Compounds Targeting Only Metastatic Cells Effective
Against Breast, Prostate, and Colon Cancers
Two compounds that
zero in on cancer cells spreading throughout the body, while
ignoring primary tumor cells, could some day 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.
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—“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.”#
