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<p>Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy with limited predictive markers to guide personalized treatment, particularly in human papillomavirus (HPV)-negative cases, which exhibit poor outcomes. Identifying reliable biomarkers for prognosis and therapeutic response remains a critical challenge. In a retrospective cohort of 51 patients with primary HPV-negative HNSCC, we investigated the prognostic significance of the Hedgehog (HH) signaling pathway and its association with imaging biomarkers. Genomic and transcriptomic analysis revealed that HH pathway activation correlated with distinct [<sup>18</sup>F]FDG PET/CT radiomic features, notably the PET-derived “<i>histogram:ih.max</i>”, a surrogate for peak [<sup>18</sup>F]FDG uptake that was associated with inferior survival outcomes. Functionally, pharmacologic inhibition of HH signaling demonstrated anticancer efficacy across multiple models, including HNSCC cell lines, patient-derived tumoroids, and in vivo xenograft models. Importantly, HH pathway inhibition induced reproducible changes in imaging characteristics in xenografts, including a measurable reduction in [<sup>1</sup>⁸F]FDG uptake, closely mirroring patterns observed in patient tumors. Together these findings demonstrate that integration of multi-level molecular profiling with functional imaging captures HH-driven tumor biology in HPV-negative HNSCC. Our study underscores the value of [<sup>18</sup>F]FDG PET/CT multiomics in linking tumor biology with imaging features, providing a framework for biologically-informed patient stratification and hypothesis-driven evaluation of treatment response. These results support further translational validation of HH pathway inhibition in HPV-negative HNSCC within appropriately designed preclinical and clinical studies.</p>

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[18F]FDG PET/CT multiomics identifies Hedgehog-driven HPV-negative head and neck squamous cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月29日

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  • Stefan Stoiber,
  • Daniel Pölöske,
  • Clemens P. Spielvogel,
  • Elisabeth Gurnhofer,
  • Michaela Schlederer,
  • David Haberl,
  • Cécile Philippe,
  • Dominik P. Elmer,
  • Richard Morrigl,
  • Heidi A. Neubauer,
  • Vojtěch Bystrý,
  • Karolína Trachtová,
  • Hanne Verswyvel,
  • Hannah Zaryouh,
  • Abraham Lin,
  • Christophe Deben,
  • Gregor Heiduschka,
  • Maik Dahlhoff,
  • Fritz Aberger,
  • Daniel Schramek,
  • Marcus Hacker,
  • Alexander R. Haug,
  • Lukas Kenner

摘要

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy with limited predictive markers to guide personalized treatment, particularly in human papillomavirus (HPV)-negative cases, which exhibit poor outcomes. Identifying reliable biomarkers for prognosis and therapeutic response remains a critical challenge. In a retrospective cohort of 51 patients with primary HPV-negative HNSCC, we investigated the prognostic significance of the Hedgehog (HH) signaling pathway and its association with imaging biomarkers. Genomic and transcriptomic analysis revealed that HH pathway activation correlated with distinct [18F]FDG PET/CT radiomic features, notably the PET-derived “histogram:ih.max”, a surrogate for peak [18F]FDG uptake that was associated with inferior survival outcomes. Functionally, pharmacologic inhibition of HH signaling demonstrated anticancer efficacy across multiple models, including HNSCC cell lines, patient-derived tumoroids, and in vivo xenograft models. Importantly, HH pathway inhibition induced reproducible changes in imaging characteristics in xenografts, including a measurable reduction in [1⁸F]FDG uptake, closely mirroring patterns observed in patient tumors. Together these findings demonstrate that integration of multi-level molecular profiling with functional imaging captures HH-driven tumor biology in HPV-negative HNSCC. Our study underscores the value of [18F]FDG PET/CT multiomics in linking tumor biology with imaging features, providing a framework for biologically-informed patient stratification and hypothesis-driven evaluation of treatment response. These results support further translational validation of HH pathway inhibition in HPV-negative HNSCC within appropriately designed preclinical and clinical studies.