Acute myelogenous leukemia (AML) is a disease in which the accumulation of primitive non-functional precursor cells results in the death of patients due to bleeding and infection. Only 10-20 percent are cured by combination chemotherapy. Although allogeneic bone marrow transplantation is potentially curative, only 25 percent of AML patients are eligible for this therapy and only half of actually transplanted patients survive longterm. The participants in this Program have made major progress in understanding mechanisms of resistance to chemotherapy, focusing on apoptosis pathways and cell cycle checkpoints. The goal of this renewal application is to build on the substantial work accomplished during the prior funding period, and to explore novel strategies for overcoming roadblocks to apoptosis in AML. The new program has two major additions: Dr. C. Croce and his group has joined us in studying the role of microRNAs in AML and already identified miR's that target Bcl-2, Mcl-1 and KIT and Drs. G. Mills and S. Kornblau have developed reversephase protein arrays (RPPAs) that allow the analysis of (phospho-) proteins of 100 AML samples and stem cell populations on a single slide. RPPA greatly improves our ability to rapidly interrogate signaling pathways and apoptosis proteins in AML and in AML stem cells. The projects are highly integrated. They share common targets, but approach them from different directions. Projects 1 (Andreeff), 2 (Reed), 4 (Croce) and 5 (Estey) have a long-standing interest in Bcl-2 family members and lAPs. They will further investigate the activity of BH3 mimetics against bulk AML cells and AML stem cells, alone and in the context of the bone marrow microenvironment in vitro and in vivo. The activity of novel BH3 mimetics will be determined against all 6 anti-apoptotic Bcl-2 members, and RPPA will be used to correlate baseline and post-treatment protein expression levels with response. Mcl-1 has been identified as a protein critical to the survival of hematopoietic stem cells and as a significant prognostic factor in newly diagnosed and relapsed AML. It is also a major resistance factor for the most potent BH3 mimetic. TR3 (Nur77) mimetics will be further explored for their ability to convert Bcl-2 from a protector into a killer protein. Clinical trials will be conducted with BH3 mimetics (in Project 5). XIAP has also been a joint target for Projects 1 and 2, resulting in a clinical trial of XIAP-AS (Project 5) and the ongoing development of SMAC and non-SMAC mimetics in Project 2. Project 4 (Croce) has identified miRs 15 and 16 as targeting Bcl-2. They also found an association between chr. 7qand miRs targeting Mcl-1.
They aim at studying the role of microRNA genes in the pathogenesis and progression of AML and will identify altered microRNA genes as targets for the development of novel therapies. The recent development of selective MDM2 inhibitors (Nutlins) provided the basis for studying p53 signaling in AML (Project 1). In the vast majority of AML with wild-type p53 (>95 percent), Nutlins disrupt MDM2/ p53 resulting in increased p53 levels, activation of p53 target genes, and apoptosis. The observed synergy between BH3 mimetics and MDM2 inhibitors prompted us to develop mechanistic studies of p53-Bcl-2 interactions. Because of the exceptionally high synergy between Bcl-2 and MEK inhibition discovered in Project 1, Project 2 will add a siRNA-based kinome screen to identify kinases that will further enhance the activity of BH3 mimetics. Project 3 (Plunkett) will continue to focus on strategies to dysregulate the molecular checkpoint pathways that limit the efficacy of nucleoside analogs in AML. They will also explore how nucleotide analogs inhibit DNA repair in AML and conduct studies to validate their hypotheses in AML cells from patients receiving therapy with Clofarabine and Sapacitidine. Several novel strategies developed during the prior funding period will be tested in clinical trials of BH3 mimetics, XIAP, Raf/Flt3 kinase and CXCR4 inhibitors in Project 5, which will test hypotheses specific to these targets, but also those of general importance for leukemia therapy (e.g. correlation of target expression and response to specific therapies, importance of CRp for patient survival and whether it can be justified to treat relapsed AML patients with non-cytotoxic therapy). The transplant program (Project 6, Dr. Champlin) will continue to develop the highly successful strategy of phamacokinetically adjusted Busulfan, will add Clofarabine to Bu-Flu, and will investigate the novel triterpenoid CDDO (developed as a potent anti-leukemia agent by Projects 1 and 2) for the treatment of GVHD. They will explore the concept of CXCR4 inhibition developed in Project 1 to enhance the anti-leukemia effect of the busulfane-fludarabine preparative regimen. The projects are supported by outstanding and well-established Cores and the new high-throughput Proteomics and Genomics Core. In summary, we hope to develop therapies targeted to molecular defects in AML with reduced toxicity to normal tissues and more durable remissions for all subsets of AML. Because the therapeutic approaches developed here are also relevant to the treatment of epithelial neoplasms, we expect that the concepts developed by this program to provide directions for the improvement of solid tumor therapy as well.
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