Essentially all chemotherapeutic drugs commonly used in the treatment of cancer, as well as radiation, have been shown to ultimately kill tumor cells by triggering a form of cell death called """"""""apoptosis"""""""". Consequently, alterations in the regulation of cellular genes that control the apoptotic cell death process can play an important role in determining he relative chemosensitivity and resistance of tumors. Members of the Bcl-2 family of proteins are critical regulators of apoptosis, with some functioning as blockers of apoptosis (Bcl-2, Bcl-XL, Mcl-1) and others acting o promote cell death (Bax, Bcl-Xs, and Bad). Elevations in Bcl-2 expression have been associated with chemoresistance in several settings. Furthermore, recently we have shown that alterations in the expression of other members of this gene family such as Bcl-XL and Bax can occur in drug-resistant cancers, in the absence of changes in Bcl-2. We therefore propose to compare the relative levels of Bcl-2, Bcl-X, Mcl-1, Bax, and other members of the Bcl-2 family in AMLs, using antibodies which we have raised. These results will be correlated with response rates, remission duration, and overall survival. Comparisons will be made at the time of diagnosis and again at relapse, thus determining whether alterations in Bcl-2 family gene expression occur in association with progression of a chemoresistant phenotype. Bcl-2 family protein levels will also be correlated with cytogenetic data in an effort to seek an explanation for the differential clinical behavior of AMLs in the favorable (inv 16 and 8;21) and unfavorable (monosomy 5 and 7, 5q-, and trisomy 8) prognostic groups. Finally, biological response modifiers, including cytokines and retinoids, will be employed in an attempt to identify methods for altering the ratios of anti-and pro-apoptotic Bcl-2 family proteins and thus rendering AML cells more sensitive to chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055164-09
Application #
6338676
Study Section
Project Start
2000-08-04
Project End
2001-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
9
Fiscal Year
2000
Total Cost
$163,224
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
001910777
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
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
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

Showing the most recent 10 out of 422 publications