ASCO: Hedgehog Drug Stirs Hope for Some Pediatric Brain Tumors

CHICAGO -- Positive early phase results could put a novel inhibitor of "sonic hedgehog" signaling in line to be the first targeted agent in the most common type of childhood brain tumor.

The 13 children with refractory medulloblastoma included in the proof-of-principle study tolerated the drug known as GDC 0449 with no grade 4 toxicity or any of the dental or bone growth problems that were considered a risk based on animal studies, found Amar Gajjar, MD, of St. Jude Children's Research Hospital in Memphis, Tenn., and colleagues.
Of the two children confirmed to have activation of the hedgehog pathway in their tumor, one progressed after roughly six months of daily oral therapy and the other remains in the study without progression after 391 days of follow-up, Gajjar reported here at the American Society of Clinical Oncology meeting.

Action Points  

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• Caution interested patients that this drug is not FDA approved for any indication.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

"This is very atypical for medulloblastoma when the tumor comes back," since less than 5% of children typically survive recurrence, he said at a press conference.
In the one patient who consented to cerebrospinal fluid testing, the drug had effectively crossed the blood-brain barrier, as needed for a brain cancer drug, he added.
Although cautioning that these are early results that need much further validation and study, Lynn Schuchter, MD, of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, echoed the sentiment of many oncologists at the conference in calling the results exciting.
The hedgehog signaling pathway appears important in a number of cancer types, she said at the press conference she moderated.
But childhood medulloblastoma may be the best cancer target for a drug aiming at hedgehog signaling, said Julia Glade Bender, MD, of Columbia University, who moderated the oral abstract session at which the results were presented.
"This has the potential to be the Gleevec [imatinib] of hedgehog-mutated medulloblastoma," she said in an interview. "It is early but I don't think it's hype."
Imatinib revolutionized survival rates in chronic myeloid leukemia (CML) by attacking a specific kinase mutated in all these cancers, and did so as a single agent, which the hedgehog pathway inhibitor shows promise of acting as too, Glade Bender explained.
The reason for all the excitement is the seemingly clear biological basis from the clinical model of basal cell nevus syndrome, or Gorlin syndrome, she said.
In these families with an inherited mutation in the hedgehog pathway -- which signals to turn on transcription processes that activate tumor cells -- about 5% develop medulloblastoma during childhood.
Only about a fifth of pediatric medulloblastomas have the hedgehog pathway turned on when analyzed by molecular methods, Gajjar noted.
And it may well be that only patients with these types of cancers would benefit from the drug, Glade Bender noted.
To test this, a phase II trial is underway in young adults with medulloblastoma that has been stratified by hedgehog status, Gajjar said.
That study is using a dose close to the 170 mg/m² recommended by the pharmacokinetic data of the phase I pediatric study, in which patients were treated for a median of 55 days in 28-day courses of once-daily oral administration, he said.
In Gajjar's phase I study, the one case of dose-limiting toxicity was a grade 3 elevation in the liver enzyme gamma-glutamyl transpeptidase.
This limited toxicity suggested that the drug truly is a targeted agent, without side effects beyond the expected pathways, said study discussant Richard Greg Gorlick, MD, of The Children's Hospital at Montefiore in New York City.
However, he cautioned that "given the rarity of pediatric tumors, restricting clinical trial eligibility to a particular histology or to tumors with a particular molecular profile" could make trials difficult, requiring cooperative group or international collaboration.

The study was funded by the Pediatric Brain Tumor Consortium, the National Institutes of Health, and the St. Jude Children's Research Hospital.
Gajjar reported no conflicts of interest. Coauthors reported conflicts of interest with Genentech and Curis.
Schuchter reported conflicts of interest with Pfizer. Gorlick provided no information on conflicts of interest.