© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 3, 188,
February 5, 2003
© 2003 Oxford University Press
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Animal Models Offer Insights Into Human Brain Tumors
Primary brain tumors have long been a mystery with regard to their pathogenesis, and in too many cases such tumors grow beyond modern medicine’s ability to treat them. But now some neuroscientists are using mouse models to offer new insights into the pathogenesis and possibly improved treatments for the various kinds of brain tumors.
In December at the annual meeting of the Society for Neuroscience, several prominent investigators gave updates on their research in mice and what their findings, hopefully, will ultimately mean for man.
Thus far, the animal models look promising, said Luis Parada, Ph.D., of the University of Texas Southwestern Medical Center, Dallas, who chaired the symposium on brain tumors. First of all, he said, "we’re taking lesions from these tumors and reconstructing them in the mouse and getting similar kinds of tumors, which tells us we’re on the right road. And second, it’s enabling us to identify and understand better what cells are giving rise to the tumor."
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Astrocytomas
Some brain tumors run a slow course, and patients can be cured if the tumors are completely removed. But in the case of the most deadly kind—high-grade astrocytomas—there has been little to offer besides palliation.
Ronald DePinho, M.D., and his colleagues at Dana-Farber Cancer Institute, Boston, have developed a mouse model that closely mimics high-grade astrocytomas. They bred knockout mice that lack the tumor suppressor gene Ink4a/Arf with mice that produce excess epidermal growth factor receptor (EGFR), a known tumor promoter. The mice developed what looked very much like the high-grade astrocytomas seen in humans.
The researchers then analyzed the tumors and found several other genes that are presumed to increase lethality by interacting with Ink4a/Arf and EGFR. These particular genes, said DePinho, "could make for good drug targets."
Also taking aim at astrocytomas are Terry Van Dyke, Ph.D., of the University of North Carolina at Chapel Hill and her colleagues. As a first step, they developed mice that produce a protein fragment that inactivates the retinoblastoma (pRb) tumor suppressor gene in their astrocytes. This caused the astrocytes to proliferate, eventually causing the development of astrocytomas. The researchers also found during the experiments that the genetic alteration of another molecule, PTEN, further accelerated tumor growth.
Van Dyke said these findings indicate that pRb and PTEN expression could be therapeutic targets in astrocytomas.
Oligodendrogliomas, Medulloblastomas
Other kinds of brain tumors with promising mouse proxies include the medulloblastomas of childhood and the oligodendrogliomas seen in young and middle-aged adults.
William Weiss, M.D., Ph.D., of the University of California at San Francisco, and his group have developed a mouse model for oligodendrogliomas, and from it they were able to determine that Ink4a/Arf also plays a role in oligodendroglioma development. They have also found that an immature cell responsible for producing oligodendrocytes—aptly named the oligodenrocyte precursor cell—may be the starting point for tumor development. (Previous lore held that oligodendroglioma tumors arose from the oligodendrocytes themselves.)
And at St. Jude Children’s Research Hospital in Memphis, Tenn., Thomas Curran, Ph.D., and colleagues have developed a mouse model missing two genes involved in cell growth, the well-known p53 gene, which is involved in a number of cancers, along with a gene called Patched-1. When both of these genes are knocked out, Curran said, the genetically altered mice develop medulloblastomas in 12 weeks.
So where to now, in terms of therapy based on these knockout mice studies?
Weiss said that many of the new drugs now in phase I, II, or even phase III trials—the largest class being the kinase inhibitors—hold promise. The idea, he said, "Is rational therapy—to find a specific pathway and block it."
He added: "I think the brain tumor community has learned from AIDS, and that is that you can take a lethal disease and turn it into a chronic one. I’m thinking the idea with brain tumors is to change life expectancy—maybe from 1 year to 10 or 20 years."
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