Timothy Eubank, Ph.D.

   Dr. Eubank’s research program focus is on the role of myeloid cells/mononuclear phagocytes in tumor growth and angiogenesis as well as monocyte and macrophage HIF (hypoxia inducible factor) biology. His group reported that monocytes and macrophages can be “re-educated” in solid tumors to become anti-angiogenic and were the first to report that GM-CSF stimulates tumor macrophages to overexpress the soluble form of VEGFR-1, which sequesters tumor-produced VEGF from bioactivity, and become more “M1”-like depending on local tumor microenvironment (TME). Further, they were the first to report the disparate functions of HIF-1α and HIF-2α in tumor-associated macrophages and that a hypoxia inducible factor (HIF-2α) can be anti-angiogenic. In more recent and current work, they are focused on understanding the macrophage subsets and functions responsible for generating and perpetuating the hypoxic and immunosuppressive TME in both breast and pancreatic cancers. They are also investigating methods to alleviate hypoxia and immunosuppression by directing macrophage functions. Dr. Eubank has numerous publications in Immunity, Blood, Cancer Research, and J of Immunology pertaining to this focus. Further, he received the K99/R00 Pathway to Independence Award from the NCI for his work with macrophage regulation of breast cancer growth and angiogenesis. His expertise in macrophage HIF biology has led to several patent applications using a novel small molecule compound to stabilize HIF-2α to regulate dysfunctional and unproductive angiogenesis that perpetuates hypoxia.

The sphere of interest:

   Dr. Eubank’s current interests include the continuous investigation into the role of novel macrophage subtypes which augment tumor progression and unproductive angiogenesis that perpetuate tumor hypoxia, as determined by particulate and soluble oxygen-sensing EPR probes (in collaboration with Dr. Andrey Bobko, Dept of Biochemistry, Dr. Valery Khramtsov, Dept of Biochemistry, Dr. Benoit Driesschaert, Dept of Pharmaceutical Sciences, WVU) and EPR imaging (in collaboration with Dr. Mark Tseytlin, Dept of Biochemistry) and immunohistochemistry/micro-CT techniques. He is also interested in how the different macrophage HIFs regulate degree of success of chemotherapy compounds in mouse models of breast cancer. Finally, he is collaborating with Dr. Ray Raylman, Dept of Radiology, Dr. Valery Khramtsov and Dr. Mark Tsyetlin on elucidating the origin and role of macrophages that initiate and maintain treatment resistance in breast and pancreatic cancers (in collaboration with Dr. Brian Boone, surgical oncologist).

Selected publications:

- Eubank TD, Bobko AA, Hoblitzell EH, Gencheva M, Driesschaert B, Khramtsov VV, 2023, In Vivo Electron Paramagnetic Resonance Molecular Profiling of Tumor Microenvironment upon Tumor Progression to Malignancy in Animal Model of Breast Cancer, Mol. Imaging Biol. DOI: 10.1007/s11307-023-01847-0

- Shaw MA, Poncelet M, Viswakarma N,  Vallerini GP, Hameed S, Gluth TD, Geldenhuys WJ, Hoblitzell EH, Eubank TD, Epel B, Kotecha M, Driesschaert B. SOX71, A Biocompatible Succinyl Derivative of the Triarylmethyl Radical OX071 for In Vivo Quantitative Oxygen Mapping Using Electron Paramagnetic Resonance, Mol Imaging Biol. 2023, https://doi.org/10.1007/s11307-023-01869-8 

- Mihalik NE, Wen S, Driesschaert B, Eubank TD. Formulation and in vitro characterization of PLGA/PLGA-PEG nanoparticles loaded with murine granulocyte-macrophage colony-stimulating factor. AAPS PharmSciTech, 22 (5): 191 

 - Velayutham M, Poncelet M, Eubank TD, Driesschaert B and Khramtsov VV. Biological Applications of Electron Paramagnetic Resonance Viscometry Using a 13C-Labeled Trityl Spin Probe. Molecules 2021, 26(9), 2781; https://doi.org/10.3390/molecules26092781.

 - Ye Q, Mohamed R, Dukhlallah D, Gencheva M, Hu G, Pearce MC, Kolluri SK, Marsh CB, Eubank TD, Ivanov AV, Guo NL. Molecular Analysis of ZNF71 KRAB in Non-Small-Cell Lung Cancer. Int J Mol Sci. 2021 Apr 4;22(7):3752. doi: 10.3390/ijms22073752. PMID: 33916522

 - Mattes MD, Eubank TD, Almubarak M, Wen S, Marano GD, Jacobson GM, Ma PC. A Prospective Trial Evaluating the Safety and Systemic Response From the Concurrent Use of Radiation Therapy with Checkpoint Inhibitor Immunotherapy in Metastatic Non-Small Cell Lung Cancer. Clin Lung Cancer. 2021 Jan 25:S1525-7304(21)00015-2. doi: 10.1016/j.cllc.2021.01.012. PMID: 33608212

 - Madan E, Peixoto ML, Dimitrion P, Eubank TD, Yekelchyk M, Talukdar S, Fisher PB, Mi QS, Moreno E, Gogna R. Cell Competition Boosts Clonal Evolution and Hypoxic Selection in Cancer. Trends Cell Biol. 2020 Dec;30(12):967-978. doi: 10.1016/j.tcb.2020.10.002. PMID: 33160818

 - Steinberger KJ, Forget MA, Bobko AA, Mihalik NE, Gencheva M, Roda JM, Cole SL, Mo X, Hoblitzell EH, Evans R, Gross AC, Moldovan L, Marsh CB, Khramtsov VV, Eubank TD. Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer. J Immunol. 2020 Oct 15;205(8): 2301- 2311. doi: 10.4049/jimmunol.2000185. PMID: 32938724

 - Sanzhaeva U, Poncelet M, Tseytlin O, Tseytlin M, Gencheva M, Eubank TD, Khramtsov VV, Driesschaert B. Synthesis, Characterization, and Application of a Highly Hydrophilic Triarylmethyl Radical for Biomedical EPR. J Org Chem. 2020 Aug 21;85(16):10388-10398. doi: 10.1021/acs.joc.0c00557. PMID: 32698583

 - Steinberger KJ, Bailey MT, Gross AC, Sumner LA, Voorhees JL, Crouser N, Curry JM, Wang Y, DeVries AC, Marsh CB, Glaser R, Yang EV, Eubank TD. Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma. Cancer Prev Res (Phila). 2020 Sep;13(9):747-760. doi: 10.1158/1940-6207.CAPR-19-0370. PMID: 32518084

 - Gorodetskii AA, Eubank TD, Driesschaert B, Poncelet M, Ellis E, Khramtsov VV, Bobko AA. Development of multifunctional Overhauser-enhanced magnetic resonance imaging for concurrent in vivo mapping of tumor interstitial oxygenation, acidosis and inorganic phosphate concentration. Sci Rep. 2019 Aug 20;9(1):12093. doi: 10.1038/s41598-019-48524-3. PMID: 31431629

- Tseytlin O, Guggilapu P, Bobko AA, AlAhmad H, Xu X, Epel B, O'Connell R, Hoblitzell EH, Eubank TD, Khramtsov VV, Driesschaert B, Kazkaz E, Tseytlin M. Modular imaging system: Rapid scan EPR at 800 MHz. J Magn Reson. 2019 Aug; 305: 94-103. doi: 10.1016/j.jmr.2019.06.003. PMID: 31238278

 - Poncelet M, Driesschaert B, Tseytlin O, Tseytlin M, Eubank TD, Khramtsov VV. Dextran-conjugated tetrathiatriarylmethyl radicals as biocompatible spin probes for EPR spectroscopy and imaging. Bioorg Med Chem Lett. 2019 Jul 15;29(14): 1756- 1760. doi: 10.1016/j.bmcl.2019.05.017. PMID: 31129052

 - Gorodetskii AA, Eubank TD, Driesschaert B, Poncelet M, Ellis E, Khramtsov VV, Bobko AA. Oxygen-induced leakage of spin polarization in Overhauser-enhanced magnetic resonance imaging: Application for oximetry in tumors. J Magn Reson. 2018 Dec;297:42-50. doi: 10.1016/j.jmr.2018.10.005. PMID: 30359906

 - Bobko AA, Eubank TD, Driesschaert B, Khramtsov VV. In Vivo EPR Assessment of pH, pO2, Redox Status, and Concentrations of Phosphate and Glutathione in the Tumor Microenvironment. J Vis Exp. 2018 Mar 16;(133):56624. doi: 10.3791/56624. PMID: 29608148

 - Bobko AA, Eubank TD, Driesschaert B, Dhimitruka I, Evans J, Mohammad R, Tchekneva EE, Dikov MM, Khramtsov VV. Interstitial Inorganic Phosphate as a Tumor Microenvironment Marker for Tumor Progression. Sci Rep. 2017 Jan 24;7:41233. doi: 10.1038/srep41233. PMID: 28117423

 - Driesschaert B, Bobko AA, Eubank TD, Samouilov A, Khramtsov VV, Zweier JL. Poly-arginine conjugated triarylmethyl radical as intracellular spin label. Bioorg Med Chem Lett. 2016 Apr 1;26(7):1742-4. doi: 10.1016/j.bmcl.2016.02.048.

 - Dhimitruka I, Eubank TD, Gross AC, Khramtsov VV. New class of 8-aryl-7-deazaguanine cell permeable fluorescent probes. Bioorg Med Chem Lett. 2015 Oct 15;25(20):4593-6. doi: 10.1016/j.bmcl.2015.08.054.

 - Nelson MT, Short A, Cole SL, Gross AC, Winter J, Eubank TD, Lannutti JJ. Preferential, enhanced breast cancer cell migration on biomimetic electrospun nanofiber 'cell highways'. BMC Cancer. 2014 Nov 10;14:825. doi: 10.1186/1471-2407-14-825.

 - Samouilov A, Efimova OV, Bobko AA, Sun Z, Petryakov S, Eubank TD, Trofimov DG, Kirilyuk IA, Grigor'ev IA, Takahashi W, Zweier JL, Khramtsov VV. In vivo proton-electron double-resonance imaging of extracellular tumor pH using an advanced nitroxide probe. Anal Chem. 2014;86(2):1045-52.

 - Chen D, Bobko AA, Gross AC, Evans R, Marsh CB, Khramtsov VV, Eubank TD*, Friedman A*. Involvement of tumor macrophage HIFs in chemotherapy effectiveness: mathematical modeling of oxygen, pH, and glutathione. PLoS One. 2014; 9(10): e107511.

 - Dhimitruka I, Bobko AA, Eubank TD, Komarov DA, Khramtsov VV. Phosphonated trityl probes for concurrent in vivo tissue oxygen and pH monitoring using electron paramagnetic resonance-based techniques. J Am Chem Soc. 2013;135(15): 5904-10.

 - Roda JM, Wang Y, Sumner LA, Phillips GS, Marsh CB, Eubank TD. Stabilization of HIF-2alpha induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model. J Immunol. 2012;189(6): 3168-77.

 - Bobko AA#, Eubank TD#, Voorhees JL, Efimova OV, Kirilyuk IA, Petryakov S, Trofimiov DG, Marsh CB, Zweier JL, Grigor'ev IA, Samouilov A, Khramtsov VV. In vivo monitoring of pH, redox status, and glutathione using L-band EPR for assessment of therapeutic effectiveness in solid tumors. Magn Reson Med. 2012;67(6):1827-36.

 - Eubank TD, Roda JM, Liu H, O'Neil T, Marsh CB. Opposing roles for HIF-1alpha and HIF-2alpha in the regulation of angiogenesis by mononuclear phagocytes. Blood. 2011;117(1): 323-32.

 - Eubank TD, Roberts RD, Khan M, Curry JM, Nuovo GJ, Kuppusamy P, Marsh CB. Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. Cancer Res. 2009;69(5):2133-40.

 - Curry JM#, Eubank TD#, Roberts RD, Wang Y, Pore N, Maity A, Marsh CB. M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo. PLoS One. 2008;3(10):e3405.

 - Eubank TD, Roberts R, Galloway M, Wang Y, Cohn DE, Marsh CB. GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice. Immunity. 2004;21(6):831-42.

 - Eubank TD, Galloway M, Montague CM, Waldman WJ, Marsh CB. M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes. J Immunol. 2003;171(5):2637-43.