Jing Li
Jing Li, Ph.D.
Assistant Professor

Department of Pharmacology
Wayne State University School of Medicine
Karmanos Cancer Institute
4100 John R, HWCRC/Room 523
Detroit, MI 48201

Phone: 313-576-8258
Fax: 313-576-8928
Email: lijin@karmanos.org
RESEARCH INTERESTS:
Anticancer drugs exhibit a large interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability that can lead to therapeutic failure or severe toxicity.  My research efforts involve characterizing the PK and PD of anticancer drugs, and investigating mechanisms underlying the interindividual PK and PD variability in cancer patients, with a particular emphasis on identification of functionally and clinically relevant genetic variants in drug metabolizing enzymes (e.g., cytochrome P450s and sulfotransferases), drug transporters (e.g., ABCB1 and ABCG2), and target receptors and study of their contribution to inherited differences in drug disposition and response.  Understanding how genetic variations influence drug disposition and response could help in tailoring cancer therapy based on an individual’s genetic makeup.  Two major active projects in my laboratory are highlighted below.

Aminoflavone is a clinically investigational anticancer agent.  Metabolic activation of AF by human cytochrome P450 (CYPs) and sulfotransferases (SULTs), in particular, CYP1A1 and SULT1A1, has been implicated as an underlying mechanism for the unique pattern of tumor sensitivity to AF.  The work in my lab has demonstrated the pharmacogenetic influence of CYP1A1 and SULT1A1 polymorphisms on the bioactivation and cytotoxicity of aminoflavone.  We have established V79 Chinese Hamster cell lines and MDA-MB-231 breast cancer cell lines with stable expression of common variants of human CYP1A1 and SULT1A1.  Using these in vitro cellular models, we have identified that common polymorphisms of human CYP1A1 and SULT1A1 are associated with differential cellular metabolism and cytotoxicity of AF.  This work was presented as an oral presentation at the 2009 American Society of Clinical Pharmacology & Therapeutic (ASCPT) Annual Meeting.  We are in progress in investigating the clinical significance of these functional genetic variants on the PK, PD, and clinical outcome of aminoflavone in cancer patients in phase I trials. 

The second project in my laboratory is to employ a comprehensive, genome-wide approach to identify genes and genetic variants that may influence the response to targeted therapies.  Molecularly targeted agents have emerged as a new and promising paradigm in cancer therapy.  Because of their distinction mechanisms of action, these novel agents are likely to be effective in subsets of patients whose tumors have specific molecular characteristics.  Identification and selection of patients who are most likely to response is critical to the success of molecular targeted therapies.  Given that multiple pathways or genes are implicated in the disposition and action of targeted agents, a systemic genome-wide search for molecular markers predictive of response is critically required.  Our long-term goal is to develop a genomic strategy that can identify the responders and then guide the optimal use of molecularly targeted agents. 

In addition to pharmacogenetics/pharmacogenomics, my other research interests include pharmacometrics.  Pharmacometrics focuses on the use of models with a particular emphasis on nonlinear mixed effects (“population”) models to describe and interpret pharmacology in a quantitative fashion.  My work in pharmacometrics concerns the development and utilization of population PK/PD models for analysis of the concentration-time, response-time, or dose-concentration-response data from clinical trials of anticancer drugs and identification of inter- and intra-individual PK/PD variability and the sources accounting for this variability.  This work is crucial not only in aiding general protocol design but also in allowing specific modifications of dosing regimen based on individual patient’ characteristics (e.g., age, body weight, body surface area, liver and kidney functions, and genetic make-ups, et al).  The dose-concentration-response relationship defined in the population PK/PD model could aid in selection of optimal dose for future studies. 

Selected Recent Publications

    • Li J, Sausville EA, Klein PJ, Morgenstern D, Leamon CP, Messmann RA, LoRusso P.  Clinical pharmacokinetics and exposure-toxicity relationship of a folate-vinca alkaloid conjugate EC145 in cancer patients.  J Clin Pharmacol 2009 (in press)
    • Li J, Jameson MB, Baguley BC, Pili R, Baker SD.  Population pharmacokinetic-pharmacodynamic model of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid in cancer patients.  Clin Cancer Res. 2008;14:2102-10.
    • Li J, Zhao M, He P, Hidalgo M, and Baker SD. Differential metabolism of gefitinib and erlotinib by human cytochrome P-450 enzymes.  Clin Cancer Res 2007;13:3731-7.
    • Li J, Cusatis G, Brahmer, J., Robey R, Bates S, Sparreboom A, Hidalgo, M, and Baker SD.  Association of ABCG2 variant to the pharmacokinetics of tyrosine kinase inhibitors in cancer patients.  Cancer Biology & Therapy 2007;6:432-8
    • Li J, Karlsson MO, Brahmer J, Sparreboom A, Zhao M, Hidalgo M, and Baker SD.  CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors.  J Natl Cancer Inst 2006;98:1714-1723 



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