Andrew Raddatz, Raquel Botelho, Caroline Alting, Eshita Chhajlani, Matthew Melendez
Collaborators: Cristina Furdui (Wake-Forest), Erik Bey (Indiana U.), Baran Sumer (UT-Southwestern), Noelle Williams (UT-Southwestern), Allen Tsang (Wake-Forest), Mercedes Porosnicu (Wake-Forest), Curtis Henry
Funding Source: NCI U01CA215848, Carol Ann & David D. Flanagan Endowment
Related link: NCI Cancer Systems Biology Consortium
Variations in the distribution of proteins that metabolize foreign molecules can control a cell’s ability to respond to chemotherapeutics or environmental toxins. We have used a systems-level approach provides a framework for understanding how patient-specific variability leads to patient sensitivity to chemotherapeutic treatment at different doses. With this knowledge, we have correctly predicted complex behavior induced by pharmacological intervention strategies for manipulation of drug metabolism.
With the development of a genome-scale metabolic modeling pipeline in our lab, we have analyzed hundreds of cancer patients’ metabolic profiles to find signatures associated with therapeutic responses. These personalized modeling tools open up possibilities for adding mechanistic insight into machine learning algorithms, definition of prognostic biomarkers, and generation of new hypotheses of how cancer metabolism is related to antioxidant regulation.
Lewis, J.E., Kemp, M.L. “Integration of machine learning and genome-scale metabolic modeling identifies multi-omics biomarkers for radiation resistance”. Nature Communications, DOI: 10.1038/s41467-021-22989-1; 2021.
Lewis, J.E., Forshaw, T.E., Boothman, D.A., Furdui, C.M., Kemp, M.L. “Personalized Genome-Scale Metabolic Models Identify Targets of Redox Metabolism in Radiation-Resistant Tumors”. Cell Systems, doi: 10.1016/j.cels.2020.12.001, 2021.
Shukla, K., Singh, N., Lewis, J.E., Tsang, A.W., Kemp, M., C.M. Furdui, “MTHFD2 Blockade Enhances the Efficacy of β-Lapachone Chemotherapy with Ionizing Radiation in Head and Neck Squamous Cell Cancer”. Frontiers in Oncology, DOI: 10.3389/fonc.2020.536377; 2020.
Paudel B.B , Lewis J.E., Hardeman K.N., Hayford C.E. , Robbins C.J. , Codreanu G.S., Sherrod S.D., McLean J.A., Kemp M.L., Quaranta, V. “Elevated Redox Capacity Confers Drug-Insensitivity to BRAF inhibitors in Melanoma”. Cancer Research, DOI: 10.1158/0008-5472.CAN-19-3588, 2020.
Lewis, J.E., Costantini, F., Mims, J., Chen, X., Furdui, C., Boothman, D.A., Kemp, M.L. “Genome-scale modeling of NADPH-driven β-lapachone sensitization in head and neck squamous cell carcinoma”. Antioxidant Redox Signaling, 29(2): pp. 937-952. doi:10.1089/ars.2017.7048, 2018.
*Chen, X., *Mims, J., Huang, X., Singh, N., Motea, E., Planchon-Pope, S.M., Beg, M., Tsang, A.W., Porosnicu, M., Kemp, M.L., Boothman, D.A., Furdui, C.A. “Modulators of Redox Metabolism in Head and Neck Cancer”. Antioxidants & Redox Signaling, doi: 10.1089/ars.2017.7423, 2017.
Forshaw T.E., Holmila R., Nelson K.J., Lewis J.E., Kemp M.L., Tsang A.W., L Poole L.B., Lowther W.T., Furdui C.M. “Peroxiredoxins in Cancer and Response to Radiation Therapies” Antioxidants 8(1). pii: E11. 2019.
*Lewis J.E., *Singh N., Holmila R.J., Sumer B.D., Williams N.S., Furdui C.M., Kemp M.L., Boothman DA. Targeting NAD+ metabolism to enhance radiation therapy responses. Seminars in Radiation Oncology, 29(1), p. 6-15, 2019.