Bortezomib (PS-341, VELCADE) is a proteasome inhibitor, one of a novel class of chemotherapeutic agents that has been FDA-approved for the treatment of multiple myeloma in adults and is being tested as a chemosensitizer in a variety of adult solid tumor and hematologic malignancies. We have preclinical evidence that bortezomib is a potent inducer of apoptosis in leukemic cells and is synergistic or additive with several standard chemotherapy drugs used in leukemia treatment. Based on this data, I am directing a phase I clinical trial of bortezomib in pediatric patients with relapsed/refractory leukemia. I propose to conduct correlative biology experiments with patient samples obtained from the current phase I and two proposed phase 2 trials to improve our understanding of the mechanism(s) of action of bortezomib in vivo. Specifically, I would like to examine the effects of bortezomib on the NF-KB pathway and explore the use of bortezomib as a chemosensitizing agent in acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL). Many short-lived regulatory proteins, such the NF-KB inhibitor kB, are ubiquitinated and degraded by proteasome inhibition. There is substantial evidence that NF-KB is deregulated in leukemias and lymphomas. I hypothesize that bortezomib induces tumor cell apoptosis by inhibiting NF-KB activation. I will examine the effects of bortezomib on tumor cell apoptosis, NF-KB activation, and pretreatment protein expression profiles. Since there is evidence that bortezomib-induced apoptosis may occur through NF-KB-independent mechanisms, I will also examine other key regulatory proteins that are degraded by ubiquitination. The phase I studies will be used to further refine correlative biology studies for the proposed phase 2 clinical trials that will examine the effectiveness of bortezomib as a chemosensitizing agent in relapsed ALL and HL. ? ? ?
