VCAM-1 targeted alpha-particle therapy for early brain metastases

Aurélien Corroyer-Dulmont; Samuel Valable; Nadia Falzone; Anne Marie Frelin-Labalme; Ole Tietz; Jérôme Toutain; Manuel Sarmiento Soto; Didier Divoux; Laurent Chazalviel; Elodie A. Pérès; Nicola R. Sibson; Katherine A. Vallis; Myriam Bernaudin

doi:10.1093/neuonc/noz169

VCAM-1 targeted alpha-particle therapy for early brain metastases

Aurélien Corroyer-Dulmont^*, Samuel Valable, Nadia Falzone, Anne Marie Frelin-Labalme, Ole Tietz, Jérôme Toutain, Manuel Sarmiento Soto, Didier Divoux, Laurent Chazalviel, Elodie A. Pérès, Nicola R. Sibson, Katherine A. Vallis, Myriam Bernaudin

^*Corresponding author for this work

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Abstract

Background: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (²¹²Pb) with an anti-VCAM-1 antibody (²¹²Pb-αVCAM-1). Methods: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, ²¹²Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after ²¹²Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. Results: ²¹²Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after ²¹²Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. Conclusions: The present investigation demonstrates that ²¹²Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

Original language	English
Pages (from-to)	357-368
Number of pages	12
Journal	Neuro-Oncology
Volume	22
Issue number	3
DOIs	https://doi.org/10.1093/neuonc/noz169
Publication status	Published - 5 Mar 2020
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

alpha-particle therapy
early brain metastases
VCAM-1

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10.1093/neuonc/noz169Licence: CC BY

Publisher version (open access)Final published version, 705 KBLicence: CC BY

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@article{876fbf3b55004d859595b58d1cf07737,

title = "VCAM-1 targeted alpha-particle therapy for early brain metastases",

abstract = "Background: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti-VCAM-1 antibody (212Pb-αVCAM-1). Methods: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. Results: 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. Conclusions: The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.",

keywords = "alpha-particle therapy, early brain metastases, VCAM-1",

author = "Aur{\'e}lien Corroyer-Dulmont and Samuel Valable and Nadia Falzone and Frelin-Labalme, {Anne Marie} and Ole Tietz and J{\'e}r{\^o}me Toutain and Soto, {Manuel Sarmiento} and Didier Divoux and Laurent Chazalviel and P{\'e}r{\`e}s, {Elodie A.} and Sibson, {Nicola R.} and Vallis, {Katherine A.} and Myriam Bernaudin",

note = "Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2020",

month = mar,

day = "5",

doi = "10.1093/neuonc/noz169",

language = "English",

volume = "22",

pages = "357--368",

journal = "Neuro-Oncology",

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T1 - VCAM-1 targeted alpha-particle therapy for early brain metastases

AU - Corroyer-Dulmont, Aurélien

AU - Valable, Samuel

AU - Falzone, Nadia

AU - Frelin-Labalme, Anne Marie

AU - Tietz, Ole

AU - Toutain, Jérôme

AU - Soto, Manuel Sarmiento

AU - Divoux, Didier

AU - Chazalviel, Laurent

AU - Pérès, Elodie A.

AU - Sibson, Nicola R.

AU - Vallis, Katherine A.

AU - Bernaudin, Myriam

N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2020/3/5

Y1 - 2020/3/5

N2 - Background: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti-VCAM-1 antibody (212Pb-αVCAM-1). Methods: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. Results: 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. Conclusions: The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

AB - Background: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti-VCAM-1 antibody (212Pb-αVCAM-1). Methods: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. Results: 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. Conclusions: The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

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JF - Neuro-Oncology

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ER -

VCAM-1 targeted alpha-particle therapy for early brain metastases

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