Biomarker discovery: Staying one step ahead of cancer
Inside a cancer cell, locked tightly within spools of genetic text, reside the origins of each malignancy. For some cancers, a few misprints here or there enabled them to grow out of control. For others, a new juxtaposition of disparate pieces of genetic code granted the cells immunity from this rapid, malignant growth.
The exact nature of the molecular abnormalities that set the course for cancer can determine how quickly a malignancy will grow, how aggressively it might invade other tissues and how likely it will respond to certain therapies.
The Biomarker Discovery Program at Mayo Clinic is tapping into this knowledge to help physicians stay one step ahead of cancer.
Most cancers are diagnosed using a number of relatively crude measures, such as the size of the tumor and whether it has spread to other parts of the body. Although those parameters have been helpful in predicting overall outcomes and as a consequence how people need to be treated, they don't address the underlying genetic differences from cancer to cancer and patient to patient that could determine whether a treatment is successful or even necessary.
"Now that we are looking at those diseases more carefully, we see that patients can be very different at the molecular level, and biomarkers can tell us which way to go," says molecular biologist George Vasmatzis, Ph.D., co-director of the Biomarker Discovery Program in the Center for Individualized Medicine, and an expert in computational biology.
"Biomarkers can answer a number of different questions, depending on the type of cancer," says Vasmatzis, of Mayo Clinic's campus in Rochester, Minnesota. "There are some cancers that you want to detect early, and there are some that you want to know how to treat. There are some cancers that you want to know if you should just leave them alone."
Finding biomarkers for rare non-Hodgkin's lymphoma
Andrew L. Feldman, M.D.
Microscopic images of ALK-negative anaplastic large cell lymphomas from two patients. Genetic testing showed that the tumor on the left had an abnormality associated with a 90 percent chance of surviving five years and the tumor on the right had an abnormality associated with only a 17 percent chance.
Researchers at Mayo Clinic are spurring a bedside-to-bench movement that takes the issues physicians face in the clinic back to the laboratory in the hopes of discovering biomarkers to solve them.
Thoracic surgeon Dennis Wigle, M.D., Ph.D., urologist R. Jeffrey Karnes, M.D., and hematopathologist Andrew L. Feldman, M.D., all of Mayo Clinic's campus in Rochester, are just a few of those harnessing the power of biomarkers to benefit their patients.
With so many differences from one cancer to the next, the big challenge comes in filtering out the real biomarkers that could impact a patient's outcome from the otherwise irrelevant molecular noise. Still, Dr. Vasmatzis says the Center for Individualized Medicine is in a favorable position to go hunting for needles in a haystack.
Mayo Clinic began banking tumor samples long before most other institutions, and it now houses tens of thousands of these frozen snapshots, each with careful clinical annotations of when the cancer was diagnosed, how it was treated and if it recurred. And having this bank of frozen tumor samples has paid off.
Researchers can bring their most pressing clinical questions to Dr. Vasmatzis at the Biomarker Discovery Program, where they can design elaborate studies using these tumor samples to uncover molecular patterns that might predict the course of the disease. These studies have led Mayo Clinic researchers to dozens of discoveries of important molecular cancer biomarkers, including 32 in 2013 alone.
For example, Dr. Feldman wanted to dig up new information that he could use to better classify tumors from patients with an aggressive subtype of non-Hodgkin's lymphoma known as peripheral T-cell lymphoma, a rare and poorly studied form of cancer. Because the disease is typically fast growing and has few therapeutic options, about two-thirds of those affected don't survive the first five years.
"Most of the classifications we make are biologically accurate, but the patients are treated the same anyway," Dr. Feldman says. "As a pathologist, I would like to see the diagnosis I am giving incorporate genetic data because it is so important and will obviously affect the outcome."
A few years ago, Dr. Feldman noticed the same genetic abnormality cropping up in the T-cell lymphoma tissues he was analyzing. The abnormality — a cutting and pasting together of genetic material known as a chromosomal translocation — had all the makings of a good biomarker for the disease. Yet as Dr. Feldman tried to figure out what specific gene or genes were being rearranged, he kept hitting technological roadblocks.
That's when he enlisted the help of the Biomarker Discovery Program to apply a type of next-generation sequencing known as meet-the-pair sequencing to the problem.
"We accomplished in two weeks what I had been struggling with for two years," Dr. Feldman says. "That is the power of this technology."
Not only did the researchers uncover the genomic details of the translocation, but they also found that patients with this specific genetic abnormality actually had a very favorable prognosis.
Patients with aggressive peripheral T-cell lymphomas as determined from these biomarkers may benefit from more-intense therapies, such as stem cell transplantation. These treatments may cure patients, but they are more toxic than conventional therapy.
Biomarkers would identify patients most likely to benefit from these treatments and spare patients from toxic therapies if treatment would not benefit them.
Building on this initial success, the researchers sequenced more T-cell lymphomas for other recurrent abnormalities that might underlie the disease. They found a constellation of genetic abnormalities all related to TP53, a well-known tumor suppressor gene that encodes the p53 protein. Although half of most solid tumors have a mutation in the TP53 gene, only one-tenth of T-cell lymphomas contain p53 defects.
Dr. Feldman's findings suggest that T-cell lymphomas can be aggressive even without this powerful cancer-causing mutation because they contain associated defects, such as a mutation in the sister protein, p63.
"Importantly, if you looked under the microscope you couldn't tell these things apart. Without genetics, you wouldn't have this information," Dr. Feldman explains.
The key to individualized medicine
Dennis Wigle, M.D., Ph.D.
Although molecular profiling can have a big impact on the management of rare cancers like T-cell lymphoma, profiling can also help clinicians treating more common cancers, like lung cancer.
The system used for staging most solid tumors is more than 25 years old, and despite many revisions it still lacks the granularity demanded for today's individualized medicine approach. For instance, 70 percent of people diagnosed with stage I lung cancer will be cured with surgery or radiation, but 30 percent won't survive.
As a thoracic surgeon, Dr. Wigle has been looking for biomarkers that can better guide the treatment of his own patients than does the staging system alone.
"We need to stop treating everybody as though their disease fits in the same bucket when they don't," Dr. Wigle says. "Any kind of label that could indicate whether the patient sitting in front of me has a high chance of being cured or not is critically important. That could change how we treat patients, from the kind of surgery we do, to whether they get chemotherapy afterward, to how closely we follow them."
Dr. Wigle, who was the lead author of one of the first studies to identify a molecular biomarker for lung cancer in 2000, admits to being alternatively frustrated and exhilarated by the pace of discovery in the biomarker field.
"We are still doing things largely the same way we were doing them 25 years ago," he says. "But we are also at the cusp of an incredible exponential increase in our understanding of lung cancer biology, and the potential for biomarker discovery means those big advances everybody has been predicting may be just around the corner."
One advance came from Dr. Wigle's research team, which recently uncovered a new biomarker for identifying smoking-related lung cancer.
The researchers found that tumors with high levels of a protein called ASCL1 and a cancer-causing gene called RET had a poorer prognosis than did ASCL1 tumors with low levels of RET. The results point to new targets for treating smokers' lung cancer and also suggest that future work in biomarker discovery should focus on specific biomarkers for specific niches of patients rather than one-size-fits-all approaches.
When surveillance of prostate cancer is better than treatment
R. Jeffrey Karnes, M.D.
Among patients receiving increased attention recently are those whose tumors might never progress. One example is the clinically indolent tumors that appear in the prostates of men as they age.
A urologist with a special interest in advanced prostate cancer, Dr. Karnes says because of increased screening triggered by the prostate specific antigen (PSA) test, many tumors that may have otherwise gone unnoticed are being picked up. PSA tests, however, don't delineate between how mild or aggressive the disease is. As a result, urologists may make decisions to treat patients unnecessarily.
"Most prostate cancer diagnosed today is of lower risk disease, so the big question is whether there is a more aggressive cancer hiding in there that we aren't seeing," Dr. Karnes says. "If you can develop biomarkers to reassure a man he doesn't harbor aggressive cancer or to suggest he should be concerned about aggressive disease, it would be of value to a majority of men faced with a prostate cancer diagnosis."
Dr. Karnes has been working with the Biomarker Discovery Program to identify markers indicating when an active surveillance approach, rather than treatment, is the most appropriate for prostate cancer.
The researchers combed through a database of prostate tissue samples to find 50 recently preserved specimens of indolent tumors for their studies. They then compared the sequence of these growths with other, more aggressive tumors to find molecular signatures that suggest a tumor is destined to remain indolent.
The researchers have discovered a number of markers fitting the bill. These markers now need to be verified and validated before their clinical utility can be assessed. Having gone through this process before, Dr. Karnes knows that the vast majority of biomarkers never make it into the clinic. Most will be eliminated in further research trials from having any clinical application.
Still, there will be exceptions. A few of the biomarkers discovered in the lab will end up in the clinic. These will help physicians make more precise diagnoses, prescribe more effective treatment across a spectrum of diseases, and avoid unnecessary treatments.
Dr. Karnes credits the infrastructure, expertise and financial support provided by Mayo Clinic for making such successes possible. The sentiment is echoed by other researchers at Mayo Clinic who are eager to add biomarkers to their everyday arsenal in the fight against cancer.
"I think the institution should be lauded for investing in biomarker discovery," Dr. Wigle says. "There is a lot of amazing work happening at this institution, but without threads to bring it all together those connections don't always get made or people don't always combine their efforts to push the science forward. I think one of the strong byproducts of the Biomarker Discovery Program is that it has brought us together in a way that wasn't happening without that leadership, funding and resources."
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