Richard E. Davis, M.D., Laboratory
Targeted Therapy for Patients with Lymphoma or Myeloma
The Davis laboratory, established in 2009, wants to make “personalized medicine” a reality for patients with lymphoma or myeloma. Our vision is that future patients will receive targeted therapy based on molecular examination of their tumors, rather than a standard regimen of broadly-toxic chemotherapy based simply on the standard pathologic diagnosis of their tumor type. We are working towards this goal in two ways.
The first is the application of microarray technologies to patient samples, in order to understand the response to specific lymphoma and myeloma treatments, especially experimental therapies tested in clinical trials at MD Anderson. Gene expression microarrays, for example, simultaneously measure individual levels of the thousands of genes being expressed in a particular sample, the “gene expression profile”. This provides a wealth of information for correlation with clinical outcomes, in particular the response to therapy that a patient receives, which in turn provides markers for predicting which future patients are most likely to respond well to particular therapies. The gene expression profile also provides insight into the biological mechanisms active in a tumor, which may be specific therapeutic targets. By this and other methods, we hope to identify specific mechanisms that promote resistance to therapy in lymphoma and myeloma, which may provide new topics for detailed investigation and improve results of existing therapies in future trials.
B-Cell Receptor Signalling
The second area of investigation involves one particular mechanism, already discovered, upon which one particular type of lymphoma depends for survival. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma, with nearly 20,000 new cases each year in the U.S. DLBCL is currently diagnosed and treated as a single disease, but gene expression profiling shows that most cases belong to two subtypes. The activated B-cell (ABC) subtype has the worst prognosis when treated with standard chemotherapy, which affects many biological mechanisms in both cancerous and normal cells. However, Dr. Davis’ past research showed that ABC-DLBCL depends on several intracellular “signaling pathways” (mechanisms) that could be specifically targeted in future personalized therapy for greater efficacy and fewer side effects. Dr. Davis and former colleagues recently discovered that these pathways are activated by the B-cell receptor (BCR). In normal B cells, the BCR functions to provide immunity by recognizing foreign antigens, then activating these same pathways. This discovery has already provided several potential targets for specific therapy, but our laboratory is working to understand better the unusual mechanism of BCR signaling in ABC-DLBCL, and its cause in the absence of a foreign antigen. This could lead to future therapy that would inhibit BCR signaling only in ABC-DLBCL cells and preserve B-cell immunity.