Abstract
Brain metastases (BM) are an ever-increasing challenge in oncology, threatening quality of life and survival of many cancer patients. The majority of BM originate from lung adenocarcinoma, and stage III patients have a risk of 40–50% to develop BM in the first years of disease onset. As therapeutic options are limited, prevention of their occurrence is an attractive concept. Here we investigated whether Nintedanib (BIBF 1120), a tyrosine kinase inhibitor (TKI) targeting the VEGF pathway approved for lung adenocarcinoma, and the dual anti-VEGF-A/Ang2 nanobody BI836880 have the potential to prevent BM formation. A mouse model of brain metastasis from lung adenocarcinoma was used in which tumor cells were injected intracardially. Metastases formation occurred inside and outside of the brain and was followed by MRI, IVIS, and immunohistochemistry. BM were reduced in volume and number by both Nintedanib and the dual anti-VEGF-A/Ang2 nanobody, which translated into improved survival. Both compounds were able to normalize cerebral blood vessels at the site of brain metastatic lesions. Extracranial metastases, however, were not reduced, and meningeal metastases only partially. Interestingly, unspecific control IgG also lead to brain vessel normalization and reduction of brain and meningeal metastases. This data indicates a brain-specific group effect of antiangiogenic compounds with respect to metastasis prevention, most likely by preventing an early angiogenic switch. Thus, Nintedanib and BI836880 are promising candidates for future BM preventive study concepts in lung adenocarcinoma patients.
Highlights
Brain metastases (BM) have an increasing incidence [1,2,3] and are associated with high morbidity and mortality, affecting neurological function and quality of life, with a mean overall survival of affected patients of a few months only
A brainseeking PC14-PE6 human lung adenocarcinoma subline (PC14-PE6 pGF1 Br4) was selected, which robustly generates a sufficient number of BM for analysis, but to a lesser extent extracranial metastasis in lung, bone and other organs
In this study we examined if two antiangiogenic compounds, Nintedanib and the novel dual anti-VEGF/Ang2 nanobody BI836880, were able to prevent brain and extracranial metastases and improve survival outcomes
Summary
Brain metastases (BM) have an increasing incidence [1,2,3] and are associated with high morbidity and mortality, affecting neurological function and quality of life, with a mean overall survival of affected patients of a few months only. Many patients suffering from solid cancers are at high risk of developing BM during the course of their disease. BM occur most frequently in lung adenocarcinoma, where up to 50% of stage III patients (locally advanced) develop BM within 24 months after “definitive” treatment with surgery, radiation, and chemotherapy [4, 5]. The brain is a difficult, delicate organ where many locally aggressive and systemic therapies are not possible or not effective [3]. Can be very effective against established BM from different entities, such as BRAF and MEK inhibitors in melanoma, EGFR and ALK inhibitors in lung adenocarcinoma, and immune checkpoint inhibitors in melanoma and lung cancer [3, 7,8,9,10]. There is some promising clinical data for antiangiogenic drugs, bevacizumab, with indications for activity against BM, additional beneficial anti-edema effects, and reduction of radiation-induced necrosis [11,12,13,14,15,16,17,18]
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