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. ? ? ?
|Hanley, Michael J; Mould, Diane R; Taylor, Timothy J et al. (2017) Population Pharmacokinetic Analysis of Bortezomib in Pediatric Leukemia Patients: Model-Based Support for Body Surface Area-Based Dosing Over the 2- to 16-Year Age Range. J Clin Pharmacol 57:1183-1193|
|Niewerth, Denise; Kaspers, Gertjan J L; Jansen, Gerrit et al. (2016) Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy. J Hematol Oncol 9:82|
|Horton, Terzah M; Drachtman, Richard A; Chen, Lu et al. (2015) A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study. Br J Haematol 170:118-22|
|Horton, Terzah M; Perentesis, John P; Gamis, Alan S et al. (2014) A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 61:1754-60|
|Horton, Terzah M; Sposto, Richard; Brown, Patrick et al. (2010) Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference. Pediatr Blood Cancer 54:872-8|
|Horton, Terzah M; Jenkins, Gaye; Pati, Debananda et al. (2009) Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity. Mol Cancer Ther 8:2232-42|
|Horton, Terzah M; Ames, Matthew M; Reid, Joel M et al. (2008) A Phase 1 and pharmacokinetic clinical trial of paclitaxel for the treatment of refractory leukemia in children: a Children's Oncology Group study. Pediatr Blood Cancer 50:788-92|