Lenalidomide, a derivative of thalidomide, is a transformative therapy for a subset of patients with myelodysplastic syndrome, and has demonstrated promise in early clinical trials in acute myeloid leukemia (AML), but the mechanism of lenalidomide activity in myeloid malignancies is not known. We have identified and validated an E3 ubiquitin ligase, CRL4-CRBN, as a direct target of lenalidomide, consistent with previous reports that this complex is targeted by thalidomide. We hypothesize that the pleitropic effects of lenalidomide, including its therapeutic efficacy in myeloid malignancies, is due to altered ubiquitination of targets ofthe CRL4-CRBN ubiqutin ligase.
In Aim 1, we will use a recentiy developed proteomic approach to define the proteins that are differentially ubiquitinated in AML cells in response to lenalidomide, and we will validate that these proteins are direct targets of the CRL4-CRBN ubiquifin ligase using genetic tools and biochemical assays.
In Aim 2, we will use similar approaches to define the molecular basis of the immunomodulatory properties of lenalidomide that lead to alterations in the bone marrow microenvironment. These effects may be critical for the therapeutic efficacy of lenalidomide.
In Aim 3, we will investigate how altered ubiquitination of specific proteins may sensitize cells to additional therapies. Significant responses to lenalidomide as a single agent have been reported in AML, but only a subset of pafients respond, and complete remissions are of short duration. We will therefore seek to improve the therapeutic potential of lenalidomide by examing combinations with addifional therapies in collaboration with each of the other projects in this POl. In addition, we will examine ubiquitinated proteins and genetic abnormalities in patients treated with lenalidomide plus induction chemotherapy in a clinical trial proposed in Project 5. These studies will elucidate a novel mechanism for a cancer therapy, the direct targeting of a specific ubiquitin ligase with both cell autonomous and cell non-autonomous effects. In addition, we will identify novel combinations of lenalidomide with additional agents to develop more efficacious treatments for AML.

Public Health Relevance

Lenalidomide is an effective therapy for the treatment of specific hematologic malignancies, but its mechanism of action is unknown. We will examine the molecular basis for lenalidomide activity and identify novel approaches to the treatment of acute myeloid leukemia based on combinations of lenalidomide with additional therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA066996-16A1
Application #
8666229
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Project Start
1997-04-25
Project End
2019-08-31
Budget Start
2014-09-16
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
$327,796
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Townsend, Elizabeth C; Murakami, Mark A; Christodoulou, Alexandra et al. (2016) The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell 29:574-86
Arreba-Tutusaus, P; Mack, T S; Bullinger, L et al. (2016) Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. Leukemia 30:1220-5
Tanaka, Minoru; Roberts, Justin M; Seo, Hyuk-Soo et al. (2016) Design and characterization of bivalent BET inhibitors. Nat Chem Biol 12:1089-1096
Wu, H; Hu, C; Wang, A et al. (2016) Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia 30:173-81
Wu, H; Hu, C; Wang, A et al. (2016) Ibrutinib selectively targets FLT3-ITD in mutant FLT3-positive AML. Leukemia 30:754-7
Puram, Rishi V; Kowalczyk, Monika S; de Boer, Carl G et al. (2016) Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML. Cell 165:303-16
Brien, Gerard L; Valerio, Daria G; Armstrong, Scott A (2016) Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs. Cancer Cell 29:464-76
Zhu, Nan; Chen, Mo; Eng, Rowena et al. (2016) MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J Clin Invest 126:997-1011
Schneider, Rebekka K; Schenone, Monica; Ferreira, Monica Ventura et al. (2016) Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med 22:288-97
Hatcher, John M; Weisberg, Ellen; Sim, Taebo et al. (2016) Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor. ACS Med Chem Lett 7:476-81

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