Jing Li
Office Address
4100 John R, HWCRC/Room 523
Mail Code: HW05AO
Detroit, MI 48201
Department
Oncology
Research Interests
• Clinical pharmacology of anticancer drugs
• Physiologically based pharmacokinetic (PBPK) modeling and simulation
• Metabolomics
Research Description
The central theme of my research is to promote rational cancer therapy and drug development by better understanding the clinical pharmacology of anticancer agents, that is, how the body handles a drug (i.e., pharmacokinetics) and how a drug acts on the body (i.e., pharmacodynamics). We employ an integrated translational research approach that leverages preclinical pharmacology studies, pharmacokinetic modeling, and clinical trials to mechanistically understand and quantitatively predict pharmacokinetics and pharmacodynamics of anticancer drugs in patients.
My current research is focused on two areas, as described below.
Physiologically based pharmacokinetic (PBPK) modeling of spatial heterogeneity of drug penetration and exposure in the human central nervous system (CNS) and brain tumors. The spatial pharmacokinetics of many new and existing drugs in the human CNS and brain tumors remain poorly understood or misunderstood due to the lack of animal or cellular models that reliably predict drug penetration and disposition in the human CNS. Direct measurement of spatial-temporal drug penetration and exposure within the human brain and brain tumors is difficult or infeasible given the challenge of sampling and limitation of currently available imaging and analytical technologies. The lack of quantitative knowledge on spatial pharmacokinetics of systemically administered drugs in the human CNS and brain tumors makes development of new drugs and use of existing drugs for treating brain cancer a challenging and often unsuccessful task. PBPK modeling offers a unique mechanism-based computational modeling approach for quantitative prediction of spatial CNS pharmacokinetics, given its capability of incorporating biological system-specific data and drug-specific data into a pharmacokinetic model and predicting in vivo kinetic processes based on mechanistic scaling of in vitro data. Our research is to develop innovative CNS PBPK models for mechanistic and quantitative prediction of heterogeneous penetration and exposure of anticancer drugs in the human CNS and brain tumors. The obtained quantitative information is of enormous value to rational development of effective therapies for brain cancer, as early knowledge of drug levels in the human brain and brain tumors is critical to the decision-making regarding further clinical development and design of improved drugs and dosing regimens. This line of research is supported by the NIH R01 CA255124-01A1.
Metabolomics. Novel metabolomics technologies allow high-throughput assessment of a large number of endogenous metabolites, thus providing powerful tools for mapping biochemical pathways implicated in diseases and in response to drug treatment. We have developed a LC-MS/MS based targeted metabolomics platform that is capable of quantitative profiling of ~ 300 endogenous metabolites involved in major human metabolic pathways. In addition, we have developed metabolic flux analyses with isotope-labeled tracers (including [1,2-13C]glucose, [U-13C]glucose, [U-13C]glutamine, [2,3,3-2H]Serine) to specifically determine metabolic flow in the central carbon metabolism (including glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle) and one-carbon metabolism pathways. Our laboratory has become one of the premier institutional-based metabolomics laboratories in the nation, which provides critical metabolomics support for a number of national funded research projects and multi-center clinical trials. The Pharmacology and Metabolomics Core is supported by the NIH 5P30CA022453.
Selected publications
Li J*, Wu A, and Kim S. Mechanistic modeling of central nervous system pharmacokinetics of intrathecal chemotherapy. Clin Cancer Res 2024; 30: 1397–1408. doi: 10.1158/1078-0432.CCR-23-3062. PMID: 38289997; PMCID: PMC10984761.
Su Y, Carter J, Li X, Fukuda Y, Gray A, Lynch J, Edward H, Ma J, Schreiner P, Polin L, Kushner J, Dzinic S, Buck SA, Pruett-Miller SM, Hurrish KH, Robinson G, Qiao X, Liu S, Wu S, Wang G, Li J, Allen JE, Prabhu V, Schimmer AD, Joshi D, Kalhor-Monfared S, Watson I, Marcellus R, Awar R, Taub JW, Lin H, Schuetz JD, and Ge Y. OGDH is a key factor to death of acute myeloid leukemia cells by the imipridone ONC213. Cancer Res 2024, DOI: 10.1158/0008-5472.CAN-23-2659
Wallace-Povirk A, O'Connor C, Dekhne AS, Bao X, Nayeen MJ, Schneider M, Katinas JM, Wong-Roushar J, Kim S, Polin L, Li J, Back JB, Dann CE, Gangjee A, Hou Z, Matherly LH. Mitochondrial and cytosolic one-carbon metabolism is a targetable metabolic vulnerability in cisplatin-resistant ovarian cancer. Mol Cancer Ther. 2024 Jun 4;23(6):809-822. doi: 10.1158/1535-7163.MCT-23-0550 PMID: 38377173.
Yue Y, Bao X, Jiang J, Li J*. Evaluation and correction of injection order effects in LC-MS/MS based targeted metabolomics.. Journal of Chromatography. B, Analytical technologies in the biomedical and life sciences. 2022;1212:123513. PMID: 36283260. DOI: 10.1016/j.jchromb.2022.123513
Li J*, Jiang J, Bao X, Kumar V, Alley SC, Peterson S, Lee AJ. Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases. Clin Cancer Res 2022; 28: 3329-3341.
doi: 10.1158/1078-0432.CCR-22-0405 PubMed PMID: 35727144.
Bellail AC, Jin HR, Lo HY, Jung SH, Hamdouchi C, Kim D, Higgins RK, Blanck M, le Sage C, Cross BCS, Li J, Mosley AL, Wijeratne AB, Jiang W, Ghosh M, Zhao YQ, Hauck PM, Shekhar A, Hao C. Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors. Science Translational Medicine. 2021;13(615):eabh1486. PMID: 34644148.
Bao X, Wu J, Jiang J, Tien A, Sanai N, and Li J*. Quantitative protein expression of blood-brain barrier transporters in the vasculature of brain metastases of patients with lung and breast cancer. Clinical and Translational Science 2021 Jul;14(4):1265-1271. doi: 10.1111/cts.12978. Epub 2021 Feb 10
Li J*, Jiang J, Wu J, Bao X, Sanai N. Physiologically based pharmacokinetic modeling of central nervous system pharmacokinetics of CDK4/6 inhibitors to guide selection of drug and dosing regimen for brain cancer treatment. Clin Pharmacol Ther. 2021;109: 494-506
Bao X, Wu J, Xie Y, Kim S, Jiang J, Michelhaugh S, Mittal S, Sanai N, and Li J*. Protein expression and function relevance of efflux and uptake drug transporters at the blood-brain barrier of human brain and glioblastoma. Clin Pharmacol Ther. 2020;107(5):1116-1127.
Sulkowski PL, Oeck S, Dow J, Economos N, Mirfakhraie L, Liu Y, Noronha K, Bao X, Li J, Shuch BM, Megan CK, Bindra RS, and Glazer PM. Oncometabolites suppress DNA repair by inhibiting local chromatin signaling at the double-strand break. Nature 2020; 582: 586–591
Complete List of Publications in MyBibliography
https://www.ncbi.nlm.nih.gov/myncbi/jing.li.19/bibliography/public/
Link to KCI Pharmacology and Metabolomics Core:
http://www.karmanos.org/pharm
Education/Training
Ph.D. Pharmaceutical Sciences: National University of Singapore, Singapore
Post-Doctoral Fellow: Johns Hopkins University, Baltimore, MD
Courses Taught
CB7240 Principles of Cancer Therapy
CB7300 Special Topics in Cancer Metabolism
CB8910 Applied Cancer Omics and Data Analysis
PSC5115 Pharmacokinetics