Development of a Microvessel Density Gene Signature and Its Application in Precision Medicine
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".