Acute myelogenous leukemia (AML) is a disease in which the accumulation of primitive non-functional precursor cells results in the death of >80% of patients due to bleeding and infection. Although allogeneic bone marrow transplantation is potentially curative, only 25% of AML patients are eligible for this therapy and only half of these survive long-term. Another 10-20% are cured by combination chemotherapy. In order to develop new directions for therapy of AML, we have developed novel approaches to bone marrow transplantation. We pioneered non-myeloablative regimen (""""""""mini-transplant"""""""") which had major impact on the practice of BMT by allowing this treatment modality to be used in older patients (the majority of patients with AML is >55 yrs of age). We are now proposing to implement our improved understanding of the apoptotic mechanisms responsible for resistance to therapy in AML, both to chemotherapy and transplantation. We have made significant progress in interrogating the mitochondrial/cytochrome c/ caspase 8 and TNF-receptor family/caspase 9 pathways, with particular focus on Bcl-2 family and Inhibitor of Apoptosis (IAP) proteins. Of note, several components of these pathways were analyzed first in AML by investigators of this Program Project. We studied their expression patterns, regulation and response to apoptotic triggers. These findings have already resulted in new therapeutic concepts targeting these molecules: antisense oligonucleotide (AS), directed against the anti-apoptotic Bcl-2, Bcl-XL, XIAP and survivin proteins and modulation of Bcl-2 by the PKC-alpha inhibitors Bryostatin and UCN01. The effects of UCNO1 on mechanisms of resistance to ara-C will be studied in vitro, and in a clinical trial. Furthermore, interference with AKT and MAPK signaling in AML by PI3 kinase and MEKK inhibition (which we expect to result in de-phosphorylation of Bad and re-establishment of its pro-apoptotic function) will be further investigated. Dolostatin, which we found to exert anti-leukemic effects by the modulation of XIAP and Bcl-2 family members is in clinical trial. These targeted in vitro and clinical studies will attempt to correlate molecular changes with the induction of apoptosis and clinical response. Apoptotic pathways in AML will further be elucidated by mapping expression patterns and interrogating mitochondrial, TNF receptor and granzyme B-mediated signaling at diagnosis and at relapse in longitudinal studies of individual patients, following chemotherapy and allogeneic transplantation. Functional genomics approaches will also be utilized. Early progenitor/stem cell compartments will be analyzed, utilizing state-of-the-art FACS and cell separation techniques and in vitro models of leukemic and normal hematopoiesis. The BMT program will optimize the non-ablative preparative regimen pioneered here. Dendritic cells will be generated from AML blasts that serve as antigen-presenting cells to elicit specific immune responses (""""""""graft-vs-leukemia""""""""). The studies are supported by well-established cores that conduct the clinical trials, process and bank leukemic cells, perform in vitro studies of clonogenic cells, isolate by FACS rare stem cell candidates for molecular and FISH analysis, and provide support for clinical trials and biostatistics. In this way, we hope to develop therapies targeted to molecular and biological defects in AML, which are less toxic to normal tissues and provide more durable remissions in all subsets of AML. Because the principles of therapy are also relevant to the treatment of epithelial neoplasms, we expect the information to be derived from this program to provide directions for improvement of solid tumor therapy as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055164-14
Application #
6953098
Study Section
Subcommittee G - Education (NCI)
Program Officer
Wu, Roy S
Project Start
1992-06-01
Project End
2007-09-19
Budget Start
2005-09-09
Budget End
2007-09-19
Support Year
14
Fiscal Year
2005
Total Cost
$2,435,347
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Ngankeu, Apollinaire; Ranganathan, Parvathi; Havelange, Violaine et al. (2018) Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia. Oncotarget 9:4354-4365
Le, Phuong M; Andreeff, Michael; Battula, Venkata Lokesh (2018) Osteogenic niche in the regulation of normal hematopoiesis and leukemogenesis. Haematologica :
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Zeng, Zhihong; Liu, Wenbin; Tsao, Twee et al. (2017) High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia. Haematologica 102:1537-1548
Pan, Rongqing; Ruvolo, Vivian; Mu, Hong et al. (2017) Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy. Cancer Cell 32:748-760.e6
Jacamo, Rodrigo; Davis, R Eric; Ling, Xiaoyang et al. (2017) Tumor Trp53 status and genotype affect the bone marrow microenvironment in acute myeloid leukemia. Oncotarget 8:83354-83369

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