If stem cell transplant is not feasible, M.D. Anderson patients with relapsed AML typically receive investigational agents as first """"""""salvage therapy,"""""""" particularly if their initial remission has lasted less than one year. Although new agents are available, we do not know how a patient's AML will respond. In this program project, we will study therapies for which a """"""""target"""""""" has been proposed, enabling us to examine relationships between clinical response and the status of the putative target (Specific Aim 1). Patients will be randomized, and we will assess their responses as being predictive of the target as well as study the use of biologic markers to assign patients to specific therapies. A confounding difficulty with Specific Aim 1 is the rarity of CR in relapsed AML. This rarity has motivated new definitions of response (e.g. CR p), which are less demanding than the criteria for CR. Preliminary data in untreated patients suggest that, while CR is essential for cure, patients who achieve CR p live longer than patients who achieve neither CR nor CR p after accounting for the time needed to achieve these responses. These data, and the low rate of CR p in the patients to be studied here, have prompted a plan to continue initial therapy in patients as long as they have neither clinical complications nor a rising peripheral blast count. This approach will allow us to compare the effect of various prospectively-defined responses on survival (Specific Aim 2). Two of the agents we will investigate (GX15-070MS, an inhibitor of the BH3 binding domain of Bcl-2 family members, and the kinase inhibitior BAY43-9006) will be given without chemotherapy;we will refer to these as """"""""non-cytotoxic"""""""" therapies. The other two agents [the XIAP antisense oligonucleotide AEG35156 and AMD3100, an inhibitor of CXCR4 and thus of the blast cell-marrow stroma interaction), while themselves also non-cytotoxic, will be combined with idarubicin + ara-C (IA);these combinations will thus be called """"""""cytotoxic."""""""" We will compare survival in: (a) patients given one of the two cytotoxic combinations only after an unsuccessful trial of one of the two non- cytotoxic agents, (b) patients in whom the alternate approachwas used and (c) patients given IA alone in previous studies. This approach will allow us to test the hypothesis that it appropriate to give some patients with relapsed AML non-cytotoxic therapy as initial treatment for relapse (Specific Aim 3). While such practice is increasingly widespread both in relapsed and untreated AML, its effect on survival remains unknown. Demonstration that, in at least one case, the obvious appeal of this strategy is not offset by a decrease in survival time would presumably be reassuring to patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055164-17
Application #
7928921
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
17
Fiscal Year
2009
Total Cost
$263,310
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Ruvolo, Peter P; Ruvolo, Vivian R; Burks, Jared K et al. (2018) Role of MSC-derived galectin 3 in the AML microenvironment. Biochim Biophys Acta Mol Cell Res 1865:959-969
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 :
Jiang, Xuejie; Mak, Po Yee; Mu, Hong et al. (2018) Disruption of Wnt/?-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia. Clin Cancer Res 24:2417-2429
Ishizawa, Jo; Nakamaru, Kenji; Seki, Takahiko et al. (2018) Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition. Cancer Res 78:2721-2731
Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina et al. (2017) Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1. Oncotarget 8:34552-34564
Carter, Bing Z; Mak, Po Yee; Wang, Xiangmeng et al. (2017) Focal Adhesion Kinase as a Potential Target in AML and MDS. Mol Cancer Ther 16:1133-1144
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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