Combination of drug therapy in acute lymphoblastic leukemia with a CXCR4 antagonist

Abstract

The bone marrow (BM) stromal niche can protect acute lymphoblastic leukemia (ALL) cells against the cytotoxicity of chemotherapeutic agents and is a possible source of relapse. The SDF-1/CXCR4 axis is a major determinant in the crosstalk between leukemic cells and BM stroma. In the current study, we investigated the use of AMD11070, an orally available, small molecule antagonist of CXCR4, as an ALL-sensitizing agent. This compound effectively blocked stromal-induced migration of human ALL cells in culture and disrupted pre-established adhesion to stroma. To examine how to optimally use this compound in vivo, several combinations with cytotoxic drugs were tested in a stromal co-culture system. The best treatment regimen was then tested in vivo. Mice transplanted with murine Bcr/Abl ALL cells survived significantly longer when treated with a combination of nilotinib and AMD11070. Similarly, immunocompromised mice transplanted with human ALL cells and treated with vincristine and AMD11070 had few circulating leukemic cells, normal spleens and reduced human CD19+ cells in the bone marrow at the termination of the experiment. These results show that combined treatment with AMD11070 may be of significant benefit in eradicating residual leukemia cells at locations where they would otherwise be protected by stroma.

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

“…These data indicate the feasibility of using combinations of CXCR4 inhibitors and TKIs in CML and Ph( þ ) ALL. 13 Although this concept has already demonstrated improved therapeutic efficacy in the preclinical models of AML and multiple myeloma, 38,40,41 and has translated in the ongoing clinical trials, our findings indicate the alternative approach of lipid raft disruption to ameliorate microenvironmental resistance. The data presented here, indicate that lipid rafts facilitate key functional coupling between crosslinked CXCR4 and Lyn.…”

“…12 These in vitro observations were recently substantiated by the in vivo studies, whereby disruption of the CXCL12/CXCR4 axis by CXCR4 antagonists restored the sensitivity of Bcr-Abl-expressing cells to TKIs and prolonged the survival of mice co-treated with CXCR4 inhibitor and TKI. 4,11,13 However, the molecular mechanisms of interplay between CXCR4 and Bcr-Abl signaling have not been understood.…”

Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140

“…CXCR4 neutralization with small molecules such as AMD3100, AMD11070, and AMD3465 were already shown to reverse the protective effect of stroma and induce chemosensitivity in multiple myeloma, mantle cell lymphoma, AML, ALL, and CLL (22,25,(34)(35)(36)(37).…”

Acute lymphoblastic leukemia cells create a leukemic niche without affecting the CXCR4/CXCL12 axis

“…9,10 However, in mice suffering from ALL, CXCR4/CXCL12 inhibition as mono-treatment did not reduce the leukemic cell number in the bone marrow. 9,11 In addition, CXCL12 expression was remarkably down-regulated in murine bone marrow regions of extensive ALL growth.…”