Research Highlights

Ricardo Aguiar
Ricardo Aguiar, M.D., Ph.D.

We have recently described the preclinical validation of a new type of treatment for lymphoma. Lymphomas are malignant tumors derived from cells called lymphocytes, which reside in the bone marrow, blood and certain organs such as spleen and lymph nodes. It is important to discover new treatments to lymphomas because they are common and often fatal cancers. In the United States alone, approximately 70,000 new cases of lymphomas are diagnosed every year. Unfortunately, treatment modalities have not changed significantly in the last few decades, and approximately half of the patients diagnosed with the most common forms of lymphomas still die of their disease.

It is now well accepted that to be successful in treating cancer, we need to better understand the genes and proteins that are associated with tumor development, and utilize this knowledge to improve the diagnosis and treatment. In earlier work, we reported that high levels of a protein called phosphodiesterase 4B (PDE4B) associates with poor outcome in lymphoma. In addition, using lymphoma cells grown in the laboratory, we preliminary found that drugs that block PDE4B inhibit the survival of lymphoma cells, and may improve the efficiency of other anti-lymphoma agents.

In the manuscript highlighted here, we describe our new and exciting findings in this area. Specifically, we show that PDE4B inhibition not only directly limits the growth of lymphoma cells in vitro and in animal models, but we also uncover a mechanism by which PDE4B blockade can improve the activity of an unrelated class of drugs, glucocorticoids. These data are critically important because the use of glucocorticoid remains an integral part of the treatment of multiple tumor types, and patients that do not respond these agents are less likely to be cured.

In summary, as clinical grade PDE4 inhibitors are already available, we anticipate that our work will be translated into novel, more effective and less toxic, treatment modalities in a very near future.

Rolipram + Dexamethasone

(Left panel) Display from the gene set enrichment analysis demonstrates a significant increase of "glucocorticoid resistance" genes in lymphomas expressing high levels of PDE4B. Right panel) The development of human lymphoma in mice is markedly blocked by the rational therapeutic combination of glucocorticoids (Dexamethasone) with PDE4 inhibitors (Rolipram) (lower row).

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