Collaboration for a cure

The world’s top experts in pediatric and adult cancer are uniting to eradicate a rare cancer that kills both children and adults.

What’s the best way to find a cure for a vicious cancer that kills both children and adults? The answer seems obvious: Assemble the world’s top experts on adult and pediatric cancer. Encourage them to focus their intellect, energy and creativity on curing that disease.

It sounds simple, doesn’t it? But it has never been done before. Until now.

Recently, two groups of brilliant scientists embarked on the first direct collaboration to find a cure for ependymoma, a rare central nervous system tumor that affects people of all ages.

Ependymoma arises from cells located within the ventricles of the brain and spinal cord. In children, the tumors usually appear in the brain; in adolescents and adults, the tumors generally form along the spinal cord.

Treatment for ependymoma usually consists of surgery to remove the tumor, followed by radiation therapy. Unfortunately, scientists have no other weapons against this deadly cancer. Chemotherapy is not highly effective, so patients rarely survive if the cancer is not completely removed or if it recurs.

Researchers at St. Jude Children’s Research Hospital are working with colleagues at MD Anderson Cancer Center in Texas to increase the odds for all patients who develop ependymoma. The Collaborative Ependymoma Research Network consists of two teams with one common goal: the St. Jude group studies the pediatric form of the disease, while the MD Anderson team addresses the adult form. Investigators hope that this collaboration will mean the difference between life and death for patients around the world.

The St. Jude efforts are headed by Richard Gilbertson, MD, PhD, co-leader of the St. Jude Neurobiology and Brain Tumor Program. “This initiative is exciting because it’s the first time that clinical trials will occur for children and adults with the same disease,” he says. The St. Jude portion of the project consists of four components: cancer stem cell research, pathology and genomics, drug development and clinical trials.

Cancer stem cell research

In his St. Jude laboratory, Gilbertson is discovering ways to determine which genetic mutations are required to transform a stem cell into a cancer stem cell. His laboratory was the first in the world to isolate cancer stem cells for ependymoma.

“We have already developed the first models of the disease in the laboratory, and we think we have found a cell in the nervous system that goes wrong to make an ependymoma,” Gilbertson says. He and his colleagues also discovered that ependymomas from different parts of the nervous system contain distinct groups of genetic alterations.

“If you’re looking at tumors in the front of the brain, one from a 6-month-old child will look almost exactly the same as one from a 71-year-old man,” Gilbertson says. “Actually, that child’s tumor would look quite different from a tumor that might occur in the back of a 6-month-old’s brain. This tells us that ependymoma is not age-dependent; it is site dependent. I think that is because the tumors are dictated right from the beginning from the cell type.

“We have been doing a lot of work to understand those cells,” he continues. “Spinal tumors occur mostly in adults; they are very rare in children. Ependymomas in children occur mainly in the brain. We think the reason why spinal ependymomas occur in adults and the intracranial tumors occur in children is because the population of that cell type changes with age.”

For the past three years, Gilbertson has conducted an international study involving 230 samples of ependymoma. St. Jude researchers have used the gene array technology capabilities of the St. Jude Hartwell Center for Bioinformatics and Biotechnology to identify more than 75 genes that may play a part in causing this brain tumor. Gilbertson and his colleagues will continue this project, which promises to uncover more secrets about the cancer.

Pathology and genomics

Meanwhile, pathologists are building on Gilbertson’s recent findings to figure out how to classify ependymoma accurately. “We’re really hopeful that we can get a good understanding of what is a poorly understood disease at the present time by looking at the whole range of tumors, both in kids and adults—taking what we know of pathology at the moment and supplementing it with molecular data that Richard has derived,” says pediatric neuropathologist David Ellison, MD, PhD, of St. Jude Pathology.

Currently, pathologists classify and grade the tumors based solely on their appearance. Even though this system has been refined through the years, it is not clinically and biologically useful.

“There’s a lot of controversy about whether or not the grading of ependymomas really correlates with how the tumors behave in patients,” Ellison explains. “We can identify that a tumor is an ependymoma, but understanding the different types and grades is a gray area. We’re at the point where if we’re going to do something useful with the pathology, we need to have molecular information to supplement what we’re looking at down the microscope.”

Ellison is spearheading the effort to create a completely new classification for childhood and adult ependymoma. This project will help clinicians understand the diverse biology of the disease, allowing them to better predict prognosis and treatment response.

Ellison and his colleagues at MD Anderson will look at all the different subtypes of ependymoma and analyze them for the presence of the molecular abnormalities that Gilbertson has been identifying in his lab.

“That sort of analysis has never been done with ependymomas before,” Ellison says. “We know a certain amount about the molecular abnormalities of ependymomas, but we haven’t found anything that’s guided treatment. We will be leading this analysis of the pathological subtypes versus the molecular abnormalities. Ependymoma is a tumor that’s crying out for a good molecular study that links with what we already know about the pathology to create a combined classification that is biologically and clinically useful.”

Drug development

Ependymoma is a wily adversary that has thus far proved resistant to conventional chemotherapy.

“Currently, we have some drugs for ependymoma that cause the disease to respond, but they do not ultimately affect survival,” Gilbertson says. “Radiation therapy plays an important role in the treatment of ependymoma, but basically if you don’t take the whole tumor out, the child will have a much reduced chance of surviving. So what this tells us is that conventional treatments aren’t working, and we need to have completely new approaches.”

Kip Guy, PhD, St. Jude Chemical Biology and Therapeutics chair, is leading the hospital’s effort to identify and develop chemicals that will be effective against ependymoma. Faculty and staff in the St. Jude Chemical Biology and Therapeutics department will screen thousands of compounds to pinpoint ones that inhibit cancer stem cells and block tumor formation.

Currently, Guy’s team is looking at drugs that already exist, but that may have not been considered for use with ependymoma. “That’s about 1,200 existing different drugs,” Guy says. “We’re also looking at combinations of those drugs. Obviously, that’s a way to really jump-start a development program: If you can identify an existing drug, then all you have to do is basically reapply it. That’s our first-path strategy.”

In the long term, the researchers in Guy’s area will concentrate on finding chemicals that might be starting points for new drugs. They will carry them forward through testing and development for use in clinical trials.

Clinical trials

The ultimate destination for these new drugs is the clinic. Because ependymoma is a rare cancer that affects about 140 children in the United States each year, an effective clinical trial would need to enroll patients from several institutions. St. Jude and MD Anderson will serve as hubs for other clinical affiliates that are participating in the project.

The adult and pediatric programs will open joint protocols, with the first one scheduled to start within the next few months. The pediatric and adult trials will run simultaneously and will have many similarities. Amar Gajjar, MD, co-leader of the Neurobiology and Brain Tumor Program, will direct the clinical portion of the St. Jude project. Thomas Merchant, DO, PhD, Radiation Oncology division chief, will lead the radiation oncology portions. Clinton Stewart, PharmD, of Pharmaceutical Sciences, will provide pharmacokinetic and pharmacogenetic support to the pediatric clinical trials.

The first clinical trial will build on discoveries Gilbertson’s lab has made within the past year. He and his colleagues recently demonstrated for the first time in any disease that cancer stem cells are similar to normal stem cells and that the cancer stem cells exist in special environments called niches. The niche is required to protect the stem cell and control it.

“Whereas normal stem cells constantly communicate with the niche to say, ‘Now it’s time to divide; now it is time to stop,’ cancer stem cells say, ‘Now it’s time to divide; now it’s time to divide,’ and they just keep proliferating,” Gilbertson explains.

“The upcoming clinical trial will use a novel combination of drugs,” Gajjar explains. “One drug will target the vascular niche, whereas the other two drugs will actually hit the cancer stem cells. We hope the combination of hitting the stem cells and the vascular niche will kill the tumor.”

The hospital’s participation in the Collaborative Ependymoma Research Network allows pediatric oncologists at St. Jude to take the lead in finding a cure for a cancer that has eluded treatment for years. It’s just one more example of how St. Jude excels in finding ways to move discoveries quickly from the research laboratory to the bedside.

Reprinted from Promise Spring 2008

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