Abstract 5136: Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib

Abstract

Abstract Lenvatinib is a multiple receptor tyrosine kinase inhibitor and an angiogenesis inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. In our previous study, we reported that human xenograft tumors sensitive to lenvatinib showed higher microvessel density (“MVD (IHC)”) than relatively resistant tumors in immunohistochemistry (IHC). Although MVD (IHC) is a potential indicator to predict antitumor activity of lenvatinib, available IHC data are limited. Here, we investigated a novel gene expression signature (MVD gene score) calculated from RNA-sequencing (RNA-seq) data that reflects MVD (IHC) and antitumor effect of lenvatinib. Tumor tissues were collected from 12 mouse syngeneic tumor models followed by RNA-seq. We also stained CD31 in the same tumors and calculated MVD (IHC) score by dividing the number of CD31 positive blood vessels by tumor area. Genes that met the following criteria were selected for MVD gene score calculation: (1) genes that are specifically expressed on endothelial cell cluster in in-house single cell RNA-seq data using Hepa 1-6 mouse hepatocellular carcinoma tumor tissues; (2) well-known angiogenesis markers from literature or genes whose expression show significant correlation with MVD (IHC) in mouse syngeneic tumor models. MVD gene score was calculated as the average of logarithm transformed gene expression values. In order to examine applicability of MVD gene score, we compared MVD (IHC) and MVD gene score to lenvatinib antitumor activities on mouse syngeneic tumors. We measured MVD (IHC) and computed MVD gene score from RNA-seq data using matched tumor tissues of 12 mouse syngeneic models. MVD gene score was correlated with MVD (IHC). As reported, lenvatinib sensitive tumor models showed higher MVD (IHC) score. They also showed higher MVD gene score calculated from RNA-seq data. Our newly developed MVD gene score has a potential to predict the antitumor activity of angiogenic inhibitors such as lenvatinib using RNA-seq data in tumor samples. Further validation study is ongoing using various human tumor samples. Citation Format: Megumi Kuronishi, Yoichi Ozawa, Takayuki Kimura, Yu Kato. Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5136.