TY - JOUR
T1 - Genetically engineered cancer models, but not xenografts, faithfully predict anticancer drug exposure in melanoma tumors
AU - Combest, Austin J.
AU - Roberts, Patrick J.
AU - Dillon, Patrick M.
AU - Sandison, Katie
AU - Hanna, Suzan K.
AU - Ross, Charlene
AU - Habibi, Sohrab
AU - Zamboni, Beth
AU - Müller, Markus
AU - Brunner, Martin
AU - Sharpless, Norman E.
AU - Zamboni, William C.
PY - 2012
Y1 - 2012
N2 - Background. Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed. Methods. In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs). Results. Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors. Conclusions. The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors.
AB - Background. Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed. Methods. In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs). Results. Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors. Conclusions. The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors.
KW - Carboplatin pharmacokinetics
KW - GEMM
KW - Genetically engineered mouse models
KW - Melanoma models
KW - Microdialysis
KW - Mouse tumor models
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U2 - 10.1634/theoncologist.2012-0274
DO - 10.1634/theoncologist.2012-0274
M3 - Article
C2 - 22993143
AN - SCOPUS:84868113123
SN - 1083-7159
VL - 17
SP - 1303
EP - 1316
JO - Oncologist
JF - Oncologist
IS - 10
ER -