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Updated: Jun 1, 2025
Author Spotlight: Creating Human Vascularized Micro-Tumors as Models for Translational Cancer Research
Published on: September 15, 2023
Development of a Microvessel Density Gene Signature and Its Application in Precision Medicine
Megumi Kuronishi1, Yoichi Ozawa1, Takayuki Kimura1
1Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan.
Abstract:
Combination therapy with antiangiogenic drugs and immune checkpoint inhibitors has shown enhanced clinical activity and has been approved for the treatment of multiple tumor types. Despite extensive research, predictive biomarkers for combination therapy remain poorly understood. Microvessel density (MVD), a surrogate marker for aberrant angiogenesis measured by IHC, has been associated with response to monotherapy with antiangiogenic inhibitors. However, obtaining tumor tissue with a sufficient mass for IHC analysis is not always practical, and IHC-based MVD measurements are unavailable in large public datasets. In this study, we developed an MVD gene score based on RNA sequencing data that reflects MVD by using RNA sequencing and MVD measured by IHC in 12 mouse syngeneic tumor models. We explored the relationship between the MVD gene score and a gene signature, predicting the response to anti–PD-1 therapy in mouse and human tumor datasets. The MVD gene score correlated with the antitumor activity of lenvatinib, a multiple tyrosine kinase inhibitor mainly targeting VEGFRs and FGFRs, in mouse tumor models, and MVD measured by IHC in commercially available human formalin-fixed, paraffin-embedded tumor samples. Tumor types in The Cancer Genome Atlas were classified into four subgroups based on the MVD gene score and T cell–inflamed gene expression profile, which were correlated with clinical indications for treatment. In conclusion, the newly developed MVD gene score enables the estimation of MVD in large public datasets in which IHC data are unavailable and has potential clinical utility together with the T cell–inflamed gene expression profile to characterize tumors of patients for precision medicine.
Significance:
A novel gene signature for MVD was developed. This MVD gene score enables the estimation of MVD, reflecting the sensitivity to antiangiogenic inhibitors, in transcriptomic datasets. We demonstrated the utility of the MVD gene score together with a T cell-inflamed gene signature for potential future use as a clinical biomarker.
Insights
A new gene score estimates microvessel density (MVD) from RNA sequencing data, aiding in predicting response to antiangiogenic drugs and immunotherapy. This biomarker shows potential for precision medicine in cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Combination therapy with antiangiogenic drugs and immune checkpoint inhibitors is approved for multiple cancers.
- Predictive biomarkers for this combination therapy are poorly understood.
- Microvessel density (MVD) measured by IHC is a marker for antiangiogenic inhibitor response but requires tumor tissue.
Purpose of the Study:
- To develop a gene-based score to estimate MVD using RNA sequencing data.
- To explore the relationship between this MVD gene score and response to anti-PD-1 therapy.
- To assess the clinical utility of the MVD gene score for precision medicine.
Main Methods:
- Developed an MVD gene score using RNA sequencing data from 12 mouse syngeneic tumor models.
- Correlated the MVD gene score with IHC-measured MVD and response to lenvatinib in mouse models.
- Analyzed the MVD gene score in human tumor datasets (The Cancer Genome Atlas) alongside a T cell-inflamed gene signature.
Main Results:
- The MVD gene score accurately reflected MVD and correlated with lenvatinib's antitumor activity in mouse models.
- The MVD gene score showed correlation with IHC-measured MVD in human tumor samples.
- Tumor classification based on MVD gene score and T cell-inflamed signature correlated with clinical treatment indications.
Conclusions:
- The MVD gene score provides a method to estimate MVD from transcriptomic data, overcoming limitations of IHC.
- This score can be used in large public datasets where IHC data is unavailable.
- The MVD gene score, combined with T cell-inflamed gene signatures, offers potential clinical utility for patient stratification in precision medicine.
