In a genome-wide analysis of 13 metastatic prostate cancers, scientists at the Johns Hopkins Kimmel Cancer Center found consistent epigenetic “signatures” across all metastatic tumors in each patient. The discovery of the stable, epigenetic “marks” that sit on the nuclear DNA of cancer cells and alter gene expression, defies a prevailing belief that the marks vary so much within each individual’s widespread cancers that they have little or no value as targets for therapy or as biomarkers for treatment response and predicting disease severity.
A report of the discovery, published in the Jan. 23 issue of Science Translational Medicine, describes a genomic analysis of 13 men who died of metastatic prostate cancer and whose tissue samples were collected after a rapid autopsy.
Samples from three to six metastatic sites in each of the patients and one to three samples of their normal tissue were analyzed to determine the amount of molecular marks made up of methyl groups that attach to sites along the genome in a process known as DNA methylation. The process is part of an expanding target of scientific study called epigenetics, known to help drive cell processes by regulating when and how genes are activated. Mistakes in epigenetic processes also are known to trigger or fuel cancers.
“Knowing both the genetic and epigenetic changes that happen in lethal prostate cancers can eventually help us identify the most aggressive cancers earlier and develop new therapies that target those changes,” says Srinivasan Yegnasubramanian, M.D., Ph.D., assistant professor of oncology at The Johns Hopkins University School of Medicine. “But there has been an open question of whether epigenetic changes are consistently maintained across all metastatic sites of an individual’s cancer.”
The research team found that while methylation patterns vary from one patient to another, many methylation patterns occur “very consistently” within different metastatic sites in an individual patient. They identified more than 1,000 regions of the genome where various types of DNA methylation were consistently maintained within their 13 subjects’ genomes.
“As they evolve and grow, cancer cells acquire and maintain changes that enable them to continue thriving,” says Yegnasubramanian. “We know that cancer cells maintain and pass along genetic changes in the nucleus of cells across metastatic sites, and our research now shows that epigenetic changes also are maintained to nearly the same degree.”
Prostate Cancer Metastasis: Where Next?
Prostate cancer has a definite tendency to spread to the bones. The bones of the pelvis, upper legs, and lower spine are the most common sites for prostate cancer bone metastasis, but all of the body’s bones are potential targets.
Prostate cancer can involve the liver, intestines, brain, lungs, and other tissues as well, though these are far less common than the bones.
Why Would Prostate Cancer Metastasis Be Suspected?
Prostate cancer metastasis may be suspected if you have specific symptoms. For example, new lower back pain may raise your doctor’s suspicion that you have metastasis to the lower spine, or newly elevated liver enzymes may cause your doctor to suspect spread to the liver.
Additionally, PSA levels that continue to rise despite treatment, especially if they are rising particularly fast, may raise your doctor’s suspicion about the possibility of metastasis somewhere in your body.
How Is Prostate Cancer Metastasis Detected?
Imaging studies are the primary tool for this discovery.
A common imaging workup would include a bone scan and a CT scan of the abdomen and pelvis. Additionally, an MRI might be done.
A bone scan results in images of the entire skeleton. Metastasis to the bone will usually show up as “hot spots” on the bone scan.
A CT scan can be used to look for metastases in the abdomen and pelvis. Prostate cancer that has spread to the liver, intestines, or bones of the abdomen and pelvis can usually be found. Additionally, spread to the lymph nodes can sometimes be detected if the lymph nodes have become enlarged.
MRIs are sometimes used if there is a question as to whether the cancer has spread into tissues very near the prostate or to see if there is tissue left behind in the prostate bed following surgery.
Govindan R, Arquette MA. Washington Manual of Oncology. 2002.
The scientists say that the consistent methylation changes they found appear to represent so-called driver changes critical to the cancer’s development and could be targets for treatment. By contrast, other methylation changes found only sporadically in the metastatic sites are more likely what are called passenger changes that occur by chance and are less promising as treatment targets or biomarkers than driver changes.
“Our study shows that for prostate cancer, at least, each person develops his own path to cancer and metastasis, and we can find a signature of that path in the epigenetic marks within their tumors,” says Yegnasubramanian, who envisions that certain epigenetic changes can be grouped into clusters to be used as biomarkers signaling a lethal cancer.
Q When prostate cancer metastasizes, does the PSA level go up?
A In general, higher-than-normal PSA levels signal that
something has changed in the prostate gland. If a man has
been treated for prostate cancer with surgical removal of the
gland, most physicians believe that PSA levels should be very
low – that is, less than 0.2 nanograms per milliliter (ng/mL)
of blood. If the PSA number goes up during two consecutive
readings after surgery, it may mean that prostate cancer
has returned. In men who have been treated with radiation,
doctors look for three consecutive rises in the PSA number.
They may also order other tests to further evaluate the
Q Can I continue to do exercise, like brisk walking, when I am treated for metastatic prostate cancer?
A It’s certainly a good idea to engage in as much physical
activity as is comfortable. Exercise helps promote heart health
and can relieve stress and fatigue. In general, activities like
walking or swimming are preferable to high-impact activities,
such as jogging. Men who are having a difficult time finding an
exercise routine that works for them should seek the help of a
physical therapist or rehabilitation specialist.
Yegnasubramanian and his team also plan to study how each of the driver changes work and how they influence cancer metastasis.
The research was funded by the Department of Defense Prostate Cancer Research Program (PC073533/W81XH-08-1-0049), the National Institutes of Health (CA58236, CA070196, CA113374, CA135008, GM083084), the Prostate Cancer Foundation Creativity and Challenge Awards, the Patrick C. Walsh Prostate Cancer Research Fund/Dr. and Mrs. Peter S. Bing Scholarship, the V Foundation for Cancer Research Martin D. Abeloff V Scholar Award, the German Research Foundation Research Fellowship, the Finnish Academy of Sciences Finnish Distinguished Professor Award, the Commonwealth Foundation, Mr. David H. Koch, and the Irving A. Hanson Memorial Foundation.
Cancer of the prostate gland is the most common cancer affecting men. Most of the time when prostate cancer is diagnosed and treated, the tumor is still confined to the gland.
But when this cancer becomes metastatic and spreads to other parts of the body, treatment can stop cancer growth, control pain and other symptoms, and extend survival. In this way, prostate cancer is somewhat unusual compared with other types of cancers, which are more difficult to treat when they spread.
If a man has already been treated for prostate cancer with surgery or radiation, rising levels of PSA may indicate that his prostate cancer has returned. (PSA refers to “prostate-specific antigen,” a protein produced by the prostate gland.) PSA may rise even though tests are unable to detect any obvious disease in the bone or other organs. For these men the disease is considered “micrometastatic,” meaning that cancer cells are believed to be present somewhere in the bloodstream, but they cannot be detected with the usual imaging tests.
Scientists participating in this research included Martin Aryee, Julia Engelmann, Philipp Nuhn, Meltem Gurel, Michael Haffner, David Esopi, Rafael Irizarry, Robert Getzenberg, William Nelson, Jun Luo, Jianfeng Xu, and William Isaacs from Johns Hopkins; Wennuan Liu from Wake Forest University; and G. Steven Bova from the University of Tampere in Finland.
Yegnasubramanian, Haffner, Esopi, Nelson, and Isaacs and The Johns Hopkins University have provisional or fully executed patents relating to DNA methylation biomarkers in prostate cancer. Yegnasubramanian and Nelson, along with The Johns Hopkins University, hold a patent for a polypeptide for detection of methylated DNA. This reagent has been made available to the research community via a nonexclusive license with Clontech, Inc., which provides royalties to The Johns Hopkins University, Yegnasubramanian, and Nelson from sales of kits containing this reagent. The authors are pursuing intellectual property protection for the new prostate cancer biomarkers described in this research.
Treatments on the Horizon
Researchers are developing a number of new medications for
the treatment of metastatic prostate cancer. Some of the most
Abiraterone This drug works by blocking the hormones
that fuel the growth of metastatic prostate cancer. Early
clinical trials showed that abiraterone helped shrink
metastatic prostate tumors and slowed their growth.
Currently, abiraterone is being studied in a large multi-center
MDV3100 This new drug has been shown to help stall the
growth of metastatic prostate cancer in men whose tumors
resist treatment with standard hormonal therapy.
Ipilimumab (MDX-010) In clinical trials, this drug has been
shown to be effective in men whose metastatic prostate cancer
does not respond to hormonal treatment or chemotherapy.
Ipilimumab blocks a molecule that reduces the immune
system’s ability to kill tumors, including metastatic prostate
cancer cells. By blocking this molecule, ipilimumab helps
restore the ability of the immune system to destroy tumors.
Bisphosphonates Because lowered testosterone levels
lead to a loss of calcium in the bones, which weakens them,
doctors often give drugs called bisphosphonates to men
with metastatic prostate cancer. Bisphosphonates help
manage bone pain and minimize the risk of fractures to
the hip and spine. Some research suggests that combining
bisphosphonates with the drug leuprolide may benefit men
with metastatic prostate cancer. These medications are
approved for men whose metastatic prostate cancer does
not respond to first-time hormonal therapy.
Johns Hopkins Medicine