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Zoellner A.-K.,Ludwig Maximilians University of Munich | Zoellner A.-K.,Clinical Cooperative Group Leukemia | Bayerl S.,Clinical Cooperative Group Leukemia | Hutter G.,Clinical Cooperative Group Leukemia | And 5 more authors.
Leukemia and Lymphoma | Year: 2015

Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB = 30-66%, ABC = 45-57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB = 16-38%, ABC = 25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus + bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction. © 2015 Informa UK, Ltd.

Weinkauf M.,Clinical Cooperative Group Leukemia | Hutter G.,Clinical Cooperative Group Leukemia | Zimmermann Y.,Clinical Cooperative Group Leukemia | Hartmann E.,University of Würzburg | And 2 more authors.
Talanta | Year: 2010

Despite recent advances in treatment, mantle cell lymphoma (MCL) still represents a disease with dismal prognosis due to its progressive clinical course, high rate of therapy refractory cases and frequent relapses. During recent years, the proteasome inhibitor bortezomib and enzastaurin, an inhibitor of protein kinase c have been explored in MCL. In relapsed disease enzastaurin achieved disease stabilization in a subset of patients. Bortezomib in relapsed and refractory MCL achieves response rates of 30-40%. To identify signal pathways and manifold interactions regulating cellular response to molecular targeted approaches several high throughput screening methods were applied. A combined network analysis of the identified target molecules based on both RNA array expression data and a survey of cellular protein levels resulted in a unified interaction network more comprehensive (bortezomib: 394 and enzastaurin: 174 molecules) than the networks of the individual screening techniques (329/44 and 117/36 molecules respectively). Interestingly, although none of the target molecules were matched in both RNA-expression and protein level analysis they were mapped nonetheless to common pathways. Additionally, the ranking of identified pathways allowed an improved characterization of the observed induction of cell apoptosis. © 2009 Elsevier B.V. All rights reserved.

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