Abstract 1728P
Background
Hypoxia is prevalent in solid malignant tumors and linked to angiogenesis. Uncoordinated expression of angiogenic factors results in dysfunctional blood vessels and promotion of metastasis, associated with poor prognosis. VEGFA, a main driver of angiogenesis, has been proven to be an efficacious target in multiple malignancies. Based on known hypoxia-regulated genes, a score of hypoxia response was established to rank various tumor types according to the magnitude of hypoxia response. It was further used to interrogate whether hypoxia response is linked to patient prognosis. Finally, the score was integrated with patient survival data and VEGFA expression in a multidimensional framework (MDF) to explore the potential to anticipate sensitivity to VEGFA-blockers.
Methods
A total of 200 genes from the Molecular Signature Database (Liberzon 2015) shown to be upregulated upon hypoxia in cell lines, were analyzed. The signature was validated using published hypoxia/normoxia cell culture data (Chen 2008) and then applied to data from the TCGA consortium. A “hypoxia score” was computed for each sample, based on the mean standard gene expression of the hypoxia-related genes. A MDF was built by integrating survival data, VEGFA-expression, and its correlation with the hypoxia score.
Results
Validation of the signature confirmed a significant increase of the hypoxia score under hypoxia compared to normoxia. Next, the score was applied to 10550 samples across 33 tumor types, which showed a significantly higher hypoxia score in solid compared to non-solid tumors. Additionally, patients with a high hypoxia score have a significantly decreased life expectancy. The MDF suggested tumor types for which VEGFA-blocker are approved. Furthermore, this framework suggested adrenocortical carcinoma and head and neck squamous cell carcinoma to be novel tumor types potentially responsive to VEGFA-blockers.
Conclusions
These results confirmed that hypoxia is associated with a poor prognosis and predominantly occurs in solid tumors. Furthermore, our results suggest a potential benefit of VEGFA-blockers in adrenocortical carcinoma and head and neck squamous cell carcinoma.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Idorsia Pharmaceuticals Ltd.
Funding
Idorsia Pharmaceuticals Ltd.
Disclosure
The author has declared no conflicts of interest.