Phase II Study of Enzastaurin, a Protein Kinase C Beta Inhibitor, in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Robertson, Michael J.; Kahl, Brad S.; Vose, Julie M.; Vos, Sven de; Laughlin, Mary J.; Flynn, Patrick J.; Rowland, Kendrith M.; Cruz, José C.; Goldberg, Stuart L.; Musib, Luna; Darstein, Christelle; Enas, Nathan; Kutok, Jeffery L.; Aster, Jon C.; Neuberg, Donna; Savage, Kerry J.; LaCasce, Ann S.; Thornton, Donald E.; Slapak, Christopher A.; Shipp, Margaret A.

doi:10.1200/jco.2006.09.3146

Cited by 229 publications

(149 citation statements)

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“…18 This finding led to a phase II study of enzastaurin (LY317615) in the treatment of relapsed DLBCL. 19 Preliminary results indicate that the drug is well tolerated and, in heavily treated patients, a 22% freedom from progression was obtained.…”

Section: Discussionmentioning

confidence: 95%

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma

et al. 2007

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Recent studies of gene expression and immunohistochemistry have shown that protein kinase C-beta II (PKCbeta II) might have prognostic significance in patients with diffuse large B-cell lymphoma (DLBCL). We sought to determine the prognostic significance of the expression of PKC-beta II in patients with nodal DLBCL. Formalin-fixed, paraffin-embedded tissues were stained with a monoclonal antibody to PKC-beta II protein. A total of 125 patients were studied; 83 patients (66%) were in the low-risk International Prognostic Index (IPI) group. Forty-eight patients (38%) were positive for PKC-beta II. Complete remission was obtained in 70%, and was not influenced by the PKC-beta II status (67 vs 71%). The 5-year event-free survival (EFS) was worse in highrisk patients (14 vs 58%, Po0.001) and in those with PKC-beta II positivity (36 vs 49%, P ¼ 0.054). In low-risk IPI patients, PKC-beta II expression was related to a worse 5-year overall survival (OS) (60 vs 76%, P ¼ 0.033) and a worse 5-year EFS (48 vs 66%, P ¼ 0.014). In a Cox regression analysis for EFS, both PKC-beta II expression (hazard ratio ¼ 1.68, P ¼ 0.037) and the IPI (HR ¼ 3.07, Po0.001) were independent poor prognostic factors. PKCbeta II (HR ¼ 1.72, P ¼ 0.046) and the IPI (HR ¼ 5.16, Po0.001) were also independent poor prognostic factors for the OS. PKC-beta II expression, along with the IPI, were associated with a worse EFS and OS in patients with nodal DLBCL specially in low-risk IPI patients.

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Section: Discussionmentioning

confidence: 95%

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma

et al. 2007

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“…Enzastaurin is a selective PKCβ inhibitor that is under clinical investigation as anticancer drug in phase II trials [1][2][3]. The PKC family of serine-threonine protein kinases have not only been implicated in the processes that control tumor cell growth, survival, and progression [43], but also in the processes essential for NK cell function [4-6, 20, 44-46].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, enzastaurin inhibited glycogen synthase kinase 3 (GSK3) phosphorylation both in tumor tissues and peripheral blood mononuclear cells (PBMC) from treated mice [1]. It is currently used in phase II trials for the treatment of colon cancer, refractory glioblastoma and diffuse large B cell lymphoma [2,3].…”

Section: Introductionmentioning

confidence: 99%

The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β

Ogbomo

Biru

Michaelis

et al. 2011

Biochemical Pharmacology

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Please cite this article as: Ogbomo H, Biru T, Michaelis M, Loeschmann N, Doerr HW, Cinatl Jr. J, The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3␤, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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“…We sought to determine to what extent enzastaurin treatment would inhibit signaling throughout this pathway in cancer cell lines representing diverse cellular lineages (colon carcinoma, glioma, B-cell lymphoma). The chosen clinical dose for enzastaurin (500 or 525 mg per day) routinely yields 3 mmol/L mean plasma concentrations of total drug, reaching 8 mmol/L in some patients (26,27). We therefore evaluated enzastaurin at 1 to 4 mmol/ L.…”

Section: Resultsmentioning

confidence: 99%

Modulation of 4E-BP1 Function as a Critical Determinant of Enzastaurin-Induced Apoptosis

Dumstorf

Konicek²,

McNulty³

et al. 2010

Molecular Cancer Therapeutics

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Enzastaurin (LY317615.HCl) is currently in a phase III registration trial for diffuse large B-Cell lymphoma and numerous phase II clinical trials. Enzastaurin suppresses angiogenesis and induces apoptosis in multiple human tumor cell lines by inhibiting protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathway signaling. PI3K/AKT pathway signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding proteins (4E-BP). When hypophosphorylated, 4E-BPs associate with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex. Herein, we show that enzastaurin treatment impacts signaling throughout the AKT/mTOR pathway leading to hypophosphorylation of 4E-BP1 in cancer cells of diverse lineages (glioblastoma, colon carcinoma, and B-cell lymphoma). Accordingly, enzastaurin treatment increases the amount of eIF4E bound to 4E-BP1 and decreases association of eIF4E with eIF4G, thereby reducing eIF4F translation initiation complex levels. We therefore chose to evaluate whether this effect on 4E-BP1 was involved in enzastaurin-induced apoptosis. Remarkably, enzastaurin-induced apoptosis was blocked in cancer cells depleted of 4E-BP1 by siRNAs, or in 4EBP1/2 knockout murine embryonic fibroblasts cells. Furthermore, eIF4E expression was increased and 4E-BP1 expression was decreased in cancer cells selected for reduced sensitivity to enzastaurininduced apoptosis. These data highlight the importance of modulating 4E-BP1 function, and eIF4F complex levels, in the direct antitumor effect of enzastaurin and suggest that 4E-BP1 function may serve as a promising determinant of enzastaurin activity.

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Phase II Study of Enzastaurin, a Protein Kinase C Beta Inhibitor, in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Abstract: Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

Cited by 229 publications

References 20 publications

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma

The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β

Modulation of 4E-BP1 Function as a Critical Determinant of Enzastaurin-Induced Apoptosis

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