Min H. Kang, Pharm.D.
Pharm.D. Clinical Pharmacology
University of Colorado HSC, 1997
Department of Cell Biology and Biochemistry
Texas Tech University Health Sciences Center
3601 4th Street, Mail Stop 6540
Lubbock, TX 79430
Phone: (806) 743-2694
Fax: (806) 743-2691
Pharmacokinetics, pharmacogenomics, drug resistance, pediatric cancers, neuroblastoma,
pediatric acute lymphoblastic leukemia.
Pharmacokinetics, pharmacogenomics, and clinical outcome of 13-cis retinoic acid in
Neuroblastoma is a malignant childhood tumor of the sympathetic nervous system. 13-cis
retinoic acid (13-cis-RA) induces differentiation of human neuroblastoma cells, and
high-dose, pulse 13-cis-RA treatment significantly improves overall survival of high-risk
neuroblastoma patients, but many children develop recurrent disease during or after
13-cis-RA treatment. In this project, we study pharmacokinetic and metabolic profiling
of 13-cis-RA in samples from 600 high-risk neuroblastoma patients enrolled in phase
III clinical trials; 2) determine PG of enzymatic polymorphisms using rapid throughput
screening methods requiring minimal amounts of gDNA samples of neuroblastoma patients;
3) and demonstrate that PK and/or PG for 13-cis-RA correlates with clinical outcomes
for neuroblastoma patients undergoing 13-cis-RA treatment. This proposed study will
potentially define PK and/or PG parameters that can be used to optimize dosing of
13-cis-RA in high-risk neuroblastoma patients.
Dynamics of MYC and MYCN in drug resistant neuroblastoma
13-cis retinoic acid down-regulates N-MYC protein in neuroblastoma cells, and thus
it is part of standard of care for high-risk neuroblastoma patients. It improves survival
of neuroblastoma patients as mentioned in the previous paragraph, but many patients
develop resistance to 13-cRA and eventually die of disease. We found that c-MYC protein
is increased when N-MYC protein is suppressed by 13-cRA in some cell line models of
neuroblastoma. In the current project, we investigate the mechanisms of c-MYC increase,
and identifies potential markers for c-MYC up-regulation.
Pharmacokinetics and metabolism of PPMP, a sphingolipid modulator
Sphingolipids are essential structural components of cell membranes and have messenger
functions that regulate growth, differentiation, apoptosis and senescence of cells.
Drugs targeting the sphingolipid pathway are being developed. PPMP is a glucosyl ceramide
synthase inhibitor that may potentially accumulate cytotoxic ceramides in cancer cells.
PPMP is currently being tested in clinical trials in combination with fenretinide,
a cytotoxic retinoid that also modulate ceramides. In pharmacokinetic studies in rodent,
we found that PPMP significantly alter pharmacokinetics of fenretinide. We study enzymes
that are inhibited by PPMP using rat and human liver microsomes, isozymes, and hepatocytes.
Roles of Ceramide Synthases in cancer
Microarray data suggest that cancer cells metabolize sphingolipids differently compared
with normal cells. Ceramides are a group of the key intermediating lipids in the sphingolipid
pathway. Six different isoforms of ceramide synthase (CERS1-CERS6) with varying substrate
specificity generate ceramides of diverse chain lengths, each of which have differential
roles in maintaining cellular homeostasis. This project is to determine the roles
of each ceramide synthase in catalyzing and synthesizing different ceramides and to
identify the roles of ceradmides in apoptosis of cancer cells.
- CP Hall, CP Reynolds, MH Kang. (2015) Modulation of glucocorticoid resistance in pediatric T-cell Acute Lymphoblastic
Leukemia by altering expression of BCL-2 family proteins with the PI3K/mTOR inhibitor
BEZ235. Clinical Cancer Res (in press). PubMed
- MH Kang, J Wang, M Makena, JS Lee, N Paz, CP Hall, MM Song, RI Calderon, A Hindle, W Ko,
J Fitzgerald, DC Drummond, T Triche, CP Reynolds. (2015) Activity of MM-398, nanoliposomal
irinotecan (nal-IRI), in Ewing’s family tumor xenografts is associated with high exposure
of tumor to drug and high SLFN11 expression. Clinical Cancer Research 21(5):1139-1150.
- P Sonawane, A Tagde, X Chen, AL Yu, CP Reynolds, MH Kang. (2014) Metabolic characteristics of 13-cRA and anti-tumor activity of the 13-cis
retinoic acid metabolite 4-oxo-13-cis retinoic acid in neuroblastoma. Br J Pharmacology
- Y Ryu, CP Hall, CP Reynolds, MH Kang. (2014) Caspase-dependent Mcl-1 cleavage and effect of Mcl-1 phosphorylation in ABT-737-induced
apoptosis in human ALL cell line. Exp Biol Med 239:1390-402. PubMed
- C Hall, SM Troutman, DK Price, WD Figg, MH Kang. (2013) Bcl-2 Family of Proteins as Therapeutic Targets in Genitourinary Neoplasms.
Clin Genitourin Cancer. Oct 16. pii: S1558-7673(12)00177-2. doi: 10.1016/j.clgc.2012.09.002.
- MH Kang, CP Reynolds, JM Maris, R Gorlick, EA Kolb, R Lock, H Carol, ST Keir, J Wu, D Lyalin,
RT Kurmasheva, PJ Houghton, MA Smith. (2014) Initial Testing (Stage 1) of the mTOR
Kinase Inhibitor MLN0128 by the Pediatric Preclinical Testing Program. Pediatr Blood
Cancer 61(8):1486-9. PubMed