The research team led by Marc M. Loriaux from the Division of Hematology & Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA said "Given the role of NLCs in CLL as well as possible therapeutic implications, we evaluated the impact of CSF1R inhibition using highly selective small-molecule inhibitors across a broad spectrum of primary CLL samples."
They went on to explain that this research proposes enhancing this strategy in CLL patients through combination drug approaches by simultaneously giving CSF1R inhibitors, which target NLCs, with BTK and/or PI3K inhibitors as well as other agents, which target the leukemia cells themselves.
Ultimately, tumor-associated macrophages have been shown to provide microenvironmental support that maintains tumor cell viability and proliferation in a variety of solid tumor types.
TAMs have also been isolated from the peripheral blood, spleen, and lymph nodes in CLL patients where they have shown to be essential for CLL cell survival in the tumor microenvironment.
Figure 1: Ex vivo inhibitor screening reveals CSF1R sensitivity in CLL patient specimens. A. Mononuclear cells isolated from peripheral blood or bone marrow of CLL patients were added to 384-well plates containing dose-escalating concentrations of small-molecule inhibitors. Following incubation for 72 hours, the relative number of remaining viable mononuclear cells was evaluated by subjecting cells to a colorimetric cell viability assay. B. GW-2580 and ARRY-382 are highly specific small-molecule inhibitors of CSF1R (and not other class III receptor tyrosine kinases). C.-D. CLL primary patient specimens were exposed to C. GW-2580 and D. ARRY-382, as described in A., and dose-response curves for each specimen were included along with an average dose-response curve for all specimens. E.-F. Waterfall plot of the IC50 values for each patient specimen after exposure to E. GW-2580 and F. ARRY-382. The IC50 was calculated from the dose-response curve using a cubic logarithmic regression, and each specimen was positioned in order of increasing IC50.
Specifically, these NLCs are derived from CD14-positive monocytes and, in the presence of CLL cells, differentiate into abnormal macrophages, which promote CLL cell survival.
Furthermore, using patient samples, neutralization or inhibition of CSF1R has been shown to inhibit NLC formation and decrease CLL cell viability, a finding mimicked by NLC depletion.
Given the role of NLCs in CLL as well as possible therapeutic implications, the research team evaluated the impact of CSF1R inhibition using highly selective small-molecule inhibitors across a broad spectrum of primary CLL samples.
The Loriaux research team concluded "These findings support the concept of simultaneously targeting supportive NLCs and CLL cells and demonstrate the potential clinical utility of this combination."
Full text - https://doi.org/10.18632/oncotarget.25191
Correspondence to - Marc M. Loriaux - [email protected]
Keywords - colony-stimulating factor 1 receptor, chronic lymphocytic leukemia, tumor-associated macrophages, tumor microenvironment, small-molecule inhibitors
