The vascular disrupting agent ombrabulin (AVE8062) enhances the efficacy of standard therapies in head and neck squamous cell carcinoma xenograft models

Abstract

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.

Tubulin-interactive stilbene derivatives as anticancer agents

“…Ombrabulin enhances the efficacy of standard therapies (radiation plus cisplatin and radiation plus cetuximab) in head and neck squamous cell carcinoma (HNSCC) xenograft models. A specific action of ombrabulin towards intratumoral vessels rather than to the peritumoral vasculature was demonstrated by means of immunochemical staining of HNSCC tumors [92]. The design of CA-4 analogs as VDAs was the subject of a concise review by Rajak et al, who paid special attention to cis-restricted isomers [93].…”

Recent Advances in Vascular Disrupting Agents in Cancer Therapy

“…Synergistic effects [76] KML001 Irinotecan Colon carcinoma Preclinical Increased antitumor activity [83] Ombrabulin (AVE8062) Irradiation + cisplatin or cetuximab HNSCC Preclinical Increased tumor growth delay [88] ASA404 Taxanes Glioblastoma Preclinical Synergistic effect [77] ASA404 Everolimus Renal cell carcinoma Preclinical Extensive necrosis and reduction in the viable rim [79] ASA404 Photodynamic therapy Colon adenocarcinoma tumors Preclinical Potentiated antitumor activity [80] ASA404 Taxanes Advanced prostate cancer Clinical (Phase II) Activity with acceptable toxicity [32] ASA404 Carboplatin and paclitaxel NSCLC at stage III or IV Clinical (Phase III) Failed [33] Plinabulin (NPI-2358)…”

“…AVE8062, associated to irradiation and either cisplatin or cetuximab, increased tumor growth delay in experimental tumor models [88].…”

Vascular Targeting Approaches to Treat Cancer

“…A recent mouse model of head and neck squamous cell carcinoma demonstrated that ombrabulin treatment augmented the anti-tumour effectiveness of the standard treatment regimen of radiation and cisplatin or cetuximab [ 101 ]. Ombrabulin is in phase III trials for the treatment of soft tissue sarcoma, in phase II trials in combination with taxane and platinum drugs (docetaxel and cisplatin or paclitaxel and carboplatin) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) and in a number of phase I trials in combination with other drugs in solid tumours.…”