A gene associated with breast cancer also may play a major role in the
recurrence of prostate cancer, according to new research from the University
of North Carolina at Chapel Hill School of Medicine and UNC Lineberger
Comprehensive Cancer Center.
The most common cancer in men, prostate cancer can be effectively treated
with surgery or radiation when detected early. But advanced prostate cancer
is usually treated by drugs or surgery aimed at reducing the level of
testosterone and other male hormones, or androgens, that stimulate cancer
cell growth. While the disease usually regresses after such treatment,
prostate cancer invariably comes back, although it's not clear why it recurs
and progresses.
The UNC study, published in the journal Cancer Research, indicates
that the gene HER-2 is a key culprit in prostate cancer recurrence. The
findings also suggest a new treatment strategy for targeting HER-2 in
patients with advanced prostate cancer.
HER-2 refers to human epidermal growth factor receptor 2. The gene helps
control how cells grow, divide and repair themselves, and directs the
production of a special protein called HER-2 tyrosine kinase. This protein
acts as receptors on the cell membrane, and when activated by external
hormones, it promotes cell growth and division.
In about one in four breast cancers, a genetic mutation creates too many
HER-2 receptors. This helps spur rapid cancer cell growth. While treatment
with the antibody drug Herceptin can be effective in slowing breast cancer
growth, this is not the case in prostate cancer, researchers said.
"The treatment with the antibody has been a uniform failure in prostate
cancer because the gene is not over-expressed in this disease. We need a
different approach to attack HER-2 in prostate cancer," said the study's
senior author, Dr. Young Whang. He is an assistant professor of medicine and
medical oncologist at UNC and a member of UNC Lineberger.
"We believe that the driving force for recurrence of prostate cancer is the
reactivation of the androgen receptor, which normally requires the presence
of androgen, and this reactivation of the androgen receptor underlies tumor
progression of prostate cancer despite hormonal therapy. Exactly how this
occurs, we're not sure, but our hypothesis is that activation of HER-2
tyrosine kinase leads to activation of the androgen receptor."
In testing their hypothesis, Whang and his co-authors inhibited HER-2
activity in two laboratory experiments involving human cancer cells. In the
first, they used an artificial antibody to HER-2 delivered directly into the
cells via a modified virus. In the second, they used an experimental drug
that specifically inhibits HER-2 tyrosine kinase activity. The oral drug
lapatinib (GlaxoSmithKline) is currently in an advanced clinical trial
involving patients whose breast cancer is driven by HER-2.
In both experiments, tyrosine kinase activity and androgen receptor function
were largely derailed.
"We discovered that inhibition of HER-2 strongly inhibits proliferation of
prostate cancer cells and the function of androgen receptor," Whang said.
To properly carry out its function, the androgen receptor protein binds
specifically to the regulatory DNA sequence of the genes regulated by
androgens such as testosterone, he said. "And we have shown that inhibition
of HER-2 impairs the androgen receptor function at this step of binding to
the DNA sequence of critical genes such as prostate specific antigen."
The implication of this work, he added, is that HER-2 is important and
necessary for prostate cancer viability and progression.
"This provides the rationale for initiating a clinical trial of this novel
drug inhibiting HER-2, which is being planned for patients within several
months," Whang said. "I envision this drug becoming one of several that
could be used in combination with other specifically targeted drugs to
prolong the lives of prostate cancer patients."
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