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Preclinical Studies and Early Drug Development: In Vitro and In Vivo Assays and Models

The effect of EC78, a novel Hsp90 inhibitor alone and in combination with radiation in head and neck squamous cell carcinoma

University of North Carolina, Chapel Hill, NC and Conforma Therapeutics Corporation, San Diego, CA

Abstract

B4

The effect of EC78, a novel Hsp90 inhibitor alone and in combination with radiation in head and neck squamous cell carcinomaXiaoying Yin, Hong Zhang, Francis Burrows, and Carol G ShoresDepartment of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, NC 27599Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. The majority of patients present with stage III or IV disease and the primary treatment for such patients is either surgery followed by radiation with or without chemotherapy or concurrent radiation and chemotherapy. The only curative role for chemotherapy in treatment of HNSCC is radiosensitization. Current regimens with cytotoxic agents are very toxic, frequently requiring chemotherapy dose reductions. Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. Hsp90 inhibitor can target multiple pathways involved in tumor growth simultaneously and should lead to more effective radiosensitization effect.A novel dimeric ansamycin-based Hsp90 inhibitor, EC78, was evaluated for its anti-tumor activity in 4 head and neck squamous cell carcinoma (HNSCC) cell lines as well as in HNSCC xenograft alone and in combination with radiation. The results were compared with 17-AAG, a Hsp90 inhibitor currently in phase II clinical trials. Both 17-AAG and EC78 inhibited tumor cell proliferation effectively, but EC78 was more potent, with an IC₅₀ lower than that of 17-AAG in most cell lines, especially in cells resistant to 17-AAG. When combined with radiation in cell culture, synergistic growth inhibition was observed with EC78 in the original radiation resistant cell line UM11B, while additive growth inhibition was observed in the radiation sensitive cell line JHU12. Additive growth inhibition effects were observed between 17-AAG and radiation in both UM11B and JHU12 cell lines. EC78 induced G1 growth arrest of tumor cells and apoptosis, with the degradation of client proteins including EGF-R, c-Raf-1, and Akt.Current models of chemotherapy radiosensitization frequently do not reflect clinical practice. Patients are treated 5 out 7 days a week for 6-7 weeks to fractionate the dose and reduce complications. This allows for recovery of normal tissue between doses. Differential recovery between normal and cancerous tissue may be the only parameter providing a therapeutic index. Single doses of radiation to model systems do not recapitulate fractionation and therefore do not reflect clinical practice or response. Indeed, most data supporting radio-chemosensitization is from clinical trials rather than preclinical studies.In our in vivo model, 20 mg/ml EC78 alone can moderately reduce the growth rate of established HNSCC xenografts in nude mice. Mice treated with 1.5 Gy of gamma radiation 4 days a week for 3-5 weeks also showed significantly reduced the tumor growth. 20 mg/ml EC78 combined with 1.5 Gy fractionated radiation dramatically inhibits tumor growth, in some cases, tumor regression, the effect is synergistic and more potent than 17-AAG in combination with radiation. These results suggest that this novel Hsp90 inhibitor affects multiple pathways involved in tumor development and progression, inhibits tumor growth in vitro and in vivo, and may represent a better strategy for the treatment of HNSCC patients alone or as a radiosensitizer. It also demonstrates the feasibility of preclinical models of chemosensitizaiton of radiotherapy using clinically relavent radiation dosing schems.