VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Abstract

Purpose: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n ¼ 5-6/group) were injected intravenously with VCAM-1targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T 2 Ã -weighted MRI. Control groups of na€ ve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included.Results: All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T 2 Ã -weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; twosided) than control cohorts, despite a lack of blood-brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1-positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types.Conclusions: VCAM-1-targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.

Radionuclide spatial distribution and dose deposition for in vitro assessments of 212Pb‐αVCAM‐1 targeted alpha therapy

“…This work formed part of a preclinical study that evaluated the therapeutic potential of TAT, combining an α‐emitting radionuclide ( 212 Pb) to an anti‐VCAM‐1 antibody ( 212 Pb‐αVCAM‐1). The upregulation of vascular adhesion molecule (VCAM‐1) has been shown to be specific to early stage brain metastases . The objective of this study was thus to perform accurate and reliable dosimetry for in vitro irradiations with 212 Pb‐αVCAM‐1.…”

“…The upregulation of vascular adhesion molecule (VCAM-1) has been shown to be specific to early stage brain metastases. 8,[13][14][15] The objective of this study was thus to perform accurate and reliable dosimetry for in vitro irradiations with 212 Pb-aVCAM-1. The first step of this work was the experimental determination of the spatial distribution of radionuclides in culture medium using a energy spectra measurements and Monte Carlo (MC) simulations.…”

Frontline Science: Kindlin-3 is essential for patrolling and phagocytosis functions of nonclassical monocytes during metastatic cancer surveillance

“…VCAM, a ligand for VLA‐4 integrin, has been shown to play several distinct roles in cancer progression. For example, while VCAM is implicated as a mode of entry for circulating tumor cells into metastatic sites, 29 VCAM also functions as an adhesion molecule on ECs that allows antitumoral effector CD8 T cells to infiltrate tumors 30 . Therefore, regulation of VCAM is an important factor in determining metastatic outcomes.…”

Cerebrovascular inflammation promotes the formation of brain metastases

“…Such control MPIOs were tested by Cheng et al . in mouse models of BMs and only weak signal voids were observed relative to the targeted MPIOs …”