Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer

Oh, Yun; Herbst, Roy S.; Burris, Howard A.; Cleverly, Ann; Musib, Luna; Lahn, Michael; Bepler, Gerold

doi:10.1200/jco.2007.14.3685

Cited by 59 publications

(47 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In a clinical study performed in our institution enzastaurin reduced VEGF plasma levels . However, a recent clinical trial in advanced NSCLC patients treated with enzastaurin did not show a consistent change in plasma VEGF levels, but low baseline VEGF levels were associated with longer progression-free survival (Oh et al, 2008). Therefore, future studies are warranted to determine whether VEGF levels can be used as a predictive marker of the activity of enzastaurin alone or in combination with other anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, other inhibitors of PKCs, such as staurosporine and its analogue UCN-01, have the same properties as enzastaurin when it comes to inhibition of the cell cycle, but are less selective than enzastaurin. This non-selective inhibition of PKCs makes them too toxic and hence their use in the clinical setting seems limited, whereas enzastaurin which is a selective PKCb inhibitor, has shown to be well-tolerated by patients in clinical trials (Carducci et al, 2006;Oh et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Currently enzastaurin is being evaluated in several clinical trials and tolerability and survival data obtained in a recent phase II trial as second-or third-line therapy in NSCLC suggest further evaluation in combination with cytotoxic drugs (Oh et al, 2008). Indeed other studies have demonstrated the safety of enzastaurin combination with conventional chemotherapy (Hanauske et al, 2006;Rademaker-Lakhai et al, 2007), and the inhibition of selected targets, including PKCb, can enhance the effect of cytotoxic drugs, such as pemetrexed.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

et al. 2008

View full text Add to dashboard Cite

Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKCb inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription -PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3b and Akt phosphorylation, which was additionally reduced by drug combination (À58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (450% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Despite significant activity in preclinical models, enzastaurin did not show significant activity in human subjects with glioblastoma multiforme or heavily pretreated advanced breast cancer (5,28). 5 Although the primary end point of a 20% PFS rate was not achieved with enzastaurin as salvage therapy in patients with advanced non-small cell lung cancer, 13% exhibited a progression-free survival of ≥6 months, which might indicate a significant benefit in an undefined subset of patients (29). Given the activity in lymphomas, enzastaurin is being evaluated in a phase III trial as maintenance therapy for the treatment of non-Hodgkin's lymphoma in the Preventing Relapse in Lymphoma Using Daily Enzastaurin trial (8,9).…”

Section: Discussionmentioning

confidence: 99%

Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine

Jian

Yamashita²,

Levitt³

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through protein kinase C (PKC)-β and the phosphatidylinositol 3-kinase/AKT pathways. We preclinically evaluated enzastaurin alone and in combination with gemcitabine for transitional cell cancer (TCC). Immunohistochemistry (IHC) was done on 105 human samples from a microarray to show the expression of PKC-β. The preclinical antitumor activity of enzastaurin and gemcitabine as single agents and in combination against aggressive human -lines (-SUP and 5637) and murine subcutaneous xenografts bearing 5637 cells was determined. Western Blot was done on tumor cells in vitro to detect signaling through PKC-β, GSK-3β, and AKT. The effect on cell migration was determined in vitro. Modulation of proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (CD31) in vivo was determined by IHC. IHC done on human TCC samples from a microarray showed the expression of PKC-β in 33% of tumors. Enzastaurin induced significant apoptosis and inhibited proliferation in vitro at low micromolar concentrations. The in vitro inhibitory activity of combination enzastaurin and gemcitabine by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay seemed synergistic. Western Blotting revealed down-regulation of Akt, PKC-β, and GSK-3 β phosphorylation. Enzastaurin inhibited migration at an earlier time point independent of antiproliferative activity. Combination therapy had significantly superior antitumor activity in murine xenografts compared with untreated controls, whereas single agents did not. IHC showed reduced Ki-67 and CD31 and increased cleaved caspase-3 with combination therapy compared with controls. Enzastaurin showed preclinical antitumor activity against human TCC and enhanced the activity of gemcitabine.

show abstract

“…Several tyrosine kinase inhibitors and serine/threonine kinase inhibitors that block serine/threonine signaling pathways have been introduced as anti-neoplastic agents against lung cancer (4,5). Therefore, we attempted to characterize the association between the polymorphisms of the PIM-1 gene that encodes serine/threonin kinase and the risk of developing lung cancer in a Korean population by using genotype and haplotype analysis.…”

Section: Introductionmentioning

confidence: 99%

Association of Single Nucleotide Polymorphisms in PIM-1 Gene with the Risk of Korean Lung Cancer

et al. 2008

View full text Add to dashboard Cite

Purpose:The expression of the PIM-1 gene, which is a proto-oncogene that encodes a serine/threonine kinase, is associated with multiple cellular functions such as proliferation, differentiation, apoptosis and tumorigenesis. In particular, several studies have reported that the PIM-1 gene is associated with the development of lymphoma, leukemia and prostate cancer. Therefore, this study was conducted to evaluate the association between the single nucleotide polymorphisms in the PIM-1 gene and the risk of lung cancer occurrence in the Korean population.Materials and Methods: To evaluate the role of the PIM-1 gene in the development of lung cancer, the genotypes of the PIM-1 gene were determined in 408 lung cancer patients and 410 normal subjects. Results: We found that the T-C-T-C haplotypes of the

show abstract

Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer

Abstract: Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for >or= 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.

Cited by 59 publications

References 43 publications

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine

Association of Single Nucleotide Polymorphisms in PIM-1 Gene with the Risk of Korean Lung Cancer

Contact Info

Product

Resources

About