Is ‘Sonic hedgehog’ a cancer culprit?

Scientists suspect that an important regulatory mechanism that controls normal growth during embryonic development of the prostate gland can become the culprit in prostate cancer later in life.

Wade Bushman, a professor of urology at the UW Medical School, says signaling in the gene known as Sonic hedgehog appears to accelerate the growth of some cancers that arise in tissues where the pathway is active during fetal development. The gene was first identified as a critically important control element in the development and organization of key organs such as the brain, pancreas, lung, and prostate.

“Once human development is complete, hedgehog genes are normally turned off,” Bushman says. “But in the prostate, hedgehog signaling continues into adulthood.”

Bushman’s laboratory was the first in the country to study hedgehog signaling in the prostate gland and show that it played a role in normal prostate development. Bushman also has collaborated with Curis Inc., a biotechnology company that is developing agents to inhibit hedgehog signaling and suppress tumor growth.

In work published this summer in the journal Endocrinology, Bushman and his colleagues described how activation of hedgehog signaling in a mouse model of prostate cancer increased tumor growth. Complementary studies were subsequently published by two other research teams, including one that showed that blocking the hedgehog pathway slowed and often reversed prostate tumor growth in mice.

Cancer is an unusual field for Bushman, whose urological specialty is bladder problems and incontinence. “I started studying hedgehog signaling in the prostate because I was interested in understanding why the prostate enlarges in aging men,” Bushman says. “I never intended to study cancer.”

His outlook changed, however, when a member of his family got leukemia. Suddenly, his relative’s life was depending on leukemia research, and he began to appreciate firsthand the impact of research on cancer therapy. “That’s when we started doing our preliminary work in cancer — to see if Sonic hedgehog might show the way to newer, more effective treatment for prostate cancer,” Bushman says.

In fact, Bushman’s work could lead to a significant therapeutic breakthrough. Using an inhibitor to shut down the hedgehog pathway could potentially slow tumor growth, offering a significant advantage to patients who develop prostate cancer at advanced age.

“The great advantage is that you can use an inhibitor for a pathway that is not active in most adult tissues,” Bushman explains. “The result would be effective treatment without the toxic side effects of standard chemotherapy or radiation.”

If this potential is realized, doctors might greatly improve the prognosis for patients with advanced prostate cancer that is not curable by either surgery or radiation. Bushman notes that much work remains to be done before treatments become available. Still, he expects development will lead eventually to improved treatment.

Bushman’s work is supported by the National Institutes of Health, the National Cancer Institute and the Department of Defense Prostate Cancer Program. n