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Cancers 2017, 9(9), 121; doi:10.3390/cancers9090121

The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL

1
Department of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA
2
Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
These authors contribute equally to this work.
*
Author to whom correspondence should be addressed.
Received: 23 August 2017 / Revised: 6 September 2017 / Accepted: 6 September 2017 / Published: 10 September 2017
(This article belongs to the Special Issue Integrins in Cancer)
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Abstract

The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Aktser473. Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1α in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kδ inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL. View Full-Text
Keywords: ALL; PI3K; drug resistance; CAM-DR; idelalisib; migration; mouse model; leukemia ALL; PI3K; drug resistance; CAM-DR; idelalisib; migration; mouse model; leukemia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Adam, E.; Kim, H.N.; Gang, E.J.; Schnair, C.; Lee, S.; Lee, S.; Khazal, S.; Kosoyan, O.; Konopleva, M.; Parekh, C.; Bhojwani, D.; Wayne, A.S.; Abdel-Azim, H.; Heisterkamp, N.; Kim, Y.-M. The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL. Cancers 2017, 9, 121.

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