Genetically-engineered preclinical models predict pharmacodynamic response

September 19, 2012, University of North Carolina Health Care

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."

Explore further: Gene inactivation drives spread of melanoma: study

Related Stories

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 ...

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 ...

Preclinical studies use specialized ultrasound to detect presence of cancer

July 10, 2012
From the air, the twists and turns of rivers can easily be seen. In the body, however, tracing the twists and turns of blood vessels is difficult, but important. Vessel "bendiness" can indicate the presence and progression ...

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 ...

Heterogeneous ER+ breast cancer models allow more accurate drug testing

August 6, 2012
(Medical Xpress) -- Cell cultures are homogeneous. Human tumors are not. A University of Colorado Cancer Center study recently published in the journal Breast Cancer Research and Treatment reports the development of human-derived ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

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.