Grants and Contracts Details
Description
Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic cells, characterized
by the proliferation of abnormal blast cells and impaired hematopoiesis. While younger patients
with favorable cytogenetics have increasingly favorable outcomes with dose intensive
chemotherapy, they represent a distinct minority of patients with this disease. Patients with
unfavorable cytogenetics, advanced age (~60), and antecedent hematologic disorders have a
decreased incidence of complete remission; even in those who achieve an initial remission, the
majority relapse and survival is poor. Clearly this is a patient population for whom novel therapies
are needed. Studies from our laboratory have demonstrated that the combination of the
proteasome inhibitor, bortezomib, with the anthracycline, idarubicin, at concentrations readily
achievable in vivo can rapidly induce apoptosis in primary human AML cells in vitro. Studies from
our laboratory have demonstrated that apoptosis induced in this fashion correlates with several
specific changes in primary AML cells. Following treatment with bortezomib and idarubicin strong
inhibition of NF-KB is rapidly observed, indicating inhibition of important survival signals. . In
addition, levels of p53 protein are strongly increased in treated AML cells, suggesting p53 mediated
changes in gene expression might be involved in the apoptosis induced by this combination. Based
on our observations we propose a phase I and II clinical trial with the novel agent, bortezomib, and
idarubicin given to newly diagnosed, elderly or relapsed AML patients. Monitoring for in vivo
induction of apoptosiS, as well as, important correlative studies assaying for inhibition of NF-KB and
increased p53 expression are proposed. We anticipate that with this novel treatment regimen we
will observe potent anti-leukemic activity and complete clinical remissions.
Status | Finished |
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Effective start/end date | 9/20/04 → 8/31/07 |
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