Genetically Modified Lab Mice Provides Best Way to Test Melanoma Drug Delivery

Genetically engineered laboratory mice appear to be the most effective preclinical forecaster of how cancer-fighting drugs are administered to melanoma patients, a new study has found.

A new study, led by University of North Carolina (UNC)-Chapel Hill (USA) researchers, with colleagues in the Research Triangle Park (NC, USA), and from other institutions, published their data online September 2012 in the journal the Oncologist. The study evaluated how four different kinds of mouse models predict the delivery of carboplatin, a typically used anticancer drug, to melanoma tumors in patients.

Before a new cancer drug can be utilized in clinical trials, it is assessed in lab mice or other preclinical models to evaluate how it acts on a living organism. Key parts of this process include pharmacokinetic and pharmacodynamic (PK-PD) research, which gauges the pharmacologic response and the length and extent of response observed in comparison to the concentration of the drug at an active site in the organism.

“Because carboplatin is widely used, we have good data on how the drug works pharmacokinetically in humans. For the first time, we were able to compare these various laboratory techniques used in countless labs and the pharmaceutical industry to evaluate how carboplatin was delivered to the tumor and compare it to actual human data,” said study coauthor Bill Zamboni, PharmD, PhD, associate professor of pharmacotherapy and experimental therapeutics at the UNC Eshelman School of Pharmacy and a member of UNC Lineberger Comprehensive Cancer Center. “None of these laboratory models are perfect, but the genetically engineered model is the best in terms of predicting the amount of drug that is delivered to the tumor in human patients.”

Traditional anticancer drug development has relied on engrafts (transplanting of human cancer cell lines in immune-compromised mice), but the benefits of this practice has recently been questioned. This study offers the first direct, comparison of the efficacy of xenograft models, genetically modified mouse models (GEMMs), and two types of orthotopic syngeneic transplants (OSTs), where tumor cells are transplanted to the appropriate part of the body.

“We are continually looking for ways to build better laboratory models so that new therapies move from the lab to the patient as quickly and safely as possible,” said study co-author Ned Sharpless, MD, professor of cancer research and associate director for translational research at UNC Lineberger. “This study provides valuable validation that genetically engineered models can help us accomplish this objective.”

Researchers examined plasma and tumor pharmacokinetic (PK) parameters--a critical factor influencing the predictability of rodent tumor models--in the four models and compared those parameters to human patients. Dissimilar to xenografts and OSTs, which transplant active human or rodent cancer cells into an animal, the GEMM application allows tumors to develop on their own over time in the mice, providing the most relevant process as to how they develop in humans.

“This study could advance the pharmacokinetic testing of other anticancer drugs, and on various types of cancer--and it’s especially important for testing small-molecule cancer drugs in an effort to minimize side effects and improve safety,” said Martin Murphy, Jr., PhD, DMedSc, executive editor of the Oncologist.

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