New targeted therapies are urgently needed for acute myeloid leukemia (AML), where little progress has been made in improving long-term patient survival despite significant inroads into understanding the molecular pathogenesis of this disease. We previously discovered spleen tyrosine kinase (SYK) as a new target in AML, with FLT3-ITD a biomarker of response to SYK inhibitors in AML cells. These findings become immediately translatable as numerous SYK inhibitors are entering clinical trials for patients with cancer, including AML. The translation of SYK inhibitors to the clinic for patients with AML is the focus of this project.
In Aim 1 of this proposal, we will study SYK activation in AML cell lines and patient blasts to determine whether SYK activation promotes resistance to current AML therapy. In this Aim, we will also determine whether SYK inhibitors synergize with drugs currently used to treat patients with AML, both in vitro and in vivo, to inform second- generation SYK inhibitor clinical trials.
In Aim 2, we will test specific hypotheses and conduct unbiased functional genomic studies to identify resistance mechanisms to SYK inhibitors in AML. We expect that these experiments will inform new drug combinations for testing with SYK inhibitors.
Aim 3 will focus on performing the correlative biology studies for two Phase I/II clinical trials testing SYK inhibitors in patients with AML. In this Aim, we will use next-generation sequencing of panels of leukemia-associated genes, immunohistochemistry and intracellular phospho-specific flow cytometry to measure activated SYK, BH3 profiling, and gene expression signature assays to identify biomarkers of response to SYK inhibitors and to confirm target inhibition using AML samples from patients treated on the clinical trial. At the completion of this study, we expect to confirm on-target, anti-leukemia activity of a SYK inhibitor in patients with AML and to inform second- generation clinical trials through the identification of drug combinations with SYK inhibitors and through the identification of biomarkers of response in patients with AML treated with a SYK inhibitory drug.

Public Health Relevance

New targeted therapies are urgently needed for acute myeloid leukemia (AML), where cure will be achieved only for a minority of patients despite an improved understanding of the molecular underpinnings of this disease. We discovered that the enzyme spleen tyrosine kinase (SYK) is a potential therapeutic target in AML. In this project, we will study the role of SYK in primary patient AML samples, determine the resistance mechanisms to drugs inhibiting SYK, identify highly effective drug combinations with SYK inhibitors in AML cells in vitro and in mouse models of AML, and perform the essential correlative biology studies to determine predictors of response to SYK inhibitors in two clinical trials testing SYK inhibitors in patients with AML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
7P50CA206963-03
Application #
9920860
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Kuzmin, Igor A
Project Start
Project End
Budget Start
2019-04-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
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

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