Vesci Loredana, Milazzo Ferdinando Maria, Anastasi Anna Maria, Petronzelli Fiorella, Chiapparino Caterina, Carollo Valeria, Roscilli Giuseppe, Marra Emanuele, Luberto Laura, Aurisicchio Luigi, Pacello Maria Lucrezia, Spagnoli Luigi Giusto, De Santis Rita
Biotechnology, Research & Development, Sigma-Tau SpA, 00071 Pomezia, Rome, Italy.
Tissue Macro Array Lab, University of Tor Vergata, via della Ricerca Scientifica, 00133, Rome, Italy.
Oncotarget. 2016 Jan 5;7(1):914-28. doi: 10.18632/oncotarget.6089.
For locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC), the current clinical use of Cetuximab in chemo/radiotherapy protocols is often associated to severe systemic toxicity. Here we report in vitro data in human FaDu pharynx SCC cells, showing that inactive concentrations of biotinylated Cetuximab (bCet) become active upon anchorage to AvidinOX on the surface of tumor cells. AvidinOX-anchored bCet induces apoptosis and DNA damage as well as specific inhibition of signaling, degradation and abrogation of nuclear translocation of EGFR. In the mouse model of FaDu cancer, we show that intra-tumor injection of AvidinOX allows anti-tumor activity of an otherwise inactive, intraperitoneally delivered, low dose bCet. Consistently with in vitro data, in vivo tumor inhibition is associated to induction of apoptosis, DNA damage and reduced angiogenesis. AvidinOX is under clinical investigation for delivering radioactive biotin to inoperable tumors (ClinicalTrials.gov NCT02053324) and present data support its use for the local treatment of HNSCC in combination with systemic administration of low dose bCet.
对于局部晚期和转移性头颈部鳞状细胞癌（HNSCC），西妥昔单抗在化疗/放疗方案中的当前临床应用常常与严重的全身毒性相关。在此，我们报告在人FaDu咽鳞状细胞癌中的体外数据，表明无活性浓度的生物素化西妥昔单抗（bCet）在锚定到肿瘤细胞表面的抗生物素蛋白OX上时会变得有活性。抗生物素蛋白OX锚定的bCet诱导细胞凋亡和DNA损伤，以及对信号传导、降解和表皮生长因子受体（EGFR）核转位的特异性抑制。在FaDu癌的小鼠模型中，我们表明肿瘤内注射抗生物素蛋白OX可使原本无活性的、经腹腔递送的低剂量bCet具有抗肿瘤活性。与体外数据一致，体内肿瘤抑制与细胞凋亡诱导、DNA损伤和血管生成减少相关。抗生物素蛋白OX正在进行临床试验，用于将放射性生物素递送至无法手术的肿瘤（ClinicalTrials.gov NCT02053324），目前的数据支持其与低剂量bCet全身给药联合用于HNSCC的局部治疗。
