Our current, ongoing laboratory projects are described in detail below:
We have identified a key role for the ubiquitin ligase UBE4B in the regulation of growth factor receptor trafficking in neuroblastoma tumor cells. The UBE4B gene is located in the chromosome 1p36 region deleted in approximately one-third of neuroblastoma tumors, and we have shown that UBE4B gene expression is strongly associated with neuroblastoma patient outcomes. We have also shown that UBE4B expression and activity are correlated with growth factor receptor trafficking, responses to therapy, and neuroblastoma tumor differentiation, suggesting it may function as a novel tumor suppressor, prognostic marker, and therapeutic target. We have also identified an association between a polymorphism in the FGFR4 gene and neuroblastoma incidence and receptor trafficking in neuroblastoma cells, and are currently investigating the role of FGFR4 polymorphisms in other pediatric solid tumors.
Our continued research looks to build on these findings through a better understanding of growth factor receptor trafficking and its link to chemotherapy responses and resistance to targeted therapies and through direct targeting of receptor trafficking as a unique approach to pediatric solid tumor therapy.
Whittle, S., S. Reyes, M. Du, M. Gireud, L. Zhang, S.E. Woodfield, M. Ittmann, M. Scheurer, A.J. Bean, and P.E. Zage. A Polymorphism in the FGFR4 Gene is associated with Risk of Neuroblastoma and Altered Receptor Degradation. Journal of Pediatric Hematology/Oncology 2016; 38(2): 131-8. PMID: 26840079.
Woodfield S.E., R. Guo, Y. Liu, A.M. Major, E.F. Hollingsworth, S.M. Indiviglio, S.B. Whittle, Q. Mo, A.J. Bean, M. Ittmann, D. Lopez-Terrada D, and P.E. Zage. UBE4B Levels Are Correlated with Neuroblastoma Patient Outcomes, Tumor Differentiation, and ERK Activation. Genes & Cancer. 7(1-2): 13-26. PMID: 27014418.
Sirisaengtaksin N., M. Gireud, Q. Yan, Y. Kubota, D. Meza, J. Waymire, P.E. Zage, and A.J. Bean. 2014. UBE4B Couples Ubiquitination and Sorting Machineries to Enable EGFR Degradation. Journal of Biological Chemistry. 289: 3026-39. PMID: 24344129
Zage P.E.*, N. Sirisaengtaksin*, Y. Liu, M. Gireud, B.S. Brown, S. Palla, K.N. Richards, D.P.M. Hughes, and A.J. Bean. 2013. UBE4B Levels Are Correlated with Clinical Outcomes in Neuroblastoma Patients and with Altered Neuroblastoma Cell Proliferation and Sensitivity to EGFR Inhibitors. Cancer. 119: 915-23. PMID: 22990745
Zage, P.E. and A.J. Bean. 2012. Growth Factor Receptor Trafficking as a Potential Therapeutic Target in Pediatric Cancer. Frontiers in Biology. 7 (1): 1-13. (Cover Photo)
Ongoing research projects in my laboratory are investigating mechanisms underlying neuroblastoma pathogenesis, and we identified a potential role for the cell cycle regulator RASSF1A as a neuroblastoma tumor suppressor. We have also identified key roles for histidine kinase activity and the Notch and REST pathways in neuroblastoma tumor cell growth, viability, and response to therapy.
Adam K, Lesperance J, Hunter T, Zage PE. 2020. The Potential Functional Roles of NME1 Histidine Kinase Activity in Neuroblastoma Pathogenesis. International Journal of Molecular Sciences, 21(9): 3319. PMID: 32392889
Zage, P.E.*, R. Nolo*, W. Fang, J. Stewart, G. Garcia-Manero, and P.A. Zweidler-McKay. 2012. Notch Pathway Activation Induces Neuroblastoma Tumor Cell Growth Arrest. Pediatric Blood & Cancer. 58: 682-9. PMID: 21744479
Singh, A., C. Rokes, M. Gireud, S. Fletcher, J. Baumgartner, G. Fuller, J. Stewart, P. Zage, and V. Gopalakrishnan. 2011. Retinoic Acid Induces REST Degradation and Neuronal Differentiation by Modulating the Expression of SCFb-TRCP in Neuroblastoma Cells. Cancer. 117: 5189-202. PMID: 21523764.
Liu, S., Y. Tian, A. Chlenski, Q. Yang, P.E. Zage, H. Salwen, S. Crawford, and S.L. Cohn. 2005. "Cross-Talk" Between Schwann Cells and Neuroblasts Influences Tumor Differentiation, Apoptosis, and Angiogenesis. American Journal of Pathology. 166: 891-900. PMID: 15743800
Yang, Q., P.E. Zage, D. Kagan, Y. Tian, R. Seshadri, H.R. Salwen, S. Liu, A. Chlenski, and S.L. Cohn. 2004. Association of Epigenetic Inactivation of RASSF1A with Poor Outcome in Human Neuroblastoma. Clinical Cancer Research. 10: 8493-500. PMID: 15623630
3. Using preclinical models of pediatric solid tumors, we have identified several promising novel targeted agents that are effective against pediatric solid tumors, and we have translated many of these therapies into early phase clinical trials for children with relapsed and refractory solid tumors. We are currently directing an investigator-initiated, multi-institutional national clinical trial ("A National Phase I Study of Cabozantinib in Combination with 13-cis-Retinoic Acid in Children with Relapsed or Refractory Solid Tumors") to explore the efficacy and tolerability of the novel therapeutic combination of cabozantinib and 13-cis-retinoic acid. Additionally, we have identified a number of pathways required for neuroblastoma tumor cell survival after 13-cis-retinoic acid treatment, and these studies are likely to identify treatment combinations using readily available drugs that can also be rapidly tested in clinical trials, leading to improved treatments, reduced relapse rates, and improved survival for children with all forms of cancer.
Subramonian, D., N. Phanthilath, Y. Huo, S. Flynn, H. Rinehardt, J. Zhang, K. Messer, Q. Mo, S. Huang, J. Lesperance, P.E. Zage. 2020. Regorafenib Is Effective Against Neuroblastoma in Vitro and in Vivo and Inhibits the RAS-MAPK, PI3K/Akt/mTOR, and Fos/Jun Pathways. British Journal of Cancer, 123(4): 568-579. PMID: 32457362
Phanhthilath N, Hakim S, Su C, Liu A, Subramonian D, Lesperance J, Zage PE. 2020. Mechanisms of Efficacy of the FGFR1-3 Inhibitor AZD4547 in Pediatric Solid Tumor Models. Investigational New Drugs, 38(6): 1677-1686. PMID: 32436058
Flynn S, Lesperance J, Macias A, Phanhthilath N, Paul MR, Kim JW, Tamayo P, Zage PE. 2019. The Multikinase Inhibitor RXDX-105 is Effective Against Neuroblastoma In Vitro and In Vivo. Oncotarget, 10(59): 6323-33. PMID: 31695841; PMCID: PMC6824878
Whittle, S.B., K. Patel, L. Zhang, S.E. Woodfield, M. Du, V. Smith, P.E. Zage. 2016. The Novel Kinase Inhibitor Ponatinib Is An Effective Antiangiogenic Agent Against Neuroblastoma. Investigational New Drugs. 34(6): 685-92. PMID: 27586230.
Du, M., L. Zhang, K.A. Scorsone, S.E. Woodfield, P.E. Zage. 2016. Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine. Scientific Reports. 6, 27458. PMID: 27282514.
Woodfield, S.E., L. Zhang, K. Scorsone, and P.E. Zage. Binimetinib Inhibits MEK and Is Effective Against Neuroblastoma Tumor Cells With Low NF1 Expression. BMC Cancer. 16: 172. PMID: 26925841.
Zhang, L., K. Scorsone, S.E. Woodfield, and P.E. Zage. 2015. Sensitivity of Neuroblastoma to the Novel Kinase Inhibitor Cabozantinib Is Mediated by ERK Inhibition. Cancer Chemotherapy & Pharmacology. 76: 977-87. PMID: 26407819
Scorsone, K.S., L. Zhang, S.E. Woodfield, J. Hicks, and P.E. Zage. 2014. The Novel Kinase Inhibitor EMD1214063 Is Effective Against Neuroblastoma. Investigational New Drugs. 32(5): 815-24. PMID: 24832869
Zage P.E., L. Zeng, S. Palla, W. Fang, M.B. Nilsson, J.V. Heymach, and P.A. Zweidler-McKay. 2010. A Novel Therapeutic Combination for Neuroblastoma: the VEGFR/EGFR/RET Inhibitor Vandetanib with 13-cis-Retinoic Acid. Cancer. 116(10): 2465-75. PMID: 20225331