LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib

Abstract

Abstract N‐cadherin is a homophilic cell‐cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre‐clinical studies have shown that the N‐cadherin antagonist peptide, ADH‐1, increases the permeability of tumor‐associated vasculature thereby increasing anti‐cancer drug delivery to tumors and enhancing tumor response. Small molecule library screens have identified a novel compound, LCRF‐0006, that is a mimetic of the classical cadherin His‐Ala‐Val sequence‐containing region of ADH‐1. Here, we evaluated the vascular permeability‐enhancing and anti‐cancer properties of LCRF‐0006 using in vitro vascular disruption and cell apoptosis assays, and a well‐established pre‐clinical model (C57BL/KaLwRij/5TGM1) of the hematological cancer multiple myeloma (MM). We found that LCRF‐0006 disrupted endothelial cell junctions in a rapid, transient and reversible manner, and increased vascular permeability in vitro and at sites of MM tumor in vivo. Notably, LCRF‐0006 synergistically increased the in vivo anti‐MM tumor response to low‐dose bortezomib, a frontline anti‐MM agent, leading to regression of disease in 100% of mice. Moreover, LCRF‐0006 and bortezomib synergistically induced 5TGM1 MM tumor cell apoptosis in vitro. Our findings demonstrate the potential clinical utility of LCRF‐0006 to significantly increase bortezomib effectiveness and enhance the depth of tumor response in patients with MM.

Keywords

• combination therapy
• endothelial cell
• multiple myeloma
• tumor‐associated vasculature
• vascular permeability