Source:      Cornell University
Date Posted:2005-03-26
Web Address:
http://www.sciencedaily.com/releases/2005/03/050325161409.htm

FIRST-EVER COMPOUNDS TO TARGET ONLY METASTATIC CELLS ARE HIGHLY
EFFECTIVE AGAINST BREAST, PROSTATE, AND COLON CANCERS

NEW YORK (March 16, 2005) -- Two compounds that zero in on cancer
cells spreading throughout the body, while ignoring primary tumor
cells, could someday give doctors a whole new weapon in the fight
against tough-to-treat metastatic disease, according to Weill Medical
College of Cornell University researchers.

The compounds, called synthetic migrastatin analogues, prevented 91 to
99 percent of metastatic breast cancer cells in mice, and are the
first to target only metastatic cells.

"They're unbelievably effective, and in vitro study suggests they'll
work just as well at inhibiting the migration of prostate and colon
cancer cells", said senior researcher Dr. Xin-Yun Huang, Professor
of Physiology and Biophysics at Weill Cornell Medical College in New
York City.

The findings have just been published in Proceedings of the National
Academy of Sciences.

For decades, doctors have fought cancer by using surgery,
chemotherapy, or radiation to excise or shrink the primary tumor.

"However, in too many cases it's simply impossible to completely
remove the tumor", Dr. Huang explained. "So recently the idea
of targeting cell migration -- metastasis -- has become an alternative
strategy that's gained a lot of interest among researchers".

If compounds could be found that slowed or halted cancer spread,
doctors could gain valuable time in shrinking the primary tumor.
"If we had the luxury of time, we could treat that primary tumor at
lower doses, too, with fewer side effects for the patient", Dr. Huang
said.

Until now, agents that specifically target metastatic cells have
remained elusive. However, a new avenue of research opened up when Dr.
Huang's team noticed that the Streptomyces bacterium -- the bug that
gives us the antibiotic streptomycin -- also produces a natural
compound called migrastatin, which appears to inhibit cell migration.

Natural migrastatin's effect is relatively weak, but Dr. Huang
suspected the molecule might be manipulated into something more
potent. In collaboration with the laboratory of Dr. Samuel Danishefsky
at the Memorial Sloan-Kettering Cancer Center, the team went to work
creating what's called a "synthetic analogue".

"Starting with the basic migrastatin molecule, we cut a piece there,
add a piece here", he explained, "and what we ended up with
were two compounds -- core macroketone and core macrolactam -- that
are about 1,000 times more powerful at inhibiting cancer cell
migration".

In fact, in a mouse model, the analogues were between 91 to 99 percent
effective in stopping the spread of breast cancer cells, the
researchers report. Cell culture studies suggest they can reproduce
that success in  a wide range of other cancers, too.

"What's unique about these analogues is that they do all this
without affecting primary tumor cells, or their blood supply", Dr.
Huang said. "To our knowledge, that's a real first".

Exact mechanisms remain unclear.

"Obviously, these compounds are targeting some step in the
cell-migration process", Dr. Huang said. The activity of a
migration-linked protein called Rac appears to be much reduced in
cancer cells affected by the analogues, and the researchers also
noticed that malignant cells failed to grow tiny "antennas", called
lamellipodia, another crucial step in the migration process.

"Therefore, the migrastatin analogues must be working on something
upstream of those two important steps", Dr. Huang said.

Dr. Huang's next important step is moving these analogues into
clinical trials.

"We're trying right now to get a company interested in this,
especially because the mice used in our trial seemed to experience
minimal toxicity -- a good sign that patients might tolerate these
compounds, too", Dr. Huang said.

"It's all very exciting",he said. "Metastatic disease is
such a tough problem, and these compounds could provide patients with
a brand new kind of hope".

The research was funded by grants from the National Institutes of
Health.

Co-researchers included Ms. Dandan Shan (first author), Mr. Lin Chen,
and Dr. Xiaojing Ma, of Weill Cornell Medical College; and Dr. Jon T.
Njardarson, Dr. Christoph Gaul, and Dr. Samuel Danishefsky, of
Memorial Sloan-Kettering Cancer Center, New York.
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