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

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.

Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia

“…We then tested the combination of AZD2811 and dex in two patient-derived xenograft lines derived from relapsed B-ALL, LAX7R (KRAS G12A), and LAX56 [t(Y;7)(p1.3;p13)] (53,54). LAX7R and LAX56 were previously shown to be resistant to both dex and vincristine, another component of standard B-ALL combination chemotherapy.…”

New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances

“…CAL‐101 (Idelalisib), in Phase I/II clinical trials, is a p110δ PI3K inhibitor, and it has been tested mainly in B‐ALL, exerting cytotoxic effects with G1 blockage (presumably in consequence to upregulated p21) and inducing caspase‐dependent apoptosis . Remarkably, CAL‐101 was able to decrease Akt phosphorylation at Ser 473 on a panel of B‐ALL cell lines cocultured with OP‐9 stromal cells . It is now studied in a phase I clinical study as a new potential therapeutic alternative for ALL patients with the following characteristics: relapsed, refractory to conventional treatments, and old age (see http://www.clinicaltrials.gov: NCT03742323).…”

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

“…CAL‐101 exerted cytotoxic effects against Nalm‐6 B‐ALL cells mediated by G 1 blockage (presumably as a result of upregulated p21) and induction of caspase‐dependent apoptosis, likely through reactive oxygen species‐dependent upregulation of FOXO3a and subsequent induction of the proapoptotic target genes of p53 (Safaroghli‐Azar, Bashash, Sadreazami, Momeny, & Ghaffari, ). Furthermore, CAL‐101 increased the cytotoxicity of either doxorubicin (Safaroghli‐Azar et al, ) or vincristine (Adam et al, ). Importantly, CAL‐101 was able to decrease Akt phosphorylation at Ser 473 which was increased when B‐ALL cell lines were co‐cultured with OP‐9 stromal cells (Adam et al, ).…”

“…Furthermore, CAL‐101 increased the cytotoxicity of either doxorubicin (Safaroghli‐Azar et al, ) or vincristine (Adam et al, ). Importantly, CAL‐101 was able to decrease Akt phosphorylation at Ser 473 which was increased when B‐ALL cell lines were co‐cultured with OP‐9 stromal cells (Adam et al, ). Furthermore, CAL‐101 inhibited B‐ALL cell migration to CXCL‐12 (SDF‐1α) in vitro and blocked homing of B‐ALL cells to the bone marrow in vivo.…”

“…Furthermore, CAL‐101 inhibited B‐ALL cell migration to CXCL‐12 (SDF‐1α) in vitro and blocked homing of B‐ALL cells to the bone marrow in vivo. It was thus concluded that inhibition of homing of circulating B‐ALL cells to the bone marrow or even mobilization of leukemic cells from their protective niches in the bone marrow might interfere with cell adhesion‐mediated drug‐resistance (Adam et al, ). Overall, these findings support the rationale for clinical testing of p110δ PI3K inhibitors in B‐ALL and provide useful insights needed to optimize the therapeutic strategy.…”