Compound Derived from Corn Lilies Kills Brain Tumor Stem Cells

Cyclopamine has long been known to inhibit Hedgehog signaling.

The investigators reported their findings in the journal Stem Cells, published online on July 19, 2007. "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,” commented Charles G. Eberhart, M.D., Ph.D., associate professor of pathology, ophthalmology, and oncology, who led the investigation. "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.”

Dr. Eberhart cautioned that while his study appears to prove the principle of Hedgehog blocking, more research remains before cyclopamine or any similar drug can be evaluated in patients. Scientists still have to determine whether the drug can be effectively and safely delivered to the whole body or whether it must go just into the brain, and what if any adverse impact on normal stem cells the treatment might cause. "Once you've answered those questions in animals, the next step would be starting phase I clinical trials in humans,” Dr. Eberhart said.

The new study adds to the growing evidence that only a small percentage of cancer cells, in this case stem cells, are capable of unlimited self-renewal and that these cells alone power a tumor's growth. Dr. Eberhart focused on two pathways critical to the survival of normal brain stem cells--Hedgehog and Notch--suspecting that brain cancer stem cells cannot live without them.

The Hedgehog gene, first examined in fruit flies, got its name because during embryonic development, the mutated version causes flies to resemble a spiky hedgehog. The pathway plays a key role in controlling normal fetal and postnatal development, and later in life, helping normal adult stem cells function and proliferate.

The Johns Hopkins scientists first assessed 19 human glioblastomas removed during surgery and frozen immediately, and found Hedgehog active in five at the time of tumor removal. They also found Hedgehog activity in four of seven glioblastoma cell lines.

Next, the researchers used cyclopamine, chemically extracted from corn lilies that grow in the Rocky Mountains in the United states, to suppress Hedgehog in cells lines growing on plastic or as neurospheres, round clusters of stems cells that float in liquid nutrients. This reduced tumor growth in the cell-laden plastic by 40-60%, and caused the neurospheres to degrade without any new growth of the cell clusters.

The researchers also pretreated mice with cyclopamine before injecting human glioblastoma cells into their brains, resulting in cancer cells that failed to form tumors in the mice. Other researchers have shown that radiotherapy cannot destroy all cancer stem cells in glioblastomas, evidently because many of these cells can repair the DNA damage inflicted by radiation. The Hopkins researchers suggest that blocking the Hedgehog pathway with cyclopamine kills these radiation-resistant cancer stem cells.

In earlier laboratory studies, Dr. Eberhart used cyclopamine to block Hedgehog using medulloblastoma cells, the most common brain cancer occurring in children. In addition to childhood brain cancers, cyclopamine has shown early potential in treating skin cancer; rhabdomyosarcoma, a muscle tumor; and multiple myeloma, a cancer of the white blood cells in bone marrow. "What excites me is that we have taken things we learned about Hedgehog signaling in these relatively rare childhood brain tumors and translated them into an even more aggressive adult tumor,” Dr. Eberhart said.

More than 10,000 individuals die every year from glioblastomas in the United States alone. Radiation is the standard therapy for the disease, and several years ago, the U.S. Food and Drug Administration (FDA) approved adding the drug temozolomide to radiotherapy because the combination provided a small survival increase.

"This is an incredibly difficult tumor to treat,” noted 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.”


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