Genetically-engineered preclinical models predict pharmacodynamic response

September 19, 2012

New cancer drugs must be thoroughly tested in preclinical models, often in mice, before they can be offered to cancer patients for the first time in phase I clinical trials. Key components of this process include pharmacokinetic and pharmacodynamic studies, which evaluate how the drug acts on a living organism. These studies measure the pharmacologic response and the duration and magnitude of response observed relative to the concentration of the drug at an active site in the organism.

A new comparison of four different methodologies for pharmacokinetic and pharmacodynamic testing of the anti-melanoma agent , demonstrates that genetically-engineered mouse models provide delivery of drug most comparable to the response seen in melanoma patients.

"These studies are critically important in the case of small-molecule , which often have systemic side effects and can be toxic at high concentrations," said Ned Sharpless, MD, Wellcome Distinguished Professor of Cancer Research and study co-author.

The study, led by Bill Zamboni, PharmD and PhD, Associate Professor of Pharmacotherapy and at the UNC Eshelman School of Pharmacy and a member of UNC Lineberger Comprehensive Cancer Center, and Ned Sharpless, MD, who is also Associate Director for Translational Research at UNC Lineberger.

The collaborative study, which appears in The Oncologist, brought together a set of unique resources available at UNC to determine which preclinical models best predict delivery of carboplatin to melanoma tumors in patients. "We have a unique opportunity to evaluate an important factor in the treatment of solid tumors because of the outstanding and novel resources at UNC", said Zamboni.

"We have used a pharmacokinetics testing method called microdialysis, which uses a tiny probe to take samples that measure serial drug concentrations in a tumor over time," he added. "We plan to use this method to advance pharmacology studies of anticancer agents in tumors and tissues of patients and to evaluate the tumor delivery of nanoparticles and other classes of delivery agents."

The team used the resources of the preclinical phase I unit at UNC Lineberger to compare how pharmacokenetic levels vary in several preclinical tumor models including a genetically-engineered model, a model where tumor cells are transplanted to the appropriate part of the body (called an orthotopic syngeneic transplant or OST), and a xenograft model, where human tumor tissue is transplanted.

"Because carboplatin is widely used, we have good data on how the drug works pharmacokenetically 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. None of these laboratory models are perfect, but the genetically-engineered is the best in terms of predicting the amount of drug that is delivered to the tumor in human patients," Zamboni added.

"We know that laboratory models are imperfectly predictive of human response and if the tumor models don't predict delivery, they are most likely not an optimal research tools," he noted.

Sharpless added, "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. This study provides valuable validation that genetically-engineered models can help us accomplish this objective."

Related Stories

P Rex-1 protein key to melanoma metastasis

November 22, 2011

Researchers from UNC Lineberger Comprehensive Cancer Center are part of a team that has identified a protein, called P-Rex1, that is key to the movement of cells called melanoblasts. When these cells experience uncontrolled ...

Kinase test may yield big gains for drug-resistant cancers

April 12, 2012

In a paper published today in the journal Cell, a team from the University of North Carolina at Chapel Hill unveils the first broad-based test for activation of protein kinases "en masse", enabling measurement of the mechanism ...

Gene inactivation drives spread of melanoma: study

June 11, 2012

Why do some cancers spread rapidly to other organs and others don't metastasize? A team of UNC researchers led by Norman Sharpless, MD, have identified a key genetic switch that determines whether melanoma, a lethal skin ...

Recommended for you

Study reveals new insight into DNA repair

August 3, 2015

DNA double-strand breaks (DSBs) are the worst possible form of genetic malfunction that can cause cancer and resistance to therapy. New information published this week reveals more about why this occurs and how these breaks ...

Strange circular DNA may offer new way to detect cancers

July 30, 2015

Strange rings of DNA that exist outside chromosomes are distinct to the cell types that mistakenly produced them, researchers have discovered. The finding raises the tantalizing possibility that the rings could be used as ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.