Existing cancer therapies are geared toward massacring tumor
cells, but Johns Hopkins researchers propose a different strategy: subtly
hardening cancer cells to prevent them from invading new areas of the body.
They devised a way of screening compounds for the desired
effect and have identified a compound that shows promise in fighting pancreatic
cancer. Their study appears this week in the early edition of the Proceedings
of the National Academy of Sciences.
"This is a novel approach to cancer therapy that we believe
could fight the disease with less potential for side effects and drug
resistance than many current drugs," says Douglas Robinson, Ph.D., a professor
of cell biology in the Institute for Basic Biomedical Sciences at Johns Hopkins
University School of Medicine. "We think the new screening system we devised
will help identify drugs for many other diseases, as well."
The roots of the project go back to 1997, when Robinson,
then a postdoctoral fellow, says he first had the idea that better
understanding how a cell divides into two would shed light on how cells change
shape in general.
Since changes in cell shape figure into conditions from
cancer to chronic obstructive pulmonary disease to degenerative nerve diseases,
compounds that affect cells shape could turn out to stall disease progress.
In 2008 Alexandra Surcel, Ph.D., lead author of this study,
joined Robinson's laboratory as a postdoctoral fellow and began working on a
screen for molecules that tweak cell shape.
Most drug screens look for an effect on a specific
biochemical "pathway" that has been linked to disease; by contrast, Surcel
explains, this screen is based on the end result for a whole cellin this case,
the amoeba Dictyostelium, which closely resembles a number of mammalian cell
types. After treating the cells with a molecule, Robinson's team looked for
out-of-the-ordinary numbers of cells with two or more nuclei.
Since Dictyostelium normally have two nuclei only when they
are in the process of dividing into two daughter cells, a high proportion of
cells with more than one nucleus would indicate that the molecule had thrown a
wrench in the process of cell division, likely by tweaking the mechanics of the
A screen of thousands of molecules turned up 25 with the
effect the team was looking for. Further studies revealed that one of them,
4-HAP, affected myosin II, a building block of the cell skeleton. In
collaboration with another Johns Hopkins lab, led by Robert Anders, M.D.,
Ph.D., an associate professor of pathology, Robinson's group identified changes
in the amount of myosin II in pancreatic cancer cells as they spread from the
original tumor into other areas of the body, a crucial step in progression of
The research team tested 4-HAP on lab-grown pancreatic
cancer cells and found that it affected the myosin in their skeletons in a way
that made them harder. "We think that being relatively soft lets invading
cancer cells slip through the body and colonize new areas," Surcel says. "You
can envision an octopus having a much easier time getting through a small
opening than would a lobster. 4-HAP seems to make the cancer cells more like
The team is now testing 4-HAP in mice. The drug is already
in use in some countries as a treatment for jaundice, so if it shows success
against pancreatic cancer, it could potentially make it to market relatively
quickly, Robinson says. But even if that doesn't happen, the study demonstrates
that the new drug screen has great potential, he says.
Other authors on the paper are Win Pin Ng, Hoku West-Foyle,
Qingfeng Zhu, Yixin Ren, Lindsay B. Avery, David J. Meyers and Caren L. Freel
Meyers of The Johns Hopkins University, and Ronald S. Rock and Agata K. Krenc
of the University of Chicago.
The study was funded by the National Institute of General
Medical Sciences (grant number GM66817), the National Institute of Allergy and
Infectious Diseases (grant number AI099704), the National Cancer Institute
(grant number T32 CA009243), and the Sol Goldman Pancreatic Cancer Center.