By Duke Medicine News and Communications
DURHAM, N.C. – Because of the way solid tumors adapt the
body's machinery to bring themselves more oxygen, chemotherapy
and radiation may actually make these tumors stronger.
"In a sense, these therapies can make the tumor healthier,"
said Mark W. Dewhirst, D.V.M., Ph.D., professor of radiation
oncology at Duke University Medical Center. "Unless the
treatment is very effective in killing many if not most tumor
cells, you are shooting yourself in the foot."
Dewhirst and colleagues Yiting Cao, M.D., Ph.D., of Duke
Pathology, and Benjamin Moeller, M.D., Ph.D. have introduced
this counter-intuitive idea at recent conferences and in a
review article featured in the June issue of Nature Reviews
Cancer.
Radiation and chemotherapy do kill most solid tumor cells,
but in the cells that survive, the therapies drive an increase
in a regulatory factor called HIF1 (hypoxia-inducible factor
1), which cells use to get the oxygen they need by increasing
blood vessel growth into the tumor. Solid tumors generally have
low supplies of oxygen, Dewhirst explained and HIF1 helps them
get the oxygen they need.
The review article concludes that blocking (HIF1) would
provide a clear mechanism for killing solid-tumor cells,
particularly cells that are proving resistant to radiation or
chemotherapy treatments.
As a part of this work, Dewhirst's team has been studying
the phenomenon of rising and falling oxygen levels in tumors,
called cycling hypoxia. Oxygen levels have been found to
naturally cycle up and down in individual blood vessels as well
as large tumor regions. This instability in the tumor's oxygen
levels can increase HIF-1 production and cause radiation
therapy to fail, Dewhirst said.
"It is my opinion that the whole tumor grows more
aggressively because of this pulsation of oxygen at low
levels," Dewhirst said. "Most people thought cycling hypoxia
was caused by temporary stoppage of blood flow in single blood
vessel in tumors. In fact, however, oxygen levels cycle up and
down virtually everywhere in the tumor, which is caused by
fluctuations in blood flow rate. It has been a challenge to
convince people of this."
Dewhirst and
colleagues have made movies of oxygen transport in a tumor
of a living animal that show the oxygen levels cycle up and
down significantly, pulsing in waves seen as color changes in
the movies.
The Duke team argues that blocking HIF1 is the consistent
answer to tumor growth problems. Blocking HIF1 activity
interferes with the tumor's ability to undergo glycolysis
(energy production) in low-oxygen conditions, which blocks
tumor growth, the authors wrote. Exactly how to accomplish
chemotherapy or radiation treatment in the safest, most
effective ways, in combination with HIF1 blockade, is still
open for exploration, Dewhirst said.
For example, targeting HIF1 in the early stages of tumor
growth, especially in very early cancer spread, may help,
Dewhirst said. "For a woman who has had a primary breast tumor
removed, and who is at high risk for cancer spread, this might
be a situation in which you'd target HIF1," he explained.
"Blocking HIF1 makes sense during the early stages of
angiogenesis, which is the accelerated phase of blood vessel
formation. In this way, you could keep the early metastasis
sites inactive and prevent them from growing."
The Duke team has completed a phase I trial with a HIF1
inhibitor. "We are actively pursuing this clinically and will
be moving this study into Phase 2," Dewhirst said. "We are
interested in other applications of HIF-1 inhibition in
combination with radiation and chemotherapy for different
diseases."
View the Dewhirst team movie at:
http://www.youtube.com/watch?v=AJDqtuX4LBw
