Chronic lymphocytic leukemia (CLL) is an incurable type of B-cell leukemia. Identifying novel agents that target molecules crucial to CLL cell survival represents a powerful therapeutic strategy for this disease. The anti-apoptotic protein Mcl-1 is one such target in CLL. Reduction of Mcl-1 promotes apoptosis and enhances the efficacy of other CLL therapies. We demonstrated that the novel plant-derived agent silvestrol down-regulates Mcl-1 expression through a translation-mediated mechanism in CLL cells, with subsequent apoptosis. Silvestrol is effective against CLL cells with p53 deletions, and lacks the cellular immune suppression associated with other currently available CLL therapies. As a consequence of our work to date, silvestrol was recently selected for full preclinical development by the NCI Developmental Therapeutics Program Drug Development Group at the Stage IIA level. The research proposed here will complement the NCI preclinical work by conducting crucial mechanistic and translational investigations of silvestrol, and ultimately, a Phase I clinical trial in refractory CLL. The driving hypothesis of this investigation is that silvestrol mediates potent cytotoxicity against CLL cells via translational inhibition of the Mcl-1 protein and will represent an effective and well-tolerated therapy for CLL patients. To pursue this hypothesis, we have proposed four aims:
Aim 1 is to determine the precise mechanism of silvestrol-mediated translational inhibition and subsequent apoptosis in CLL cells.
Aim 2 includes pre-clinical in vitro and in vivo studies with silvestrol in CLL cells and murine leukemia models to identify rational combination strategies with known agents.
Aim 3 will develop strategies to further enhance tumor cell exposure and in vivo efficacy of silvestrol through the use of silvestrol-loaded nanoparticles.
In Aim 4, we will pursue a Phase I clinical trial to assess silvestrol safety, maximum tolerated dose, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy in patients with relapsed, refractory CLL. Using these approaches and working in concert with the NCI efforts, the proposed research will greatly accelerate the development of silvestrol for clinical use in CLL and other B-cell malignancies.

Public Health Relevance

The incurable disease B-cell chronic lymphocytic leukemia (CLL) presents 15,000+ new cases annually in the US. CLL results in profound immune suppression with subsequent risk of lethal opportunistic infections. Available treatments that kill B tumor cells also kill infection-fighting T cells, leaving patients at further risk. Silvestrol effectively and selectively kills B cells relative to T cells, using a mechanism unlike any drug now available for CLL. Thus, clinical use of silvestrol could potentially improve survival and reduce infections. Such an agent is also likely to be effective in other B cell cancers including lymphomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA140158-05
Application #
8521129
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$251,385
Indirect Cost
$59,736
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Mims, Alice S; Mishra, Anjali; Orwick, Shelley et al. (2018) A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. Haematologica 103:982-987
Walker, Christopher J; Oakes, Christopher C; Genutis, Luke K et al. (2018) Genome-wide association study identifies an acute myeloid leukemia susceptibility locus near BICRA. Leukemia :
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2018) Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies. Leukemia 32:1338-1348
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2018) NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome. Leukemia 32:2536-2545
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2017) Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res 77:207-218
Eisfeld, A-K; Kohlschmidt, J; Schwind, S et al. (2017) Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia. Leukemia 31:1278-1285
Walker, C J; Eisfeld, A-K; Genutis, L K et al. (2017) No evidence for microsatellite instability in acute myeloid leukemia. Leukemia 31:1474-1476
Wiczer, Tracy E; Levine, Lauren B; Brumbaugh, Jessica et al. (2017) Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib. Blood Adv 1:1739-1748
Miller, Cecelia R; Ruppert, Amy S; Heerema, Nyla A et al. (2017) Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood Adv 1:1584-1588
Tsai, Yo-Ting; Lakshmanan, Aparna; Lehman, Amy et al. (2017) BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia. Blood Adv 1:2147-2160

Showing the most recent 10 out of 229 publications