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.
Highlights
The integrity and permeability of the endothelial barrier is tightly controlled and maintained through adhesive interactions between neighboring endothelial cells (ECs), as well as between ECs and adjacent mural cells.[1,2] In addition to molecules that mediate tight junctions between ECs, cellular adhesion in blood vessels involves N-cadherin and VE-cadherin, which mediate calcium-dependent, adherens junction-type cell-cell adhesion.[3-6]
Over 80% of bortezomib is bound by plasma proteins including albumin (~70 kDa; 4-15 nm in size),[59,60] likely restricting its transvascular flow in tissues with tight endothelial transport control
Rodent studies using radiolabeled bortezomib have shown that bortezomib is rapidly accumulated in tissues, such as kidney and liver, where fenestrated capillaries allow passage of molecules up to 15 and 180 nm in size, respectively.[61,62]
Summary
The integrity and permeability of the endothelial barrier is tightly controlled and maintained through adhesive interactions between neighboring endothelial cells (ECs), as well as between ECs and adjacent mural cells (pericytes and smooth muscle cells).[1,2] In addition to molecules that mediate tight junctions between ECs (eg, occludin and claudins), cellular adhesion in blood vessels involves N-cadherin and VE-cadherin, which mediate calcium-dependent, adherens junction-type cell-cell adhesion.[3-6]. The combination did not improve time to disease progression, compared with melphalan alone.[23,24] While preliminary, these data suggest that ADH-1, and ADH-1-like agents, may enhance tumor delivery of, and response to, anti-cancer agents with high plasma protein binding affinity in other cancers. We hypothesized that LCRF-0006 would enhance the permeability of MM tumor-associated vasculature to molecules with high binding affinity for plasma proteins and would increase MM tumor response to anti-cancer therapy. To this end, we evaluated the vascular disruption and permeability-enhancing properties of LCRF-0006 in vitro and in vivo. We assessed the effectiveness of LCRF-0006 in combination with a low dose of the plasma protein-binding, frontline anti-MM agent bortezomib (VELCADE®) in the well-established, orthotopic C57BL/KaLwRij/5TGM1 mouse model of MM
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