By Arthur Hirsch,
The Baltimore Sun
6:16 p.m. EDT, September 6, 2014
A white powdered
chemical compound emerged from two University of Maryland School of Medicine
laboratories more than 10 years ago with a name destined for oblivion, but a
future that now looks promising as a treatment for the most challenging cases
of prostate cancer.
Today, VN/124-1 is a
drug candidate with a name — galeterone — a pharmaceutical company founded on
its potential and a record of strong preliminary results in clinical trials
with human patients.
The Food and Drug
Administration has put galeterone on a fast track for approval
to treat prostate cancer, which kills about 30,000 men a year in the United
States. Researchers in hospitals and clinics across the country and in Canada
are finishing the trial's second round and preparing for the third, expected to
begin early next year.
Dr. Kevin J. Cullen,
director of the University of Maryland's Marlene and Stewart Greenebaum Cancer
Center, acknowledged that results are preliminary, but he said it's an
auspicious beginning.
"I can think of
maybe one other drug in the 30 years I've been doing oncology that showed these
kind of results," Cullen said. He called it an "incredibly promising
start for this medicine."
Dr. Mario Eisenberger,
heading the clinical trial at the Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins, said the drug has had impressive results, but "I don't
think anyone can say at this point in time whether galeterone is going to be
better than the other" drugs already used to treat prostate cancer.
Before galeterone was
a medicine, it was a compound born of a collaboration that began in 1996
between two University of Maryland researchers, Angela M. H. Brodie and Vincent
C.O. Njar.
The approach was built
on work for which Brodie has won some of the most prestigious awards in the
field — research not in prostate but breast cancer.
In the last 10 years, she won the Charles F. Kettering Prize and the Dorothy P.
Landon-AACR Prize for Translational Cancer Research for her work in the 1970s
and 1980s helping to develop compounds that block production of estrogen, the
female hormone, that fuels the growth of most breast cancers.
More recently, she's
turned her attention to prostate cancer, which feeds on the male hormone. She
wondered if the approach that worked with estrogen would work with the
androgens, or hormones, that fuel prostate cancer: testosterone and the more
potent dihydrotestosterone.
Up to now, one main
treatment for the most challenging prostate cancers has been shutting down
androgen production from the testicles. The procedure, referred to as
castration, is most commonly done today by medication not surgery. The
testicles produce about 90 percent of the body's androgen. Most of the rest is
produced by the adrenal glands, and a small measure from the prostate tumor
itself.
Njar and Brodie were
looking for a way to fight prostate cancer that continutes after castration.
Their approach is one
in a succession of hormone-based treatments that have been used for years, but
it's different in combining several effects at once. This one works in three
ways to interfere with androgen's effect on prostate cells.
The medication
decreases androgen production and interferes with the process by which the
substance binds to the prostate cell molecule that responds to the hormone,
known as the receptor. These effects have been produced before, but galeterone
is the only medication that also appears to damage the receptor itself.
The triple threat
showed impressive results in tests with mice about 10 years ago. Brodie and
Njar and their research team published results in the Journal of Medicinal
Chemistry in 2005, concluding that the compound "is a potent inhibitor of
human prostate tumor growth and is remarkably more effective than
castration."
After that
publication, Tokai Pharmaceuticals, a company in Cambridge, Massachusetts,
named and licensed the compound as "galeterone." Clinical trials with
human patients started in November 2009.
To fund its
anticipated growth, Tokai applied in August to sell $75 million of stock in an
initial public offering. While its stock sale is pending, company officials are
not available for comment.
According to information
posted on Tokai's website, researchers have given the drug to 200 patients in
the first two trial phases.
Of the 49 patients in
the first trial, 24 showed 30-percent reduction in prostate specific antigen,
or PSA, and 11 showed a 50-percent cut. Elevated levels of PSA can be, but are
not necessarily, a marker for prostate cancer.
In the second phase,
51 patients — both with and without metastasis, or cancer spread beyond the
prostate — followed for 12 weeks also showed significant PSA reductions. Of
this group, 82 percent to 85 percent experienced reductions of about a third,
three-quarters saw a reduction by at least half.
Cullen said he was
struck by the results even in the first phase, conducted less for effects on
the cancer than to see how well patients can tolerate the medication at low
doses. With such low doses in the first phase of a clinical trial, results like
that are "almost unprecedented," he said.
In the third phase of
the trial, galeterone will be compared to existing treatments, Brodie and Njar
said, and could take up to another year.
The FDA "fast
track" can in some cases cut years off the time it takes to bring a drug
to market, Eisenberger said.
Galeterone causes none
of the adverse effects associated with chemotherapy, including nausea and hair
loss. So far, Brodie said, the chief side effect could be deficiency of
cortisol, but that has not been a problem so far. The hormone plays a role in
regulating blood sugar, suppressing immune response and metabolizing fat,
protein and carbohydrates.
Eisenberger said the
effects can include fatigue and itching, but nothing requiring cortisol
treatment.
Brodie and Njar are
making no bold pronouncements at this point, just eagerly awaiting further
results.
"We are
cautiously optimistic," Njar said.
"It's a wonderful
thing if we can save lives," Brodie said.
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