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2013

Going After the Big Bad Tumor

June 11, 2013
Eric Rabbe

Eric Raabe, M.D., Ph.D.

In one sentence pediatric neuro-oncologist Eric Raabe explains why he does what he does: “It’s really a frustrating situation to be in, meeting parents for the first time, looking them in the eye, introducing yourself and saying, ‘I’m sorry but I can tell you with 100 percent certainty that your child will die within two years.’”

It is a blunt statement Raabe has never wanted to make but has had to because the brainstem tumor Diffuse Intrinsic Pontine Glioma (DIPG) is aggressive and 100 percent lethal. The classic deeply infiltrated presentation of the tumor on MRI alone is enough to confirm the deadly diagnosis, negating the need for a biopsy that poses the risk of neurologic deficit for a child with little time left. The tumor is unresectable and uncompromising—although it does respond to radiation therapy for a period of months, all children have regrowth of tumor and ultimately succumb. Thirty years of chemotherapy clinical trials have shown little benefit.

“There are only a few case reports of anyone surviving beyond a few years,” says Raabe. “In glioblastoma almost everybody dies – in DIPG, everyone dies.”

Through his bench research, Raabe aims to change that outcome, and as a pediatrician with joint appointments in oncology, pediatric neuro-oncology and pathology, he’s uniquely qualified to make a difference. The pathology piece particularly comes into play, enabling him to study the cellular activity of brainstem tumor tissues, which may lead to a greater understanding of these tumors and, eventually, to therapeutic targets that prolong survival. But with few patients having undergone the high-risk biopsies needed to extract a sliver of the cancer, Raabe notes, tumor samples have been sparse over the last three decades.

“We’ve essentially been flying blind,” says Raabe.

No more. Thanks to a recent push from the medical science community and patient advocates for more DIPG research, groups like the Mid-Atlantic DIPG Consortium—comprised of Johns Hopkins, Children’s National Medical Center and the National Institutes of Health—have formed, giving researchers like Raabe access to multiple DIPG cell lines and the molecular tools to study them in animals and, eventually, in clinical trials with humans. Also, these consortia and patient families have made it possible to perform rapid autopsies to obtain the critical DIPG tumor tissue. Most pediatric DIPG patients tend to die at home or in hospice, posing a logistical challenge for rapid biopsy.

What does it all mean? Now more than ever before, Raabe stresses, investigators have an opportunity to figure out how DIPG tumors are different, what’s driving them and how they propagate—and how they may respond to different therapies. DIPG, Raabe explains, is not one disease. “Even though these tumors may look the same under the microscope, there are different drivers that will push them in different ways,” Raabe says. “DNA analysis tells us there are certain mutations that appear to be very significant for this tumor that may give us its Achilles’ heel and a target for traditional chemotherapy and radiation to improve survival time.”

Some DIPGs appear to have mutations in two distinctly different mechanisms that regulate how cells divide and grow. One group’s mutations are predominantly found in a pathway called PDGF, or platelet derived growth factor, Raabe explains, while other mutations tend to develop in an EGF, or epidermal growth factor, pathway. It’s already known that certain drugs are more effective in treating these faulty pathways. Now Raabe is testing combination therapies in mice models with DIPG tumors derived from patient samples.

“Each drug by itself does not contribute much in causing the can-cer cells to die,” says Raabe, “but in combination the drugs force the cells to die.”

To better guide therapy for DIPG, Raabe’s colleagues, pediatric neuro-oncologist Ken Cohen and pediatric neurosurgeon George Jallo, have launched a new clinical trial in which newly diagnosed DIPG patients are offered biopsies. Jallo is well experienced in doing biopsies in the brainstem, Raabe explains, which will provide tissue for study and treatments tailored to the patient.

“You can envision a clinical trial that would require a patient to have a biopsy up front to determine which type of DIPG they have, which would allow us to get patients the right treatment based on their mutational status,” says Raabe.

“Now we have the molecular tools to figure out what’s going wrong, and with more and more therapies becoming available, we’re going to be able to hit those targets, the Achilles’ heel of the DIPG tumor.”