NEW ANIMAL MODELS PROVIDE AVENUE TO ANALYZE AND ATTACK DEADLY BRAIN CANCER

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NEW ANIMAL MODELS PROVIDE AVENUE TO ANALYZE AND ATTACK DEADLY BRAIN CANCER.

ORLANDO, Tuesday, Nov. 5 - Brain tumors are notoriously difficult to treat, much less cure, making their diagnosis particularly devastating. But now the development of animal models, which mimic several forms of this cancer, are putting researchers on track toward finding what may be definitive treatments.

"The research advances our basic understanding of the factors that contribute to the development of different types of brain tumors, which will allow us to develop treatments that target these specific contributors," says Luis Parada, PhD, of the University of Texas Southwestern Medical Center and chair of a symposium on brain tumors at this meeting. "Importantly, the animal models also permit us to rapidly test any new therapies we develop. A corollary of this is that we learn more about the developing cells that give rise to the specific subsets of tumors." New research was reported today during the 32nd annual meeting of the Society for Neuroscience.

Doctors will diagnose over 186,000 brain tumors in the United States during 2002, according to estimates by the American Brain Tumor Association. These tumors are comprised of a growing mass of cells that can wreak havoc in the brain. Depending on the tumor's size and location, paralysis, behavior changes and dizziness, to name a few of the symptoms, may occur. If left unchecked, the proliferating tumor cells often cause death.

In an effort to develop specific techniques to stop this growth process one group of researchers developed an animal model of the astrocytoma brain tumors by genetically altering specific molecular pathways that are thought to suppress tumor development.

An astrocytoma is an exceptionally lethal type of brain tumor thought to arise from astrocyte brain cells, which make up the supportive tissue of the brain. Surgery only temporarily improves the condition. Other current cancer treatments such as chemotherapy and radiation are ineffective.

"Our finding of a model that replicates the biology of this deadly form of human brain cancer provides a better understanding of the biology of the tumors and provides an avenue for identifying and testing new drug targets and therapies," says Terry Van Dyke, PhD, of the University of North Carolina.

In the work, Van Dyke and her colleagues first bred mice that were genetically altered so that they produced a fragment of a protein that interacts with and inactivates the retinoblastoma (pRb) tumor suppressor protein in astrocytes. Normally this protein is thought to suppress the development of tumors. The researchers examined the mice and found that their astrocytes significantly proliferated and ultimately led to an astrocytoma. In addition, the researchers found that genetic alterations of another molecule, termed Pten, further accelerated the growth of the tumors.

"These findings indicate that the molecules pRb and Pten play a role in preventing astrocytoma development and that restoring these functions or targeting the pathways activated as a result of their loss may help in the treatment of the tumors," says Van Dyke.

As a next step, the researchers plan to use imaging techniques to further track the development of the tumors in live animals.

Another group of researchers also gained insight into the underlying biology of astrocytomas with the aid of a mouse model that mimics an advanced form or "high grade" of astrocytoma.

"Our model identifies key factors in the development of high grade astrocytomas, which are considered the deadliest human cancer," says Ronald DePinho, MD, of Dana-Farber Cancer Institute in Boston.

DePinho and his colleagues developed the model by breeding mice that lacked the gene Ink4a/Arf, known for its functions in suppressing tumor growth, with mice that had excess production of a molecule known to promote the growth of cells, termed epidermal growth factor receptor (EGFR). The mice grew tumors that mimicked high grade astrocytomas in humans. The researchers analyzed the tumors and found several other genes that appear to mutate and likely interact with Ink4a/Arf and EGFR to contribute to the lethality of these tumors.

"This indicates that these genes and interactions between Ink4a/Arf and EGFR are key in the development of the advanced tumors and could make for good drug targets," says DePinho.

As a next step, the researchers plan to test whether drugs that block these genes and interactions can stop the growth of the tumors and prolong the survival of the mice.

Another group of researchers developed an animal model that provides clues on how oligodendroglioma brain tumors arise and ways to stop them. This form of brain cancer most frequently occurs in young and middle-aged adults.

"The new model we developed will advance our understanding of the biology of brain tumors," says William Weiss, MD, PhD, of the University of California in San Francisco. "It will also help us develop and evaluate therapies that interfere with the process and stop the cancer's growth."

Previous analysis of the oligodendroglioma tumors suggests that they arise from another cell that makes up the supportive tissue of the brain, known as an oligodendrocyte. Under the microscope these cells have shorter processes and are not as star-shaped as astrocytes.

Weiss and his colleagues developed the oligodendroglioma model by breeding mice genetically altered to produce excess amounts of a version of EGFR. The molecule, similar to the one that DePinho examined in his model, also is known to promote the growth of cells. The mice developed tumors that contained the same qualities as human oligodendrogliomas. Furthermore the researchers found that they could increase the "grade" or severity of the tumor if they altered the Ink4a/Arf gene.

"This shows that the EGFR version we studied and Ink4a/Arf are important factors in the development of the oligodendroglioma brain tumor in mice," says Weiss.

In the research, the scientists also analyzed the cells of the tumors in the mice models and found that they actually arise from a type of immature cell that is responsible for producing oligodendrocytes, termed the oligodendrocyte precursor cell.

"In the future we hope to test different therapies in the models that might target the precursor cells or some of the other factors that trigger the tumor development," says Weiss.

Animal models also may help researchers find treatments for medulloblastoma brain tumors, a fast-growing and often lethal form of cancer that typically occurs in children.

"To improve the outlook for children, it is imperative that we elucidate the molecular basis of medulloblastoma tumors and use this information to design new treatments," says Thomas Curran, PhD, of St. Jude Children's Research Hospital in Tennessee. "Our animal model of the tumor is helping us get closer to this goal."

Curran and his colleagues developed the medulloblastoma model by breeding mice that are missing genes, termed Patched-1 and p53. Both of these genes are known to be involved in controlling cell growth. "We found that the genetically-altered mice develop medulloblastoma tumors in 12 weeks," says Curran. "This provides us with a good model to study the cancer."

As a next step, the researchers are testing a variety of compounds in the model to see if they can target the cell growth pathways and prevent tumor development.