UM/Sylvester Physician-Scientist Wins Prestigious Award to Support Research on Viruses and Cancer
Juan Carlos Ramos, M.D., member of the Viral Oncology Program at UM/Sylvester and assistant professor of clinical medicine, Division of Hematology-Oncology at the University of Miami Leonard M. Miller School of Medicine, is one of only five researchers in the nation to receive a prestigious Damon Runyon Clinical Investigator Award. The award will support his groundbreaking work on the role of an oncogenic protein in adult T-cell leukemia/lymphoma (ATLL). Ramos’s work promises to help predict which patients will respond to interferon-based therapy so that all ATLL patients receive the best treatment soon after diagnosis.
ATLL is caused by the human T-cell leukemia virus (HTLV-I) and is endemic in southern Japan, in certain regions of Brazil, and in western Africa. HTLV-I is mostly transmitted from mother to child through breast milk, and only a small percentage of infected individuals develop the cancer in their lifetime. ATLL is a relatively rare diagnosis in the United States, affecting fewer than 1,000 people. But because the disease is also prevalent in the Caribbean islands which are largely populated by African descendants, like Haiti, Jamaica and the West Indies, South Florida has the highest incidence rate in the country. The disease carries a dismal prognosis.
Ramos recently showed that ATLL patients whose tumors expressed high amounts of the interferon regulatory factor 4 (IRF-4)/MUM-1 didn’t respond to interferon-based therapy. Patients whose tumors didn’t express the protein did respond to interferon and survived long-term. This study may help identify patients who will benefit from interferon treatment up front. Other aggressive non-Hodgkin lymphomas also express the same protein so those patients could also benefit.
“It’s a translational project in which we will study the role of IRF-4/MUM-1 in ATLL tumor cell lines and in a rare laboratory mouse model, and then we’ll have the analysis of primary tumors as part of clinical trial with eligible patients receiving interferon-based therapy,” said Ramos. “We’ll be examining the response to interferon and its B (which regulates IRF4 gene) and otherkassociation with IRF-4/MUM1, NF- molecular factors.” As part of the application process for this award, Ramos designed a clinical trial to test his hypothesis.
Ramos’s clinical trial will enroll up to 35 patients with leukemia-type ATLL who will be treated with the combination of the antiretroviral drug AZT and interferon, and includes the novel use of pegylated interferon as maintenance therapy for this disease. The patient tumor cells will be analyzed for expression of a number of molecular factors. He predicts that patients with low levels of IRF4 will respond to interferon while those with high levels will not.
This trial is the first to test the idea in humans.
“In the future, in patients that don’t express factors that oppose interferon, like IRF4, we may want to exploit the therapeutic option of antiviral therapy,” said Ramos. “For those patients who do express these factors, you can probably offer a highly aggressive alternative option such as chemotherapy and perhaps stem cell transplantation.”
The Damon Runyon award provides $450,000 in research funding and investigator support over three years. It specifically recognizes promising “translational” research, or laboratory work that shows great potential to improve cancer care in patients.
Ramos and his UM/Sylvester colleagues will also test tissue samples of ATLL tumors sent from the Federal University of Bahia in Brazil. That will allow the study of a wider variety of samples and increase the integrity of the results. The partnership with Brazil is made possible by the long collaboration between UM/Sylvester and cancer investigators in Brazil.
The Damon Runyon award is a mentored grant, intended to guide promising young investigators like Ramos into successful research careers. UM/Sylvester hematologist oncologist William J. Harrington, Jr., M.D., co-leader of the Viral Oncology Program at UM/Sylvester and professor of medicine, Division of Hematology-Oncology at the Miller School of Medicine is Ramos’s primary mentor. He will also work closely with Glen Barber, Ph.D., professor of microbiology and immunology. Both Harrington and Barber are considered national leaders in the study of viral oncology and interferon.
“I’m very excited but I was actually a little surprised,” said Ramos. He was extremely interested in the Damon Runyon award but was also using it to prepare a subsequent, similarly structured NIH grant application. “It was actually the first major grant I applied for. I was intending to apply at the same time for an NIH grant but the deadline for the Damon Runyon came first, so I applied for Damon Runyon. I got word that I received it before the deadline for submitting the NIH grant.”
The application process for the Damon Runyon Clinical Investigators Award is arduous and each year only about 50 investigators in total nationwide are chosen to apply by their respective academic institutions. To illustrate the quality of the proposals, about 30, on average, are considered worthy of support, so being selected to be among the five recipients puts Ramos in exclusive company. His Clinical Investigator Award colleagues this year include physician/scientists from Harvard University’s Dana Farber Cancer Institute, the Fred Hutchison Cancer Research Center in Seattle, the University of Michigan and the University of Colorado. The award is intended to help address the shortage of physicians capable of translating scientific discovery into new breakthroughs for cancer patients. In partnerships with founding sponsor Eli Lilly and Company, and with Siemens Medical Solutions, Novartis and Genentech, the Damon Runyon Cancer Research Foundation has committed more than $30 million to support the careers of 39 physician-scientists across the United States since 2000.