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Jacobs, L.* ; Habringer, S.* ; Slawska, J.* ; Huber, K. ; Hauf, E.* ; Li, Z.* ; Refaeli, Y.* ; Schwaiger, M.* ; Rudelius, M.* ; Walch, A.K. ; Keller, U.*

Functional imaging in combination with mutation status aids prediction of response to inhibiting B-cell receptor signaling in lymphoma.

Oncotarget 8, 78917-78929 (2017)

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Aberrant B-cell receptor (BCR) signaling is known to contribute to malignant transformation. Two small molecule inhibitors targeting BCR pathway signaling include ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and idelalisib, a specific Phosphatidylinositol-4,5-bisphosphate 3-kinase delta (PI3Kd) inhibitor, both of which have been approved for use in haematological malignancies. Despite the identification of various diffuse large B-cell lymphoma (DLBCL) subtypes, mutation status alone is not sufficient to predict patient response and therapeutic resistance can arise. Herein we apply early molecular imaging across alternative activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL subtypes to investigate the effects of BCR pathway inhibition. Treatment with both inhibitors adversely affected cell growth and viability. These effects were partially predictable based upon mutation status. Accordingly, very early 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ( 18 F-FDG-PET) and 3'-deoxy-3'[18F]-fluorothymidine positron emission tomography ( 18 F-FLT-PET) reported tumour regression and reductions in tumour metabolism and proliferation upon treatment. Furthermore, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) identified alterations in the proteome of a model of ABC DLBCL upon treatment with ibrutinib or idelalisib. In conclusion we demonstrate that very early molecular imaging adds predictive value in addition to mutational status of DLBCL that may be useful in directing patient therapy.

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Publication type Article: Journal article

Document type Scientific Article

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Keywords B-cell Receptor Signaling ; Functional Imaging ; Lymphoma ; Maldi Imaging Mass Spectrometry ; Positron Emission Tomography; Chronic Lymphocytic-leukemia; Nf-kappa-b; Nedd8-activating Enzyme-inhibitor; Protein Expression Profiles; Thymosin Beta-10 Gene; Mass-spectrometry; Waldenstroms Macroglobulinemia; Antibody Microarrays; Breast-cancer; Idelalisib

ISSN (print) / ISBN 1949-2553

e-ISSN 1949-2553

Journal OncoTarget

Quellenangaben Volume: 8, Issue: 45, Pages: 78917-78929

Publisher Impact Journals LLC

Publishing Place Orchard Park

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Analytical Pathology (AAP)