4100 John R, HWCRC/Room 523
Mail Code: HW05AO
Detroit, MI 48201
• Clinical pharmacology of anticancer drugs
• Physiologically based pharmacokinetic (PBPK) modeling and simulation
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.
Physiologically based pharmacokinetic modeling of the human central nervous system (CNS) pharmacokinetics: Insufficient penetration of potentially effective chemotherapeutic agents across the human blood-brain barrier (BBB) is a huge hurdle to successful treatment of brain cancer. Mechanistic understanding and early prediction of drug BBB penetration is of paramount importance to rational drug development and treatment for brain cancer. Given the fact that the rate and extent of drug BBB penetration is determined by not only drug properties but also biological system characteristics, prediction of human BBB permeability from preclinical in vitro or animal models is complicated by biological system differences. Hence, the development of innovative approaches is imperative. The in vitro-in vivo extrapolation-physiologically based pharmacokinetic (IVIVE-PBPK) model offers a unique platform that allows simultaneous incorporation of drug- and system-specific parameters into a pharmacokinetic model and enables a priori prediction of individual in vivo kinetic processes based on mechanistic scaling of in vitro data (e.g., in vitro enzyme and transporter kinetics). Our research has been focused on the development of innovative CNS PBPK models for mechanistic prediction of heterogeneous penetration of anticancer drugs into the human brain 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.
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.
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 First published: 10 February 2021 https://doi.org/10.1111/cts.12978
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;107:1116-27.
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;582:586–91
Bao X, Wu J, Shuch B, LoRusso P, Bindra RS, and Li J. Quantitative profiling of oncometabolites in frozen and formalin-fixed paraffin-embedded tissue specimens by liquid chromatography coupled with tandem mass spectrometry. Sci Rep 2019;9:11238 |
Bao X, Wu J, Kim S, LoRusso P, and Li J. Pharmacometabolomics reveals irinotecan mechanism of action in cancer patients. J Clin Pharmacol 2019;59: 20-34.
Tien AC, Li J, Bao X, DeRogatis A, Kim S, Mehta S, Sanai N. A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort. Clin Cancer Res 2019;25:5777-86
Bao X, Wu J, Sanai N, Li J. Determination of total and unbound ribociclib in human plasma and brain tumor tissues using liquid chromatography coupled with tandem mass spectrometry. J Pharm Biomed Anal 2019;166:197-204.
Sulkowski PL, Sundaram RK, Corso CD, Oek S, Lu Y, Noorbakash S, Niger M, Boeke M, Ueno D, Bao X, Li J, Shuch B, Bindra RS and Glazer PM. Oncometabolite-producing hereditary cancer syndromes are defined by homologous recombination DNA repair defects. Nature Genetics 2018;50:1086-92.
Li J, Wu J, Bao X, Honea N, Xie Y, Kim S, Sparreboom A, Sanai N. Quantitative and mechanistic understanding of AZD1775 penetration across human blood-brain barrier in glioblastoma patients using an IVIVE-PBPK modeling approach. Clin Cancer Res, 2017;23:7454-66. (Featured in the Highlights)
Complete List of Publications in MyBibliography
Link to KCI Pharmacology and Metabolomics Core:
Ph.D. Pharmaceutical Sciences (2003): National University of Singapore, Singapore
Post-Doctoral Fellow (2006): Johns Hopkins University, Baltimore, MD
CB7240 Principles of Cancer Therapy
CB7300 Special Topics in Cancer Metabolism