More than 150,000 people will be diagnosed with a hematological malignancy, for example leukemia, this year, joining the greater than 1,000,000 people living in the United States with these diseases. Although there has been significant progress in recent years in the treatment of hematological cancers with combination therapies the 5-year survival rates for non-Hodgkin lymphoma, leukemia and myeloma are still unacceptable at 69%, 57%, and 45%, respectively.
Within the last 10 years the Food and Drug Administration has approved carfilzomib and bortezomib, both proteasome inhibitors, for treatment of multiple myeloma. In addition, these inhibitors are in clinical trials for treatment of leukemia, B-cell lymphoma, non-Hodgkin lymphoma and mantel cell lymphoma. Given the utility of proteasome inhibitors in the treatment of hematological malignancies but the lack of a diagnostic for which patients will respond versus those that are intrinsically resistant or will acquired resistance during therapy, development of tools that can be used to predict responses to proteasome inhibitors are critical.
Members in our group have recently described a set of fluorescent proteasome sensors that allow, for the first time, simultaneous monitoring all three proteolytic activities of the proteasome. Preliminary studies suggest that the ratios of these activities serve as a unique "signature" for each cell type and may be predictive of sensitivity to inhibitors. We are exploring the feasibility that these sensors can predict which subtypes of hematological malignancies are resistant and which are sensitive to proteasome inhibitors, which could be useful in identifying which patients are appropriate for this therapy.