A mouse that roars against pediatric brain cancer

Sanford-Burnham researchers establish first step to personalized treatment against particularly malignant form of medulloblastoma as as they create a new mouse model for the disease and zero in on a potential therapy

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LAJOLLA, Calif.—Scientists at the Sanford-Burnham Medical ResearchInstitute have developed a new mouse model for studying a childhoodbrain cancer called medulloblastoma. The animal model mimics thedeadliest of four subtypes of human medulloblastoma, a tumor that istriggered by elevated levels of a gene known as Myc.

Thestudy, published February 13 in the journal CancerCell,also suggests a potential strategy for inhibiting the growth of thistumor type. As Sanford-Burnham reports, "This achievement marks animportant milestone toward personalized therapies tailored to aspecific type of medulloblastoma."

"Beingable to use an animal model as a tool to test treatments has beenvery valuable in medulloblastoma, as in other types of tumors,"notes Dr. Robert Wechsler-Reya, director of the Tumor DevelopmentProgram in Sanford-Burnham's National Cancer Institute-designatedCancer Center, member of the Sanford Consortium for RegenerativeMedicine, and senior author of the study. "But for Myc-associatedtumors, that hasn't been an option because there hasn't been a modelof the disease. This is the first step to developing therapies forthis type of tumor."

Also,he tells ddn,a successful mouse model is important because pediatric brain tumorsare rare, and thus getting tumor material with which to work can be achallenge.

Childrenwith medulloblastoma develop tumors in the cerebellum, which plays animportant role in motor control. Seventy-five percent of childrenwith the disease survive after aggressive surgery, radiation, andchemotherapy—but, according to Wechsler-Reya, side effects can besevere, leading to cognitive deficits, endocrine disorders, and thedevelopment of other cancers later in life.

Inthis latest study, Wechsler-Reya, postdoctoral researcher Dr. YanxinPei and colleagues showed that cerebellar stem cells engineered withthe Myc oncogene initially gave rise to large masses of cells whentransferred to mice, but after four weeks these cells disappeared. AsSanford-Burnham notes, researchers have known for years that the Myconcogene causes cells to grow but also, paradoxically, to die. Thereason is that Myc activates another gene called p53, which sensesthat something is wrong with the cell and causes it to self-destruct.The next step was to inactivate p53, which the researchers did bygiving the cells a mutant form of the gene to block its effects.

Callingthe results "striking," the researchers note that the newlyengineered cerebellar stem cells, carrying Myc and mutant p53, formedlarge tumors in mice that continued to grow over time. Moreover,these tumors resembled those seen in humans with Myc-drivenmedulloblastoma.

"Wewere surprised at just how well the mouse model worked and howclosely it mimics the human disease, which is critical to makingobservations and assumptions with the biology and potentialtherapies," Wechsler-Reya tells ddn.

Theresearchers then profiled the genes that are expressed in the tumorsand found particularly high levels of genes that are activated by anenzyme called PI3-kinase,which is an important part of the mechanismthat cells use to stay alive. Its activity is often elevated incancer cells. Armed with this information, the team tested whetherinhibiting PI3-kinase could block the growth of Myc-driven tumors.

"Wefound that PI3-kinase inhibitors significantly increased mousesurvival," said Pei, the study's first author.

Whileit's nothing new to have PI3-kinase inhibitors in clinicaltrials—several types of cancer are being attacked that way intrials right now—what is new is that no one had yet attempted touse them as a treatment for medulloblastoma. Wechsler-Reya said hislab is now taking steps toward testing these inhibitors as apotential therapy for the disease.

"Obviouslythere are many steps between screening compounds in the lab andgiving drugs to patients," notes Wechsler-Reya. "But some of thesteps can be cut short if you use drugs that are already in trials orin use for other diseases."

Theteam plans to screen other compounds using the new mouse model totest their effectiveness in stopping tumors. Wechsler-Reya's lab isalso working on developing new mouse models to study othermedulloblastoma subtypes.

"Thekey is to take compounds that show promise in preclinical studies inthe lab and partner with clinicians to evaluate their effectivenessin the clinic," according to Wechsler-Reya. "Our hope is thatthis approach will bring new therapies to children who are sufferingfrom this extremely aggressive disease."

"Thereare other drugs that work on this PI3-kinase pathway," he adds, "soif this works out, we should be able to move fairly quickly fromtrials on those drugs for other conditions to trials for use onmedulloblastoma."

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