Repurposing a Skin Medication to Fight Glioma

Title: Pre-Clinical Studies Investigating the Use of Isotretinoin (CRA, ITR) for the Treatment of IDH1 Mutant Glioma Patients
Investigators: Albert Lai, Linda Liau
Grantee: University of California

Serendipity in science occurs when we recast something familiar in a whole new light.  Accutane, an FDA-approved skin medication, underwent just this sort of recasting in the early 1990s when scientists began thinking about it as a potential brain cancer therapy.  This was because the active ingredient in Accutane was found to be related to a molecule that seems to affect the growth rate and characteristics of a variety of cancer cell types, at least in a laboratory setting. When Accutane failed to prolong patient survival in clinical trials, however, the drug dropped off the brain cancer radar for nearly twenty years – until new genetic technology pulled it back into the spotlight.

This new genetic technology identifies the mutations that make individual brain tumors unique.  As such, it can reveal genetic trends in old clinical trial data that were undetectable at the time of the trials themselves.  University of California Los Angeles scientists searching for such trends in an older Accutane trial noticed something interesting: for patients whose brain tumors had mutations in a specific gene called IDH1, Accutane did seem to prolong survival.  In fact, patients with IDH1-mutant tumors who received Accutane lived twice as long as those who didn’t.  There weren’t many of these patients in the old trial, though, so Accutane’s beneficial effect hadn’t shown up in the trial’s original analyses.

Given this new observation, the scientists wondered if Accutane might actually slow brain cancer – but only for patients with IDH1-mutant tumors.  Accutane’s actions in the body support this idea: it works as a skin medication by altering specific chemical signals, and these very same chemical signals go awry in IDH1-mutant tumors.

Because IDH1 mutations occur in the vast majority of low-grade gliomas, identifying a drug – especially one already approved for safe human use – targeting these tumors would be a valuable discovery.  To test this exciting possibility, ABC2 funded a two-part project at UCLA to determine whether Accutane slows IDH1-mutant brain cancer.  The first part of this project examined how Accutane-driven chemical signals affect the growth of gliomas cultivated in the laboratory.  The second part used patient tumor samples and survival data from a much broader range of previous clinical trials to assess Accutane’s effect in a large patient population.

Unfortunately, serendipity can be a fickle creature.  Although the UCLA scientists discovered interesting relationships between glioma tumor growth and Accutane-driven chemical signals in the first part of the project, the large-scale analysis in the second part failed to reveal a benefit of Accutane treatment for patients with IDH1-mutant glioma.  This work has once again put Accutane on the back burner as a potential brain cancer therapy.  Perhaps, though, it will re-emerge as we continue to learn more about the molecular basis of cancer.