Somatic mutations in the core components of the pre-mRNA splicing complex, the spliceosome, are the most common genetic lesions in patients with myelodsyplastic syndromes (MDS). Specifically, recurrent missense mutations in the SF3B1 gene are present in 10-20% of all MDS cases. Inhibitors of SF3B1 have been developed and represent a promising new frontier for MDS therapy. We propose to develop pre-clinical models of Sf3b1 mutation, to test a novel SF3B1 inhibitor in these models, alone or in combination with azacitidine; and to perform correlative studies on a Phase I/II clinical trial of an SF3B1 inhibitor in collaboration with H3 Biomedicine. H3 Biomedicine has generated a compound, H3B 8800, that shows promising mutant- selective activity in cell lines and that is poised for clinical trials. The Ebert laboratory has developed a conditional knock-in mouse model that expresses the Sf3b1 K700E mutation, the most common mutation in MDS patients. Since SF3B1 mutations commonly co-occur with mutations in DNMT3A in MDS, we will create a model with both conditional Sf3b1 knock-in mutation and conditional Dnmt3a inactivation. We will test H3B 8800 in this model and will test the combination of H3B 8800 with azacitidine, a drug with efficacy in MDS and in TET2-mutated cases in particular. We will identify mechanisms of resistance to H3B 8800 using a genome- wide CRISPR-Cas9 screen. Finally, we will examine the safety and efficacy of H3B 8800 in MDS patients in a phase I/II clinical trial. This first-in-class agent has the potential for major clinical impact in a large fraction of MDS cases with aberrant spliceosome function due to somatic mutations. The studies described in this proposal will define the activity of the drug in different genetic backgrounds, examine the activity of the drug in hematopoietic stem and progenitor cells, identify mechanisms of therapy resistance as well as insights into the mode of action of the drug, and examine therapeutic efficacy in patients.
Mutations in genes involved in mRNA splicing are the most common class of mutations in myelodysplastic syndromes (MDS). The most commonly mutated splicing gene in MDS is SF3B1, and a drug targeting SF3B1, H3B 8800, has been developed with great therapeutic potential for the treatment of MDS. We propose to examine the efficacy of H3B 8800 in pre-clinical models, explore mechanisms of resistance, and perform correlative studies on a clinical trial of H3B 8800 in MDS patients.
|Pikman, Yana; Stegmaier, Kimberly (2018) Targeted therapy for fusion-driven high-risk acute leukemia. Blood 132:1241-1247|
|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|
|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