Sylvester Researchers Awarded Five-Year Grant to Study Cancer Viruses
Viruses are believed to be the cause of as many as 20 percent of all cancers, but some viruses can infect human cells and remain latent. To remain latent, they may have to suppress anti-viral host mechanisms, which can pave the way for cancer. The laboratory of Glen N. Barber, Ph.D., the Eugenia J. Dodson Chair in Cancer Research and leader of the Viral Oncology Program at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, has played a key role in unraveling these host mechanisms, referred to as innate immunity.
Barber is now leading a team of physicians and scientists at Sylvester who have been awarded a prestigious five-year PO1 grant from the National Cancer Institute, part of the National Institutes of Health, to uncover these mechanisms and study them in clinical trials.
This $8 million grant from the NCI involves multiple investigators. Barber and two other Sylvester researchers will take a three-pronged approach to studying these viral malignancies. "This is a basic research grant with a clinical component," explains Barber. "We had to show synergy and a solid blend among all the components."
For several years, Barber's lab has been working toward understanding the innate immune system, which is critical in fighting viral infections. Cancer-causing viruses seem to subvert these defense mechanisms to avoid being eliminated and in doing so, they remove a restriction which allows the genesis of cancer. Barber's goal is to understand "how these anti-viral/anti-proliferative mechanisms work and how viruses shut them down."
One of the viruses Barber has focused on is human T-lymphotropic virus type-1 (HTLV-1), which appears to subvert the innate immune process and contribute to adult T-cell leukemia (ATL). Like most viruses, HTLV-1 has a specific receptor on the cell surface that is not present on other types of cells. So Barber and his team have devised a new virus to attack and infect HTLV-1 cells using that specific receptor as a contact point. Barber has tested this therapy in the lab and says "it looks really promising." He hopes to have this portion of the research as a potential clinical trial in the future.
That's where the work of the late William J. Harrington, Jr., M.D., co-leader of the Viral Oncology Research Program at Sylvester and professor of medicine in the Division of Hematology-Oncology, and Juan Carlos Ramos, M.D., assistant professor and member of the Viral Oncology Program, comes into play in this multi-investigator grant. Harrington and Ramos examined the responses of ATL to anti-viral and immunomodulatory therapy and found that specific molecular factors were associated with treatment resistance. This work was published in the journal Blood in 2007. Based on their insight, they designed a new clinical trial to study the mechanisms of treatment resistance in this fatal viral-associated malignancy.
Joseph D. Rosenblatt, M.D., interim director of Sylvester and professor of medicine, microbiology and immunology, and William J. Harrington Chair in Hematology, who contributed to the HTLV-1 field earlier in his career, recently joined this effort and will assist Ramos with Harrington's portion of the project.
When the body is infected by a virus, it signals the production of interferon which makes anti-viral genes. However, some viruses, like HTLV-1, shut down the interferon pathways, allowing the virus to replicate. Harrington and Ramos developed a method to introduce exogenous interferon into the body to reawaken the innate immune system – a therapy that seems effective in about 25 percent of cases. The challenge, Barber explains, is that "in many instances, there's a resistance to this therapy because the exogenous interferon pathways have been destroyed by the virus, or mutated, and won't work."
With this grant, Ramos will continue his clinical trial and laboratory work on adult T-cell leukemia lymphoma (ATLL) initially started by his project funded by the Damon Runyon Cancer Foundation. He is studying the in vivo mechanisms of interferon sensitivity and resistance in this deadly disease, which is generally resistant to conventional chemotherapy. "We want to figure out which molecular factors can help us predict which patients will respond to this biological approach and where the defects which can induce interferon resistance exist," says Ramos. From there, "we hope to design a test to screen patients to predict which ones will respond to this therapy and which won't."
The study will also include a comprehensive molecular analysis of ATLL specimens obtained from patients under the clinical trial in Miami and the Brazilian state of Bahia, where HTLV-1 is also endemic. Much like HIV, HTLV-1 can be sexually transmitted and passed through direct inoculation and blood products. However, its main route of transmission is through breast milk in indigent settings. The virus causes leukemia/lymphoma in about 5 percent of the infected individuals after a long period of latency of four to five decades. Ramos will be working closely with Barber and colleagues at the Federal University of Bahia, in Salvador, where a long-standing research collaboration with Sylvester and UM established by the late Dr. Harrington Jr. still exists.
Barber expects the discoveries made with this research and clinical study to have broad implications for other viral malignancies. "Learning how these viruses shut down normal host defense pathways could be applicable to any other cancers," he says. They plan to more closely examine other cancers associated with virus infection and determine if similar defects in immunity pathways affect treatments.
The work of Edward Harhaj, Ph.D., assistant professor of microbiology and immunology and member of the Viral Oncology Program at Sylvester, makes up the third portion of the multi-investigator grant. While Barber is examining innate immunity as a whole, Harhaj is more specifically looking at how the virus blocks that normal defense mechanism. He believes that Tax, a protein created by HTLV-1, is the actual culprit that shuts down the innate immune pathways, blocking the production of interferon. "We want to determine exactly how Tax inhibits the production of interferon by identifying the precise target of Tax in these antiviral pathways," says Harhaj. He and Barber will collaborate on determining the role of Tax in blocking the innate immune pathway.