Acute myeloid leukemia (AML) comprises a genetically and clinically heterogeneous group of aggressive hematological malignancies. Despite advances in molecular characterization of AML, the majority of patients will relapse and die of their disease. In AML, oxidative phosphorylation (OxPhos) generates intracellular energy and metabolic intermediates necessary to promote growth and support survival. Unlike normal hematopoietic stem cells, AML and leukemia stem cells (LCS) overexpress anti- apoptotic mitochondrial protein Bcl-2, rely on OxPhos and are unable to utilize glycolysis when mitochondrial respiration is inhibited, indicating that the maintenance of mitochondrial function is essential for AML survival. We have identified a novel potent nanomolar inhibitor of OxPhos (OxPhosi) IACS-010759, selected from the series of more than 1,000 compounds across distinct structural classes. IACS-010759 has been found to inhibit complex I of OxPhos respiratory chain and block oxygen consumption. Our data demonstrated profound growth-inhibitory and pro-apoptotic effects of this agent in AML cell lines and primary AML cells at low nM concentrations, with minimal toxicity against normal BM cells. In turn, combination of OxPhos inhibitors and Bcl-2 inhibitor venetoclax is synergistic in AML. Daily dosing of IACS-010759 was well tolerated in mice, demonstrated strong efficacy in the in vivo xenograft studies utilizing the human AML patient-derived xenografts (PDX) and reduced phenotypically defined LSC fractions measured by novel technique of mass cytometry, CyTOF. Administration of OxPhosi following standard chemotherapy extended survival in primary AML PDX model. A Phase I clinical trial of IACS- 010759 in relapsed/refractory AML was recently launched at MDACC. We propose to test the hypothesis that OxPhos inhibition constitutes a novel therapeutic approach that targets a unique metabolic vulnerability of AML; and that combined blockade of mitochondrial respiration by OxPhos and Bcl-2 inhibitors will eliminate leukemia-initiating cells and produce objective responses. We will establish biomarkers of response to OxPhosi in vitro including RNA and metabolomics signatures, in a large series of primary AML with known genetic profiling, and validate these in the in vivo AML PDX models. We will further determine mechanisms of synergistic AML cell death when OxPhos inhibition is primed by Bcl-2 blockade with venetoclax, and characterize anti-AML and anti-LSC efficacy of such combination. We will further metabolically profile AML cells surviving standard chemotherapy, and test the hypothesis that OxPhosi will reduce or eliminate residual surviving AML cells. These concepts will be translated into Phase 1/2 study of standard chemotherapy and of Bcl- 2 inhibitor Venetoclax combined with IACS-010759 in patients with relapsed/refractory AML.

Public Health Relevance

A leukemia called AML cannot be cured by current treatments in more than half of adult patients. This project will test novel experimental drug affecting tumor metabolism, alone and in combinations, for suppression of AML disease development in laboratory models. Phase I/II clinical trial will examine safety and efficacy of combinations with standard chemotherapy or with targeted therapies in relapsed/refractory AML.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Yan, Fangrong; Zhu, Huihong; Liu, Junlin et al. (2018) Design and inference for 3-stage bioequivalence testing with serial sampling data. Pharm Stat 17:458-476
Kelly, Andrew D; Madzo, Jozef; Madireddi, Priyanka et al. (2018) Demethylator phenotypes in acute myeloid leukemia. Leukemia 32:2178-2188
Levis, Mark J; Perl, Alexander E; Altman, Jessica K et al. (2018) A next-generation sequencing-based assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations. Blood Adv 2:825-831
Shah, Maitri Y; Ferracin, Manuela; Pileczki, Valentina et al. (2018) Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations. Genome Res 28:432-447
Masarova, Lucia; Verstovsek, Srdan; Hidalgo-Lopez, Juliana E et al. (2018) A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis. Blood 132:1664-1674
Good, Charly Ryan; Panjarian, Shoghag; Kelly, Andrew D et al. (2018) TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer. Cancer Res 78:4126-4137
Choi, Sangbum; Kang, Sangwook; Huang, Xuelin (2018) Smoothed quantile regression analysis of competing risks. Biom J 60:934-946
Boddu, Prajwal; Kantarjian, Hagop; Garcia-Manero, Guillermo et al. (2018) The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma 59:790-802
Yang, Tian-Hui; St John, Lisa S; Garber, Haven R et al. (2018) Membrane-Associated Proteinase 3 on Granulocytes and Acute Myeloid Leukemia Inhibits T Cell Proliferation. J Immunol 201:1389-1399
Rivera-Del Valle, Nilsa; Cheng, Tiewei; Irwin, Mary E et al. (2018) Combinatorial effects of histone deacetylase inhibitors (HDACi), vorinostat and entinostat, and adaphostin are characterized by distinct redox alterations. Cancer Chemother Pharmacol 81:483-495

Showing the most recent 10 out of 487 publications