The lifecycle of a cancer
Imagine if various types of cancer were caused by a common, though currently unknown, virus. The implications for treatment options and methods of prevention could be enormous. The discovery of infectious agents, such as the human papillomavirus as the root cause of cervical cancer, opens the door to the idea that other viruses might be at work in the genesis of cancer development.
This theory is about to be tested further by Thomas P. Loughran, M.D., and his colleagues at Penn State Hershey Cancer Institute. But Loughran is no stranger to being at the forefront of cancer research.
The LGL discovery
As outlined in this previous Penn State Medicine article, Loughran, who is a professor of medicine at Penn State College of Medicine and director of the Cancer Institute, is responsible for the discovery of large granular lymphocyte (LGL) leukemia while he was an oncology fellow at the Fred Hutchinson Cancer Research Center in Washington. He has spent most of his career researching the development of the disease and establishing a treatment protocol, which has allowed many patients to live healthier and more productive lives. In 2003, he started an LGL leukemia registry to keep track of patient outcomes.
One of the most challenging aspects of LGL leukemia is getting an accurate diagnosis. Patients often present with chronic symptoms, such as joint pain, fevers, and immune system problems that can be misdiagnosed as rheumatoid arthritis (RA) or aplastic anemia.
“The diagnosis is clouded by the fact that the symptoms are not obvious,” Loughran says. “Patients can have morbidity with tiredness, shortness of breath, pain, and swelling of the joints. Ten to 30 percent have classic RA. This is a chronic disease, though, with a major complication being infections.”
A diagnosis of LGL leukemia is not difficult to come by if medical professionals know what to look for, which is an increased number of LGL cells that can be seen on a blood smear. But because this can easily be overlooked in basic blood tests, it often takes a recurrence of symptoms before an accurate diagnosis of LGL leukemia is reached.
The STAT3 link
Realizing that clonal LGL cells are the basis for this form of leukemia was only the beginning for Loughran’s research into the disease. He began partnering with other scientists to find out what the commonality was in patients with LGL.
One research collaboration with a group of medical researchers in Finland and the Taussig Cancer Institute at the Cleveland Clinic yielded a significant discovery: 40 percent of patients with LGL leukemia have a change in their signal transducer and activator of transcription 3 (STAT3) gene that causes it to be mutated and turned on.
Generally, the STAT3 gene in healthy people is only turned on briefly to fight off a virus before returning to its dormant state. But for a large group of patients with LGL leukemia, the gene stays on constantly and begins cloning itself. The results of this study were published in the May issue of The New England Journal of Medicine.
“Stat3 is a transciption factor, which means a signal from the outside environment binds to receptors on the cells through a complex biochemical reaction, “ Loughran explains. “This most recent paper was an international collaboration that took advantage of the human genome sequence by looking at protein coding genes. The initial experiment took place in Finland where they set up a sequencing study on LGL leukemia patients. They found that STAT3 was mutated in their first few patients. We then contributed a large number of LGL samples for mutation analyses and also performed a number of experiments that showed that the STAT3 being turned on is what keeps the clonal cells alive.”
STAT3 is turned on fairly frequently in other cancer patients, as well. Breast cancer and some other blood cancers, for example, may be triggered by the activity in this gene. Now that Loughran and his team have identified the likely culprit behind the development of LGL leukemia, the next step is producing treatment options that can turn off the STAT3 gene.
“The application is very important for patients because it gives us the opportunity to develop targeted therapeutics or personalized medicine,” Loughran says. “This is a prominent area in cancer treatment because the medicines physically target the abnormal protein, which is the main cause of the cancer. If we can turn it off, the cancer cells will die.”
A personalized medicine approach for LGL leukemia would be significant since it would leave the non-cancerous cells in the body untouched. Current treatment options for LGL leukemia typically involve methotrexate, an effective immunosuppressant that may cause numerous side effects, including liver problems and an increased susceptibility to infections. Because patients need to use methotrexate as a long-term therapy, their likelihood of developing complications is increased.
Finding a way to target just the problem genes has been done before with great success.
“This type of targeting therapy is miraculous as far as eradicating the clone,” Loughran says. He cites the success of Gleevec (imatinib) as an example of a molecular-targeting drug that might be developed for LGL leukemia. Gleevec has proven to be highly effective in the treatment of chronic myeloid leukemia (CML) because it turns off the protein signal that causes cancer CML. Identifying the cancer-causing signal, as Loughran already has with STAT3, greatly increases the possibility of drug development that could target the cause of LGL leukemia.
Loughran’s previous research demonstrated that turning off STAT3 will specifically kill off the LGL cells, suggesting that this approach might be indeed succeed in the clinic.. There are also promising developments in STAT3 inhibitors that are currently being worked on by several pharmaceutical companies.
“If we see the results in the inhibitors that we anticipate, we would like to get that tested in the clinic to look at patient response and remission rates,” Loughran says.
Finding the earliest agents of cancer
So now that the disease has been identified and a common gene mutation has been found in patients, the next question is: what causes the STAT3 gene to mutate in the first place? In fact, what causes any gene to mutate into a cancer causing agent?
Loughran and his researchers wonder if there could be a virus, currently unknown of, that is the causative factor in gene mutation. This theory was submitted to the National Cancer Institute’s (NCI) Provocative Questions project, which is a federally-funded opportunity for researchers to receive grants for potentially game-changing concepts in the fight against cancer. The Provocative Question project is the signature initiative of the new Director of the National Cancer Institute, Harold Varmus, M.D. Varmus wanted to find ways to fund science that would have potential for profound and revolutionarily impact on cancer research.
“We just received notification that our proposal was selected for this prestigious funding,” Loughran says. “Basically, our theory is that these cells may be turned on by a chronic virus. Since we know that other viruses can cause cancer, perhaps LGL leukemia results from a new virus.”
In all, the NCI’s project will distribute more than $22 million in grants to leading cancer researchers across the country. It is anticipated that 40 or so proposals will be funded from a pool of about 800 submitted grants. The twenty-four questions, which were developed through a community-based peer discussion process, are focused on areas that can make significant progress in the understanding of cancer development and its treatment.
Loughran’s grant will allow researchers at Penn State to search for and hopefully identify an early agent in the development of certain cancers. If a new cancer-causing infection is discovered, new strategies for avoiding or preventing the spread of such an agent could reduce both the overall occurrence of certain cancers and their mortality rates.
The prospect of identifying a virus that leads to the birth of LGL leukemia cells would bring Loughran and his research team full-circle in a lifetime of work that could be described as a reverse engineering approach to cancer. Both the scientific research community and the patients themselves await his latest discoveries.
-by Holly Swanson