Nintedanib and a bi-specific anti-VEGF/Ang2 nanobody selectively prevent brain metastases of lung adenocarcinoma cells

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.

Novel Drugs with High Efficacy against Tumor Angiogenesis

“…Brain metastases (BM) are a growing challenge in oncology, and nanobody BI836880 extended animal survival and reduced BM formation; however, extracranial metastases were not reduced [162]. The study also supports the idea that antiangiogenic compounds may be primarily effective in the brain because BM, especially in lung adenocarcinoma, shows a particularly stronger angiogenic response at this site [162,214,215].…”

FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma

“…7A ). Administration of nintedanib, a tyrosine kinase inhibitor (TKI) that targets the VEGF pathway and is approved for use in the treatment of LUAD [ 36 , 37 ], effectively suppressed the growth of control tumors. However, FOXA1-expressing tumors were less sensitive to growth inhibition by nintedanib compared with tumors from vector control A549 cells (Fig.…”

The microenvironment of brain metastases from solid tumors

“…The preventive efficacy of antiangiogenic drugs appears to be restricted to a limited number of tumor types (eg, lung adenocarcinoma) and the brain, which provides an example of how the brain TME can differ from the rest of the body. 26 , 50 , 109 In addition to monoclonal antibodies targeting VEGF-A, tyrosine kinase inhibitor, nanobody targeting VEGF-A and Angiopoietin-2, have also shown activity in BrM, which indicates a class effect of these drugs. 109 Clinically, the anti-VEGF-A antibody bevacizumab can exert even single-agent effects in BrM of breast, lung, and colorectal cancers, as shown in a recent case series and earlier studies.…”

“… 26 , 50 , 109 In addition to monoclonal antibodies targeting VEGF-A, tyrosine kinase inhibitor, nanobody targeting VEGF-A and Angiopoietin-2, have also shown activity in BrM, which indicates a class effect of these drugs. 109 Clinically, the anti-VEGF-A antibody bevacizumab can exert even single-agent effects in BrM of breast, lung, and colorectal cancers, as shown in a recent case series and earlier studies. 110–112 However, response assessment using MRI can in principle be misleading in this setting as antiangiogenic therapies can reduce gadolinium uptake, although this seems much less the case than in glioma.…”