Assistant Professor
Email: cholbert@loyola.edu
Phone: 410-617-2959
Office
Dorothy Day 051
Department of Biology
Loyola University Maryland
4501 North Charles Street
Baltimore, MD 21210-2699
Biography
Polyamines are small polycationic molecules that are protonated at physiologic pH allowing for their interaction with a variety of negatively charged macromolecules. These interactions contribute to the molecular function of polyamines, including roles in chromatin remodeling, immune cell modulation, and cell survival and proliferation. Numerous cancer types rely upon dysregulated polyamine metabolism to increase polyamines to levels capable of maintaining uncontrolled cell proliferation and tumor cell survival.
My research focuses on modulating polyamine metabolism as a cancer therapeutic. Some of my recent work has indicated that ivospemin, a polyamine analogue, is capable of depleting available polyamines and increases the survival of mice with ovarian cancer. Importantly, this survival benefit is only seen in mice with intact immune systems. Previous work has shown that enzymatic inhibition of polyamine biosynthesis impacts the immune cells within the tumor microenvironment and can sensitive tumors to immunotherapies. Ongoing work in my lab is evaluating the impact of polyamine analogues on the composition of the tumor immune microenvironment in ovarian cancer models.
My lab is focused on polyamine depletion as a therapeutic strategy in tumor types that are traditionally unresponsive to immunotherapy, including ovarian, breast, and pancreatic. Our ultimate goal is to identify the immunomodulatory impacts of polyamine analogues and leverage this knowledge to reprogram immunologically “cold” tumors into tumors more responsive to immunotherapies. This would allow for the creation of more successful combinatorial therapeutic strategies and improved patient outcomes.
Publications
• Holbert CE, Foley JR, Murray Stewart T, Casero RA Jr. (2024). The polyamine analogue ivospemin increases chemotherapeutic efficacy in murine ovarian cancer. Biomedicines. 12(6): 1157. https://doi.org/10.3390/biomedicines12061157
• Holbert CE, Casero RA Jr, Murray Stewart T. (2024). Polyamines: the pivotal amines in influencing the tumor microenvironment. Discovery Oncology. 15(1):173. https://doi.org/10.1007/s12672-024-01034-9. [Review]
• Murray Stewart T, Foley JR, Holbert CE, Khomutov MA, Rastkari N, Tao X, Khomutov AR, Zhai RG, Casero RA Jr. (2023). Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome. EMBO Molecular Medicine. 15(11):e17833. https://doi.org/10.15252/3mmm.202317833
• Holbert CE, Cullen MT, Casero RA Jr, Murray Stewart T. (2022). Polyamines in cancer: integrating organismal metabolism and anti-tumour immunity. Nature Reviews Cancer 22: 467-480. https://doi.org/10.1038/s41568-022-00473-2. [Perspective Review]
• Holbert CE, Foley JR, Yu A, Murray Stewart T, Phanstiel O IV, Oupicky D, Casero RA Jr. (2022). Polyamine-based nanostructures share polyamine transport mechanisms with native polyamines and their analogues: significance for polyamine-targeted therapy. Medical Sciences 10(3): 44. https://doi.org/10.3390/medsci10030044
• Murray Stewart T, Holbert CE, Casero RA Jr. (2022). Helping the helpers: Polyamines help maintain helper T cell lineage fidelity. Immunometabolism (Cobham) 4(3): e00002. https://doi.org/10.1097/IN9.0000000000000002. [Correspondence]
• Murray Stewart T, Foley JR, Holbert CE, Klinke G, Poschet G, Steimbach RR, Miller AK, Casero RA, Jr. (2022). Histone deacetylase 10 liberates spermidine to support polyamine homeostasis and tumor cell growth. Journal of Biological Chemistry 298(10): 102407. https://doi.org/10.1016/j.jbc.2022.102407
• Holbert CE, Foley JR, Murray Stewart T, and Casero RA Jr. (2022). Expanded potential of the polyamine analogue SBP-101 (diethyl dihydroxyhomospermine) as a modulator of polyamine metabolism and cancer therapeutic. International Journal of Molecular Sciences 23(12): 6798. https://doi.org/10.3390/ijms23126798
• Sil D, Panja S, Jogdeo CM, Kumar R, Yu A, Holbert CE, Ding L, Foley JR, Murray Stewart T, Casero RA Jr, Oupicky D. (2022). Self-assembled alkylated polyamine analogues as supramolecular anticancer agents. Molecules 27(8): 2441. https://doi.org/10.3390/molecules27082441
• Yu A, Tang S, Ding L, Foley JR, Tang W, Jia H, Panja S, Holbert CE, Hang Y, Murray Stewart T, Smith LM, Sil D, Casero RA Jr, Oupicky D. (2022). Hyaluronate-coated perfluoroalkyl polyamine prodrugs as bioactive siRNA delivery systems for the treatment of peritoneal cancers. Biomaterials Advances 136: 212755. https://doi.org/10.1016/j.bioadv.2022.212755
• Holbert CE, Dunworth M, Foley JR, Dunston TT, Murray Stewart T, Casero RA Jr. (2020). Autophagy induction by exogenous polyamines is an artifact of bovine serum amine oxidase activity in culture serum. Journal of Biological Chemistry 295(7): 9061-9068. https://doi.org/10.1074/jbc.RA120.013867
• Murray Stewart T, Khomutov M, Foley JR, Guo X, Holbert CE, Dunston TT, Schwartz CE, Gabrielson K, Khomutov AR, Casero RA Jr. (2020). (R,R)-1,12-dimethylspermine as a modulator of abnormal polyamine levels in cells from Snyder-Robinson Syndrome patients. Journal of Biological Chemistry 295(10): 3247-3256. https://doi.org/10.1074/jbc.RA119.011572
• Travers ME, Brown SM, Dunworth MR, Holbert CE, Wiehagen KR, Bachman KE, Foley JR, Stone ML, Baylin SB, Casero RA Jr, Zahnow CA. (2019). DFMO and 5-azacytidine increases M1 macrophages in the tumor microenvironment of murine ovarian cancer. Cancer Research. 79(13): 3445-3454. https://doi.org/10.1158/0008-5472.CAN-18-4018.
Areas of Specialization
• Cancer Biology and Tumor Immunology