Inappropriate expression of genes such as the homeotic (HOX) genes is found in up to 40% of cases of Acute Myelogenous Leukemia (AML). Two well-known genetic subsets, those with MLL-rearrangements and those with NPM1 mutations, are known to possess high-level expression of HOX genes and have been shown to be dependent on continued expression of these genes. Recent studies have defined the protein complexes that maintain this aberrant gene expression. Furthermore, multiple groups and pharma/biotech companies have now developed small molecule inhibitors of these complexes. Some of these small molecules, particularly those targeting DOT1L, EZH2 and Bromodomains) have recently entered early phase trials and have shown interesting biological and some complete clinical responses. Another approach to target chromatin associated complexes is inhibition of the MLL1-Menin interaction, an approach that has also been shown to reverse HOX gene expression. In this proposal we will characterize newly developed MLL1-Menin inhibitors and work to bring one of these small molecules to clinical assessment.
In Specific Aim 1 we will characterize the effects on gene expression and chromatin state after inhibition of the MLL1-Menin interaction in MLL-rearranged and NPM1 mutant AML cells.
In Specific Aim 2 we will assess the combination of MLL1-Menin inhibitors with either azacitidine, DOT1L inhibitors or FLT3 inhibitors.
In Specific Aim 3 we will initiate a phase 1 trial of MLL-1 Menin inhibitors alone and in combination with a azacitidine. These trials that will set the foundation for further assessment of combinations based on results from preclinical studies described here. The proposed experiments will propel MLL1-Menin inhibitors to clinical assessment and importantly define combination approaches that should be assessed in future clinical studies.

Public Health Relevance

Leukemias often arise due to genes being turned on in cells where they should not be active. We now understand the detailed mechanisms by which these genes become and remain active; the mechanisms depend heavily on proteins that control chromosome structure and we have helped developed drugs that inactivate these processes. We will further develop these molecules/drugs and start a trial of a recently developed inhibitor of this process in patients with AML. !

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA206963-02
Application #
9567524
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
DeAngelo, Daniel J; Brunner, Andrew M; Werner, Lillian et al. (2018) A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia. Am J Hematol 93:254-261
Nakamura, Makoto; Wu, Lizi; Griffin, James D et al. (2018) Notch1 activation enhances proliferation via activation of cdc2 and delays differentiation of myeloid progenitors. Leuk Res 72:34-44
Sievers, Quinlan L; Petzold, Georg; Bunker, Richard D et al. (2018) Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362:
Fink, Emma C; McConkey, Marie; Adams, Dylan N et al. (2018) CrbnI391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice. Blood 132:1535-1544
Pikman, Yana; Stegmaier, Kimberly (2018) Targeted therapy for fusion-driven high-risk acute leukemia. Blood 132:1241-1247
Gibson, Christopher J; Kennedy, James A; Nikiforow, Sarah et al. (2017) Donor-engrafted CHIP is common among stem cell transplant recipients with unexplained cytopenias. Blood 130:91-94
Ho, Vincent T; Kim, Haesook T; Bavli, Natalie et al. (2017) Vaccination with autologous myeloblasts admixed with GM-K562 cells in patients with advanced MDS or AML after allogeneic HSCT. Blood Adv 1:2269-2279
Ajore, Ram; Raiser, David; McConkey, Marie et al. (2017) Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations. EMBO Mol Med 9:498-507
Gibson, Christopher J; Lindsley, R Coleman; Tchekmedyian, Vatche et al. (2017) Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol 35:1598-1605
Weisberg, Ellen L; Puissant, Alexandre; Stone, Richard et al. (2017) Characterization of midostaurin as a dual inhibitor of FLT3 and SYK and potentiation of FLT3 inhibition against FLT3-ITD-driven leukemia harboring activated SYK kinase. Oncotarget 8:52026-52044

Showing the most recent 10 out of 13 publications