Experts at Johns Hopkins have linked scientific
evidence spanning more than 30 years to suggest an
explanation for why testicular cancer patients like
seven-time Tour de France winner Lance Armstrong survive
far better than patients with other advanced cancers.
Their commentary in the July 26 issue of the
Journal of the American Medical Association reveals
how a simple factor — heat sensitivity — may
make testicular cancer cells more susceptible to standard
treatments, causing them to die off more readily. Heat may
offer a strategy against other malignancies as well, they
said.
"If we understand how heat may naturally help kill
testicular cancer cells, then perhaps we can make it happen
in other solid tumors," said Robert Getzenberg, professor
and director of urology research at Johns Hopkins. "More
than 80 percent of men with widespread testicular cancer
can achieve a cure. In other cancers, the cure rate is far
less."
Armstrong's tumor, like those of all primary
testicular cancer, began in the testes, which are a few
degrees cooler than the rest of the body to keep
heat-sensitive sperm safe. When his cancer cells spread
into warmer regions of the body, the Johns Hopkins
scientists believe, the temperature boost may have weakened
protein scaffolding within the cancer cell's nucleus,
making the nuclear DNA more vulnerable to chemotherapy and
radiation.
"Heat is at the center of many cellular changes," said
Donald Coffey, the Catherine Iola & J. Smith Michael
Distinguished Professor of
Urology,
Oncology,
Pathology and
Pharmacology and Molecular Sciences in the School of
Medicine. "It drives everything from reproduction to
fighting infection, and now we'd like to harness its power
to fight cancer." Scientists in the past have observed that
fevers accompanying infections sometimes improved the
outcome for some cancer patients, but until now, Coffey
said, "scientists haven't connected precisely how heat
affects the scaffolding and might be one of the reasons
treatment can cure tumors such as Lance Armstrong's."
Support for the theory came from an unrelated study by
researchers at the Robert Wood Johnson Medical School of
men with undescended testes, a fairly common birth defect
in which the genitals remain stuck in the pelvis instead of
descending into the scrotum. Without treatment, infertility
is common, and further examination of the men's sperm
showed that the sperm cells' nuclear protein scaffolding,
known technically as the nuclear matrix, was also wrecked.
The nuclear matrix, found in the nucleus of all cells, was
first discovered in the early 1980s by a team of Johns
Hopkins scientists, led by Coffey, and shown to be heat
sensitive by researchers at Washington University in St.
Louis.
Theodore DeWeese, professor and director of the
Department of Radiation
Oncology and Molecular Radiation Sciences at Johns
Hopkins, said, "The warmer region of the pelvis made the
nuclear matrix in the cells that make sperm unstable and
prone to death, and cancer cells already have unstable
nuclear matrices." DeWeese and his colleagues say it is
logical to think that "if we give a cancer cell more heat
to completely disrupt its matrix and then add toxic drugs
and radiation, the cancer cell may be so disabled that it
won't be able to replicate and will die."
Heat therapy — which has been applied for
thousands of years as a cure-all for ailments ranging from
back pain to arthritis — is already used in a handful
of cancer centers around the country. Although people flock
to hot baths and springs to immerse their entire body, the
Hopkins scientists say they believe that selectively
heating cancer cells may not only be more effective but
also may prevent matrix damage in normal tissues.
"Once we've devised the best way to deliver heat to
cancer cells, we will test the technique in animal models
to help define the right temperature and doses of chemo and
radiation therapy," DeWeese said.
To direct heat only to cancer cells, the researchers
are investigating the use of nanoparticles that have an
affinity for surface proteins carried by cancer cells. Once
the nanoparticle finds the correct "address" of the cancer
cell, it slips through the cell's surface and heats the
cell from the inside out after exposure to a magnetic
field.
The Johns Hopkins scientists believe that magnetic
nanoparticles, if injected through the bloodstream, may be
able to reach tumors throughout most of the body. And as
long as the nanoparticles penetrate most of the cells in
the tumor, the temperature increase will spread to the
entire mass.
On a parallel track, the Johns Hopkins group is
looking at other temperature targets for heat's
cancer-fighting properties that may work in tandem with the
nuclear matrix. For example, they are looking at blocking
proteins whose primary role is to act as fire blankets to
coat the nuclear matrix and preserve it from heat damage.
These so-called "heat shock proteins" also have a second
role as "chaperones" to other proteins, ensuring their
proper interaction and shape, and, depending on these
interactions, they may play a role in cancer-cell death.
Preliminary research is under way at Johns Hopkins to
refine heat delivery systems and test them in prostate
cancer animal models.
This commentary was supported by the David Koch Funds,
which were provided by the Prostate Cancer Foundation.