Functional imaging in combination with mutation status aids prediction of response to inhibiting B-cell receptor signaling in lymphoma
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Laura Jacobs1,*, Stefan Habringer2,6,*, Jolanta Slawska2, Katharina Huber3, Elke Hauf2, Zhoulei Li1, Yosef Refaeli4, Markus Schwaiger1,6, Martina Rudelius5, Axel Walch3 and Ulrich Keller2,6
1Nuclear Medicine Department, Technische Universität München, Munich, Germany
2Internal Medicine III, Technische Universität München, Munich, Germany
3Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
4Department of Dermatology, University of Colorado, Denver, CO, USA
5Department of Pathology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
6German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
*Authors contributed equally to this work
Ulrich Keller, email: [email protected]
Keywords: lymphoma, B-cell receptor signaling, positron emission tomography, MALDI imaging mass spectrometry, functional imaging
Received: April 28, 2017 Accepted: July 31, 2017 Published: August 24, 2017
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 (PI3Kδ) 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 (18F-FDG-PET) and 3’-deoxy-3’[18F]-fluorothymidine positron emission tomography (18F-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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