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VCAM-1 targeted alpha-particle therapy for early brain metastases
Aurélien Corroyer-Dulmont1,2, Samuel Valable1, Nadia Falzone3
1Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, Caen, France.
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.
Insights
Targeted alpha therapy using 212Pb-αVCAM-1 effectively targets early brain metastases (BM) in breast cancer. This novel approach inhibits tumor growth and improves survival compared to standard radiotherapy.
Area of Science:
- Oncology
- Radiotherapy
- Molecular Imaging
Background:
- Brain metastases (BM) are a frequent complication of breast cancer, with limited survival rates despite current treatments.
- Early detection and targeted therapy are crucial for improving outcomes in patients with BM.
- Vascular cell adhesion molecule 1 (VCAM-1) is overexpressed in early BM and presents a promising therapeutic target.
Purpose of the Study:
- To investigate the therapeutic potential of targeted alpha-particle radiotherapy using lead-212 (212Pb) conjugated to an anti-VCAM-1 antibody (212Pb-αVCAM-1).
- To evaluate the efficacy and toxicity of 212Pb-αVCAM-1 in a preclinical model of breast cancer brain metastases.
Main Methods:
- Human breast carcinoma cells (MDA-231-Br-GFP) were injected into nude mice to establish brain metastases.
- Biodistribution studies assessed 212Pb-αVCAM-1 uptake in early BM.
- Therapeutic efficacy was evaluated using MR imaging, histology, and overall survival analysis, compared to external beam radiotherapy (EBRT).
Main Results:
- 212Pb-αVCAM-1 demonstrated specific uptake in early BM, with a tumor-to-healthy brain dose deposition ratio of 6.
- MR imaging revealed a statistically significant reduction in metastatic burden following 212Pb-αVCAM-1 treatment compared to EBRT (P < 0.001).
- Treatment with 212Pb-αVCAM-1 resulted in a 29% increase in overall survival (P < 0.01) with no observed major toxicity.
Conclusions:
- 212Pb-αVCAM-1 specifically accumulates at early brain metastasis sites.
- Targeted alpha therapy with 212Pb-αVCAM-1 effectively inhibits tumor growth and improves survival in breast cancer brain metastases.
- This targeted approach shows promise for treating early-stage brain metastases with minimal toxicity.
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