular significance, our preliminary data provide the rationale for a novel therapeutic strategy combining small molecule PIM kinase inhibitors and anti-angiogenic drugs that has the potential to change how we treat hypoxic tumors. My training is in two areas: cancer biology, focused on signal transduction, and drug development, focused on identifying and exploiting hypoxia in solid tumors; these skills remain pillars of my current research program studying prostate cancer biology and barriers to its effective treatment. My background greatly influences the approach I am currently taking to investigate the the cellular response to hypoxia, and this work will distinguish my laboratory as we pursue biological avenues that may have been overlooked by others.
ResearchCBIO 900 (Fall 2016)
Research ConferenceCBIO 695A (Fall 2016)
ThesisCMM 910 (Fall 2016)
CBIO GIDP Seminar SeriesCBIO 596H (Spring 2016)
Directed RsrchMCB 492 (Spring 2016)
Directed RsrchMCB 392 (Fall 2015)
Introduction to ResearchMCB 795A (Fall 2015)
- Song, J. H., Padi, S. K., Luevano, L. A., Minden, M. D., DeAngelo, D. J., Hardiman, G., Ball, L. E., Warfel, N. A., & Kraft, A. S. (2016). Insulin receptor substrate 1 is a substrate of the Pim protein kinases. Oncotarget, 7(15), 20152-65.More infoThe Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy.
- Warfel, N. A., Sainz, A. G., Song, J. H., & Kraft, A. S. (2016). PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species. Molecular cancer therapeutics, 15(7), 1637-47.More infoIntratumoral hypoxia is a significant obstacle to the successful treatment of solid tumors, and it is highly correlated with metastasis, therapeutic resistance, and disease recurrence in cancer patients. As a result, there is an urgent need to develop effective therapies that target hypoxic cells within the tumor microenvironment. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent a prosurvival pathway that is upregulated in response to hypoxia, in a HIF-1-independent manner. We demonstrate that pharmacologic or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia as compared with normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors prevent Nrf2 from accumulating in the nucleus, reducing the transcription of cytoprotective genes and leading to the build-up of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be successfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediated therapeutic resistance and induce cell death in the hypoxic tumor microenvironment. Mol Cancer Ther; 15(7); 1637-47. ©2016 AACR.
- Warfel, N. A., & Kraft, A. S. (2015). PIM kinase (and Akt) biology and signaling in tumors. Pharmacology & therapeutics, 151, 41-9.More infoThe initiation and progression of human cancer is frequently linked to the uncontrolled activation of survival kinases. Two such pro-survival kinases that are commonly amplified in cancer are PIM and Akt. These oncogenic proteins are serine/threonine kinases that regulate tumorigenesis by phosphorylating substrates that control the cell cycle, cellular metabolism, proliferation, and survival. Growing evidence suggests that cross-talk exists between the PIM and Akt kinases, indicating that they control partially overlapping survival signaling pathways that are critical to the initiation, progression, and metastatic spread of many types of cancer. The PI3K/Akt signaling pathway is activated in many human tumors, and it is well established as a promising anticancer target. Likewise, based on the role of PIM kinases in normal and tumor tissues, it is clear that this family of kinases represents an interesting target for anticancer therapy. Pharmacological inhibition of PIM has the potential to significantly influence the efficacy of standard and targeted therapies. This review focuses on the regulation of PIM kinases, their role in tumorigenesis, and the biological impact of their interaction with the Akt signaling pathway on the efficacy of cancer therapy.
- Zhang, S., Zhou, L., Hong, B., van den Heuvel, A. P., Prabhu, V. V., Warfel, N. A., Kline, C. L., Dicker, D. T., Kopelovich, L., & El-Deiry, W. S. (2015). Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer research, 75(18), 3842-52.More infoThe tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.
- Sainz, A. G., Song, J., Kraft, A., & Warfel, N. A. (2016, 07-15-2016). PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species. In AACR Annual Meeting, Cancer Research, Volume 76, Issue 14.