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

Etai Adam; Hye Na Kim; Eun Ji Gang; Caitlin Schnair; Solomon Lee; Solah Lee; Sajad Khazal; Osanna Kosoyan; Marina Konopleva; Chintan Parekh; Deepa Bhojwani; Alan S Wayne; Hisham Abdel-Azim; Nora Heisterkamp; Yong-Mi Kim

doi:10.3390/cancers9090121

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

Cancers (Basel). 2017 Sep 10;9(9):121. doi: 10.3390/cancers9090121.

Authors

Etai Adam¹, Hye Na Kim², Eun Ji Gang³, Caitlin Schnair⁴, Solomon Lee⁵, Solah Lee⁶, Sajad Khazal^{7

8}, Osanna Kosoyan⁹, Marina Konopleva¹⁰, Chintan Parekh¹¹, Deepa Bhojwani¹², Alan S Wayne¹³, Hisham Abdel-Azim¹⁴, Nora Heisterkamp¹³, Yong-Mi Kim¹⁵

Affiliations

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. etaiadam@gmail.com.
² 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. hyekim@chla.usc.edu.
³ 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. ejiang@chla.usc.edu.
⁴ 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. cschnair@chla.usc.edu.
⁵ 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. solalee@chla.usc.edu.
⁶ 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. sjkhazal@mdanderson.org.
⁷ 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. okosoyan@live.com.
⁸ Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. okosoyan@live.com.
⁹ 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. cparekh@chla.usc.edu.
¹⁰ Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. dbhojwani@chla.usc.edu.
¹¹ 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. awayne@chla.usc.edu.
¹² 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. habdelazim@chla.usc.edu.
¹³ 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. heisterk@usc.edu.
¹⁴ 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. mkonople@mdanderson.org.
¹⁵ 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. ymkim@chla.usc.edu.

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-Akt^ser473. 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.

Keywords: ALL; CAM-DR; PI3K; drug resistance; idelalisib; leukemia; migration; mouse model.

Abstract

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