Dr. Whang Comments:
This is an exciting discovery. We have been struggling with patients who develop castrate resistant prostate cancer (aka hormone refractory).
Understanding that these cancer cells produce their own androgens by genetic mutation can give us tools to fight this change.
Cleveland Clinic researcher discovers genetic
mutation in deadly form of prostate cancer
By Angela Townsend, The Plain Dealer
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on August 29, 2013 at 12:00 PM, updated August 29, 2013 at 12:48 PM
CLEVELAND, Ohio -- A Cleveland Clinic researcher has discovered a genetic mutation in one of the deadliest forms of prostate cancer.
The finding, published online today in the journal Cell, shows that the mutation occurs in an enzyme that is present in castration-resistant prostate cancer, which is a drug-resistant form of the disease.
The mutation can occur within the cancerous tumors and it can also come from DNA passed down from one's parents.
The mutation makes it possible for the tumor to make its own supply of androgens, hormones that fuels the growth of prostate cancer, even after treatment – medically or surgically – that causes the body to stop producing the hormones.
“When we made the initial observation [of the mutation], we quickly realized what it could mean,” said Dr. Nima Sharifi, who led the work at the Clinic's Lerner Research Institute. It took an additional three years to identify the mechanism by which the resistance happens, he said.
They found that laboratory models of human prostate cancer fall into two categories of androgen synthesis: those that make androgens slowly and those that do so rapidly.
The research then found that the mutation explains the difference between the two categories and that DNA from some patient tumors also contains this mutation.
The discovery not only sheds new light on how prostate cancer can change, but it also is helping direct the development of new drugs to block the enzyme, thus preventing prostate cancer from turning deadly.
The finding also adds to current research on a biomarker to predict if a patient’s tumor carries the mutant gene so a more effective treatment can be planned from the beginning.
The National Cancer Institute estimates that there will be 238,590 new cases of prostate cancer in 2013, and 29,720 deaths this year in the United States.
Patients with advanced, or metastatic, prostate cancer are treated with hormone therapy that shuts down the body’s ability to produce testosterone and other male hormones, causing medical castration. Surgical castration, the removal of the testicles, is another treatment option.
The patient’s prostate-specific antigen, or PSA, level, is tracked and bone and imaging scans are used to see how well the drug is working.
Around 80 to 90 percent of patients over time show an initial positive response to the treatment, but the vast majority of patients develop a resistance to the drugs within a few months to a few years, Sharifi said.
Almost every man who dies of prostate cancer dies with castration-resistant prostate cancer.
For decades, researchers have known that the way a prostate cancer tumor becomes drug resistant is by making its own hormones, called androgens, which a tumor needs in order to grow.
“This is probably the most important finding we’ve had to date,” Sharifi said. “If you look at the standard clinical care of prostate cancer, identifying genetics doesn’t really come into play.”
The hope is that, as with cancers such as lung and melanoma, routine genetic testing will be able to identify mutations that will be able to be targeted by specific drugs, Sharif said.
“We don’t have that in prostate cancer right now,” he said. “If we could have some way of figuring out who will respond really well versus who won’t respond at all, I think this could potentially help.”