Dataset Information

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-?VCAM-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-?VCAM-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-?VCAM-1 treatment was compared with that observed after standard EBRT.

Results

212Pb-?VCAM-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-?VCAM-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-?VCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

SUBMITTER: Corroyer-Dulmont A

PROVIDER: S-EPMC7162423 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Corroyer-Dulmont Aurélien A Valable Samuel S Falzone Nadia N Frelin-Labalme Anne-Marie AM Tietz Ole O Toutain Jérôme J Soto Manuel Sarmiento MS Divoux Didier D Chazalviel Laurent L Pérès Elodie A EA Sibson Nicola R NR Vallis Katherine A KA Bernaudin Myriam M

Neuro-oncology 20200301 3

<h4>Background</h4>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 p ...[more]

PMID: 31538194

Similar Datasets

Project description:Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of ?-emitting radionuclides, 149Tb, 211At, 212Pb, 213Bi and 225Ac; ?-emitting radionuclides, 90Y, 161Tb and 177Lu; and Auger electron (AE)-emitters 67Ga, 89Zr, 111In and 124I, for targeted radionuclide therapy (TRT). METHODS:Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative ?- and ?-emitters, 177Lu and 212Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. RESULTS:177Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 µm. The DSB yield of 212Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV ?-emissions from decay products, 212Bi and 212Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212Pb may be more effective for short range targeting of early micrometastatic lesions than 177Lu. CONCLUSION:MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of ?-, ?- and AE-emitting radionuclides for TRT. 212Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets