MOLECULAR STUDIES OF DRUG RESISTANCE IN CHRONIC LYMPHOCY

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Chronic Lymphocytic Leukemia (CLL) is the most common form of adult leukemia. The neoplastic cells in patients with this disease accumulate as a result of defective programmed cell death. In response to standard chemotherapeutic agents, drug resistance routinely develops. An increased understanding of the molecular basis for this relative chemoresistance and heterogeneity of specific tumor cell sub-populations will facilitate development of innovative therapeutic strategies. New agents which can potentially circumvent the recognized mechanisms of resistance are being introduced into the clinic. This proposal will focus on identifying specific patient populations who will be ultimately targeted for novel therapeutic agents based upon the molecular characterization of their leukemic cells to predict either response or failure to standard chemotherapeutic agents. Furthermore, the use of alternatives in vitro predictive assays will also facilitate recognition of those who are likely to have either no response or a transient response to standard agents, and thus enable these patients to avoid unnecessary toxicity. Finally, the availability of powerful technological advances in cDNA microarrays will be used to examine the differential expression of genes relevant to drug- induced apoptosis in leukemic cells. These observations will be correlated with known chromosomal aberrations and specified levels of protein expression within the malignant cell. A substantial increment in our understanding of drug sensitivity and resistance will potentially result from this genomic research.