PMID- 28891959 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201209 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 9 IP - 9 DP - 2017 Sep 10 TI - The PI3Kdelta Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL. LID - 10.3390/cancers9090121 [doi] LID - 121 AB - 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 PI3Kdelta-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-1alpha in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kdelta 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. FAU - Adam, Etai AU - Adam E AD - 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. FAU - Kim, Hye Na AU - Kim HN AD - 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. FAU - Gang, Eun Ji AU - Gang EJ AD - 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. FAU - Schnair, Caitlin AU - Schnair C AD - 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. FAU - Lee, Solomon AU - Lee S AD - 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. FAU - Lee, Solah AU - Lee S AD - 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. FAU - Khazal, Sajad AU - Khazal S AD - 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. AD - Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. okosoyan@live.com. FAU - Kosoyan, Osanna AU - Kosoyan O AD - 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. FAU - Konopleva, Marina AU - Konopleva M AD - Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. dbhojwani@chla.usc.edu. FAU - Parekh, Chintan AU - Parekh C AD - 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. FAU - Bhojwani, Deepa AU - Bhojwani D AD - 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. FAU - Wayne, Alan S AU - Wayne AS AD - 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. FAU - Abdel-Azim, Hisham AU - Abdel-Azim H AD - 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. FAU - Heisterkamp, Nora AU - Heisterkamp N AD - 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. FAU - Kim, Yong-Mi AU - Kim YM AD - 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. LA - eng GR - T32 CA009659/CA/NCI NIH HHS/United States GR - R01 CA090321/CA/NCI NIH HHS/United States GR - R01 CA172040/CA/NCI NIH HHS/United States GR - R01 CA172896/CA/NCI NIH HHS/United States GR - P30 CA014089/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20170910 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC5615336 OTO - NOTNLM OT - ALL OT - CAM-DR OT - PI3K OT - drug resistance OT - idelalisib OT - leukemia OT - migration OT - mouse model COIS- Gilead Sciences provided the drugs and some funding for this research; aside from that the authors declare no conflict of interest. EDAT- 2017/09/12 06:00 MHDA- 2017/09/12 06:01 PMCR- 2017/09/10 CRDT- 2017/09/12 06:00 PHST- 2017/08/23 00:00 [received] PHST- 2017/09/06 00:00 [revised] PHST- 2017/09/06 00:00 [accepted] PHST- 2017/09/12 06:00 [entrez] PHST- 2017/09/12 06:00 [pubmed] PHST- 2017/09/12 06:01 [medline] PHST- 2017/09/10 00:00 [pmc-release] AID - cancers9090121 [pii] AID - cancers-09-00121 [pii] AID - 10.3390/cancers9090121 [doi] PST - epublish SO - Cancers (Basel). 2017 Sep 10;9(9):121. doi: 10.3390/cancers9090121.