Targeting
tumor vasculature is an emerging strategy in
cancer treatment. Promising results have been shown in preclinical studies when vascular disrupting agents (VDAs) are used in combination with other anticancer
therapies. Because
radiation therapy with concurrent
cisplatin or
cetuximab has become standard treatment for patients with locally advanced
head and neck squamous cell carcinoma (
HNSCC), we investigated whether the VDA
ombrabulin (
AVE8062) could improve the antitumor activity of radiation plus
cisplatin and radiation plus
cetuximab combinations.
HNSCC HEP2 or FaDu
tumor bearing mice were treated with
ombrabulin,
cisplatin,
cetuximab, local
radiation therapy or combinations of these treatments.
Ombrabulin attenuated
tumor growth of HEP2 and FaDu xenografts compared to control
tumors. A more pronounced
tumor growth delay and
tumor regression were induced when
ombrabulin was added to local irradiation,
cisplatin or
cetuximab in FaDu
tumors compared to single agent treatments. Finally, triple agent
therapies combining
ombrabulin, irradiation, and either
cisplatin or
cetuximab were more effective than double combination treatment regimens and increased
tumor growth delay in both HEP2 and FaDu
tumor models. Of note, complete
tumor regression was achieved in FaDu
tumor model for the triple combination including
platinum. Immunohistochemistry on FaDu
tumors demonstrated a specificity of
ombrabulin towards intratumoral vessels, in contrast to peritumoral vasculature. Our results provide a rationale for the use of
ombrabulin in combination with two standard treatment regimens that are concurrent
cisplatin-based chemoradiation and
cetuximab plus ionizing radiation
therapies, for the treatment of
HNSCC.