- A chemical isolated from a weed that grows in mountain
meadows in the western United States kills the cells of an aggressive brain
cancer that affects some children. The compound, cyclopamine, blocks a
signaling pathway that appears to be important for the survival of medulloblastoma,
a form of cancer for which there is no effective treatment. In an article
published in the August 30, 2002, issue of the journal Science, a research
team led by Howard Hughes Medical Institute investigator Philip A. Beachy
reported that cyclopamine effectively killed cultured mouse medulloblastoma
cells and tumors implanted in animals, as well as medulloblastoma cells
extracted from human tumors.
-
- "It will be difficult to obtain sufficient quantities
of cyclopamine, since it must be extracted and purified from the plant
source, Veratrum californicum, the corn lily," said Beachy, who is
at The Johns Hopkins University School of Medicine. "However, we believe
that with this study, the evidence is in place to justify an effort to
develop a supply so that it can be tested in humans." Beachy and his
colleagues at Johns Hopkins collaborated with researchers from the Fred
Hutchinson Cancer Research Center and the University of Washington/Children's
Hospital in Seattle.
-
- Beachy said there are some parallels between cyclopamine
and taxol, a drug used to treat breast cancer drug that was initially in
short supply because it had to be isolated from the bark of the Pacific
yew tree. However, as taxol proved clinically effective, researchers developed
an alternate method of partial synthesis of the compound from a more plentiful
precursor in the needles that made the drug available in sufficient supply.
-
- Beachy and his colleagues began to explore whether cyclopamine
would be effective against medulloblastoma after studies by several groups,
including HHMI investigator Matthew Scott and his colleagues at Stanford
University, showed that both animals and humans developed tumors, including
medulloblastomas, when the Hedgehog signaling pathway was activated. The
pathway -- named for its key regulatory protein Hedgehog -- has long been
known to be critical for the growth and differentiation of cells during
embryonic development. Scott and his colleagues showed that the tumors
they studied consisted of cells that had most likely reverted to a highly
proliferative embryonic state, due to a mutation that enabled the activation
of the Hedgehog pathway.
-
- The earlier studies showed that the Hedgehog pathway
was switched on when the function of one of the pathway's key genes, called
Patched, was lost because of mutation. The protein produced by Patched
normally represses a downstream member of the Hedgehog pathway -- a protein
called Smoothened. Loss of Patched activates the Smoothened protein, turning
on the Hedgehog pathway and leading to malignancy.
-
- Beachy and his colleagues had shown previously that cyclopamine
blocks the Hedgehog pathway in mouse embryos by inhibiting the activity
of Smoothened. Reasoning that the drug might also prevent activation of
the Hedgehog pathway in tumors, the scientists tested cyclopamine's effects
on a mouse model developed in Scott's laboratory, in which one copy of
the Patched gene had been disrupted. In these mice, Beachy and his colleagues
also removed the gene for p53, a protein that normally triggers the death
of cells with damaging mutations. The mice developed medulloblastomas at
a young age when expression of the second normal Patched gene was inactivated.
-
- The researchers cultured medulloblastoma cells from the
mice and introduced those tumor cells into other mice that had compromised
immune systems. "We showed that in these tumor cells we could readily
suppress the Hedgehog pathway by treating the tumors with cyclopamine,"
said Beachy. "We next decided to see whether the drug would affect
tumors that had already been established in mice by injecting the tumor
cells. We were pleased to see that cyclopamine could not only block the
Hedgehog pathway, but could also stop the growth of these tumors and even
cause them to regress," he said.
-
- The next logical step, said Beachy, was to determine
whether cyclopamine was effective in human medulloblastomas. For these
studies, co-author James Olson and colleagues at the Fred Hutchinson Cancer
Research Center supplied medulloblastoma cells from patients who had undergone
surgery to remove the tumors.
-
- "When we treated dispersed cells from these tumors
with cyclopamine, they died very quickly, and in fact, the drug appeared
to be killing the cells faster than any drug Jim Olson and his colleagues
had yet tested," said Beachy. Also promising, said Beachy, was that
in the animal studies, the drug produced no discernible side effects. "Of
course, we can't be sure that there are no side effects at this point,
since we can't ask a mouse how it's feeling," said Beachy. "But
we saw no obvious adverse effects from the treatment."
-
- One promising result from the studies of human tumor
cells, said Beachy, was that all seven of the human medulloblastomas the
scientists tested responded dramatically to cyclopamine. "Genetic
studies have shown that only perhaps twenty percent of such sporadic tumors
can be assigned to mutations that specifically activate the Hedgehog pathway,"
he said. "So, this finding suggests that perhaps activation of the
Hedgehog pathway is essential to tumorigenesis, even when it is not specifically
switched on by mutation."
-
- Although Beachy advocates immediate pre-clinical and
clinical trials of cyclopamine for medulloblastoma, he cautioned that supply
is a critical problem. "Right now, cyclopamine must be purified from
the corn lily, and it is unclear how much could be harvested or cultivated,"
said Beachy. "Synthesizing cyclopamine might be possible, but it would
be very difficult."
-
- Editor's Note: The original
news release can be found at
-
- http://www.hhmi.org/news/beachy2.html
-
- Note: This story has been
adapted from a news release issued by Howard Hughes Medical Institute for
journalists and other members of the public. If you wish to quote from
any part of this story, please credit Howard Hughes Medical Institute as
the original source. You may also wish to include the following link in
any citation:
-
- http://www.sciencedaily.com/releases/2002/08/020830071617.htm
|