AURORA, Colo. (April 27, 2010)— Cancer research done in laboratories generally relies on two types of models: animals that have been genetically altered to get a specific kind of cancer—called transgenic mice—and human cell lines.

“The problem with these models is that they don’t work like cancer works inside a human body,” says Dr. Antonio Jimeno, director of head and neck cancer medical oncology at the University of Colorado Cancer Center (UCCC). “Conventional cancer cell lines, which have been growing on plastic for many, many years, have been shown to irreversibly lose their initial genetic profile In order to adapt to artificial culture. This can greatly decrease the accuracy of the data scientists get from experiments, be it genetic information or sensitivity to cancer drugs.”

Jimeno, associate professor at the University of Colorado School of Medicine and member of the Charles C. Gates Center for Stem Cell Biology and Regenerative Medicine, is partnering with UCCC scientist Dr. Yosef Refaeli to build a better model, one that mirrors exactly how a tumor is acting inside a human. The pair just received a three-year, $275,000 grant to build the model, which they call Xactmice.

Jimeno and others at UCCC and around the country are already using tumor explants—human tumors taken from patients in the operating room and almost immediately implanted in mice—to study cancer biology and new treatments. However, tumors become a mixture of human and mouse simply because the mouse bone marrow supports the growth of the human tumor.

The idea is simple: obtaining tumor and hematologic normal stem cells from a blood sample from the same patient, and having the tumor grow in a mouse transplanted with that same patient bone marrow. The execution though has no precedent.
Jimeno has teamed up with Refaeli, an expert in the hematopoetic (blood and bone marrow) system to solve this problem and build a better mouse model.

A member of both UCCC and the Charles S. Gates Center for Stem Cell Biology and Regenerative Medicine, Refaeli has invented a way to replace a mouse’s hematapoetic system with one from a human donor, much like a person might receive a stem cell transplant from an unmatched donor to treat leukemia. He is the first person in the world to reversibly “immortalize” bone marrow stem cells.

The technology developed in the Refaeli laboratory involves their ability to trick slow dividing blood stem cells into dividing quickly and exponentially in the lab, much like a cell line would. Importantly, the researchers can then turn off the genes responsible for the growth of the blood stem cells in the lab prior to transplantation into mice.

This is a key advance, since the two labs can now generate a large number of mice that bear the solid tumor and blood cells derived from the same patient. This will be a critical step in the development of the Xact mouse model of cancer.

“This technology, once proven through this study, could extend beyond cancer to advance the field in immunologic diseases and organ transplantation as well,” say Refaeli, assistant professor of Dermatology at the University of Colorado School of Medicine. “We want to prove that we can take tissue like a tumor and bone marrow cells and successfully implant them into an unrelated host without the complications we see with traditional transplants, such as rejection.”

Jimeno and Refaeli will use Department of Defense grant to obtain tissue and blood stem cells from at least 10 living human cancer patients who consent to have their tissue used in cancer research, then implant both into mice at the same time. They will start the study with head and neck cancer patients, possibly moving into other cancer areas in the future.

“We think we will be able to create a fully individualized and humanized mouse model that preserves the genetic profile and original tumor features,” Jimeno says. “We’ll show this by treating the mice with the same drugs that each patient received. We want the mice have the same outcomes the patient did.”

He says the overarching goal is to construct a cancer model that allows for more accurate research and faster new drug development.

“It’s a high-risk project with the potential of having enormous impact,” he says. “If we are successful, our studies have the potential to generate an ideal model of cancer that could constitute a paradigm shift in how cancer is studied.”

Contact: Lynn Clark, 303.724.3160, [email protected]

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