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Background <p>Head and neck squamous cell carcinoma (HNSCC) affects more than half a million people annually, and nearly 80% of oropharyngeal cancer cases are caused by human papillomavirus (HPV). Current treatments include chemo- and radiotherapy, though the effectiveness of these therapies is limited by the viral oncoprotein E6, which disrupts apoptotic pathways by binding and accelerating the degradation of molecules such as E6AP and caspase-8. Our lab has identified an E6 inhibitor, 30-hydroxygambogic acid (GA-OH), that is able to maintain these apoptotic signaling molecules.</p> Method <p>To further explore the therapeutic potential of this small molecule, we determined its antitumor efficacy in vivo. We developed an optimized xenograft model for HPV<sup>+</sup> HNSCC, assessed GA-OH’s toxicity, and evaluated the effectiveness of GA-OH in combination with chemotherapy utilizing the optimized concentration of 0.6&#xa0;mg/kg.</p> Results <p>GA-OH significantly increases (* <i>p</i> = 0.0105) cisplatin’s efficacy in HPV<sup>+</sup> HNSCC in vivo without overt clinical manifestations. The only toxicities noted were a 4-fold increase in creatine kinase (**** <i>p</i> &lt; 0.0001) and a 2.4-fold increase in aspartate aminotransferase (** <i>p</i> = 0.0057) in the cisplatin and GA-OH combination group compared to the vehicle group.</p> Conclusion <p>The small molecule GA-OH was tolerable in our murine model, significantly amplifying the efficacy of cisplatin treatment.</p>

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30-hydroxygambogic acid increases the efficacy of cisplatin in an HPV+ head and neck cancer in vivo model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Sonia N. Whang,
  • Valeria Rodarte,
  • Trevor Lohman,
  • Josh Barforough,
  • Lennox Chitsike,
  • Gina N. Lucas,
  • David Lee,
  • Caleb Ruiz-Jimenez,
  • Yan Chen Wongworawat,
  • Rouba Ali-Fehmi,
  • Marya Wahidi,
  • Juli Unternaehrer,
  • Valery Filippov,
  • Penelope J. Duerksen-Hughes

摘要

Background

Head and neck squamous cell carcinoma (HNSCC) affects more than half a million people annually, and nearly 80% of oropharyngeal cancer cases are caused by human papillomavirus (HPV). Current treatments include chemo- and radiotherapy, though the effectiveness of these therapies is limited by the viral oncoprotein E6, which disrupts apoptotic pathways by binding and accelerating the degradation of molecules such as E6AP and caspase-8. Our lab has identified an E6 inhibitor, 30-hydroxygambogic acid (GA-OH), that is able to maintain these apoptotic signaling molecules.

Method

To further explore the therapeutic potential of this small molecule, we determined its antitumor efficacy in vivo. We developed an optimized xenograft model for HPV+ HNSCC, assessed GA-OH’s toxicity, and evaluated the effectiveness of GA-OH in combination with chemotherapy utilizing the optimized concentration of 0.6 mg/kg.

Results

GA-OH significantly increases (* p = 0.0105) cisplatin’s efficacy in HPV+ HNSCC in vivo without overt clinical manifestations. The only toxicities noted were a 4-fold increase in creatine kinase (**** p < 0.0001) and a 2.4-fold increase in aspartate aminotransferase (** p = 0.0057) in the cisplatin and GA-OH combination group compared to the vehicle group.

Conclusion

The small molecule GA-OH was tolerable in our murine model, significantly amplifying the efficacy of cisplatin treatment.