2025 Poster Presentations
P003: THERAPEUTIC TARGETING OF HYPOXIA-INDUCIBLE FACTORS IN HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC)
Elizabeth E Wicks, MD1; Shaima Salman, PhD2; Gregg Semenza, MD, PhD2; 1The University of Vermont Medical Center; 2Johns Hopkins University Medical Center
Background: Hypoxia-inducible factors (HIFs) are transcription factors which induce gene expression to mediate the physiological responses to low oxygen (i.e. hypoxia). Many cancers, including head and neck squamous cell carcinoma (HNSCC), involve the activation of HIFs secondary to a prevalence of hypoxic regions due to functionally abnormal vessels and hyperproliferation of cells. This is correlated with increased mortality and resistance to chemotherapy and radiotherapy, making HIFs a suitable target for anticancer therapeutics. We sought to identify novel HIF-1/2 alpha inhibitors and test their efficacy on tumor growth in the HNSCC models.
Methods: Direct binding HIF-inhibitors were designed and developed utilizing virtual and cell-based assays. These inhibitors were further validated in several cancer models including the HNSCC models using gene expression analyses of HIF target genes. After validation, the inhibitory potential of the compound was further tested in vivo using the human FaDu model and the syngeneic SCCVII mouse model.
Results: Efficacious compounds were identified and proceeded into gene expression and in vivo studies in the HNSCC model. In gene expression studies, HIF-target genes were significantly induced by hypoxia in the human FaDu model and the syngeneic SCCVII mouse model. The identified inhibitor, 1.21 inhibited HIF-target genes in a dose dependent manner. In tumor studies, treatment with 1.21 twice daily significantly inhibited tumor growth when given at 10-20 mg kg-1 in both models, FaDu and SCCVII. The principal endpoint was significant tumor growth inhibition.
Conclusion: Treatment with the inhibitors can alleviate tumor burden and have a potent effect on HNSCC tumor growth inhibition, warranting further testing of HIF inhibitor in combination with other treatment modalities such as chemotherapy, immunotherapy or radiation therapy.