After a series of laboratory and animal experiments, Johns Hopkins scientists show that a drug which shuts down a critical cell-signaling pathway in the most common and aggressive type of adult brain cancer successfully kills cancer stem cells thought to fuel tumor growth and help cancers evade drug and radiation therapy.
“Our study lends evidence to the idea that the lack of effective therapies for glioblastoma may be due to the survival of a rare population of cancer stem cells that appear immune to conventional radiation and chemotherapy,” says Charles G. Eberhart, M.D., Ph.D., associate professor of pathology, ophthalmology and oncology, who led the work. “Hedgehog inhibition kills these cancer stem cells and prevents cancer from growing and may thus develop into the first stem cell-directed therapy for glioblastoma.”
In the study they blocked the signaling system, known as Hedgehog, with an experimental compound called cyclopamine to explore the blockade’s effect on cancer stem cells that populate glioblastoma multiforme. Cyclopamine has long been known to inhibit Hedgehog signaling.
The Hedgehog gene, first studied in fruit flies, got its name because during embryonic development, the mutated version causes flies to resemble a spiky hedgehog. The pathway plays a major role in controlling normal fetal and postnatal development, and, later in life, helping normal adult stem cells function and proliferate.
Other researchers have shown that radiotherapy fails to kill all cancer stem cells in glioblastomas, apparently because many of these cells can repair the DNA damage inflicted by radiation. The Hopkins team suggests that blocking the Hedgehog pathway with cyclopamine kills these radiation-resistant cancer stem cells.
“This is an incredibly difficult tumor to treat,” says first author Eli E. Bar, Ph.D., a postdoctoral fellow. “Survival for glioblastoma has not changed much in 30 years. With the addition of temozolomide, survival got bumped from 12 months to 14 or 15 months.”