How Sonic the Hedgehog became a cancer fighter

You’ve probably heard of the sonic hedgehog signaling pathway. You’ve probably also heard of Sonic the Hedgehog, the video game character. But which came first? And how, if at all, are they related?

Sonic hedgehog (lower case “h”) is a gene involved in the signaling pathway of the development of mammals very early in life. The hedgehog signaling pathway has critical functions in embryo development, particularly in the formation of limbs and nervous system cells.

The hedgehog gene was first identified in the fruit fly (Drosophila melanogaster) and reported in 1980. It was given the name “hedgehog” because a mutant version of the gene caused the fruit fly embryo to be covered in pointy spikes, which resemble a hedgehog’s spines. This discovery was a major breakthrough (and a big part of the research that won the investigators a 1995 Nobel Prize in Medicine) because it described for the first time how genes regulate the embryonic development of anatomic structures.

So, where does Sonic the Hedgehog come in? We’re just getting to that.

In the wake of this Nobel-winning research in the fruit fly, other investigators hoped to find the equivalent gene in the embryogenesis of vertebrates. Research teams at Harvard Medical School, Boston, MA, and the Imperial Cancer Research Fund, London, UK, reported in a series of papers in 1993 that they had isolated three types of hedgehog genes in mice.

The researchers named two of the genes for actual species of hedgehog: the desert hedgehog and the Indian hedgehog. The third was named for—you guessed it—the speedy blue video game character.

Robert D. Riddle, PhD, a postdoctoral fellow working in the lab of genetics professor Clifford J. Tabin, PhD, at Harvard Medical School, isolated the third gene. Dr. Riddle didn't like any of the suggested names of hedgehog species, he told the Harvard Crimsonnewspaper. He went home, randomly picked up a magazine, and opened to an ad for Sonic Hedgehog 2, the SEGA Genesis video game.

“It seemed divinely inspired that I should call it that,” Dr. Riddle said.

The other researchers at Harvard and the Imperial Cancer Research Fund weren’t too pleased with the name, but it stuck.

So, how did Sonic go from fighting Dr. Robotnik to combatting cancer?

It turns out that that embryogenesis and tumorigenesis have a lot in common. Signaling pathways for embryonic development and organogenesis become altered in tumorigenesis. Indeed, aberrant activation of hedgehog signaling is linked to tumor formation. Small-cell lung carcinoma, basal cell carcinoma, medulloblastoma, glioblastoma, as well as breast, liver, colon, pancreatic, and prostate cancers have all been shown to use the sonic hedgehog pathway. These cancers comprise approximately 35% to 40% of all cancer deaths in the United States, according to the International Agency for Research on Cancer and the World Health Organization.

In addition, sonic hedgehog signaling appears to play a pivotal role in preserving cancer-initiating stem cells, which are believed to resist chemotherapy.

Consequently, the sonic hedgehog signaling pathway is a therapeutic target for numerous cancers. In 2012, the US Food and Drug Administration approved the first hedgehog pathway inhibitor, vismodegib, for the treatment of basal cell carcinoma. More recently, a drug currently approved for treating fungal infections, itraconazole, is now being investigated as an inhibitor of hedgehog signaling in prostate cancer and basal cell carcinoma, and as an enhancement to chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic, and biliary tract cancers.

That’s pretty good work for an electronic creature whose usual job is to collect power rings and use spin attacks against his pixelated enemies.