A conditionally replicative, Wnt/beta-catenin pathway-based adenovirus therapy for anaplastic thyroid cancer

Abstract

Thyroid cancer affects between 10,000 and 15,000 people per year in the US. Typically, this disease can be controlled with surgical resection and radioiodide treatment. However, resistance to these conventional therapies is observed in some patients, who develop intractable anaplastic thyroid cancer (ATC), for which no effective therapies exist. Recently, a sizable fraction of undifferentiated or poorly differentiated thyroid cancers were shown to contain mutations in beta-catenin, an oncogenic protein involved in the etiology of cancers of many tissues. We developed a conditionally replicative adenovirus (named 'HILMI') which, by virtue of TCF response elements drives E1A and E1B expression, replicates specifically in cells with an active Wnt/beta-catenin pathway. We show that several thyroid cancer cell lines, derived from undifferentiated or anaplastic tissues and possessing an active Wnt/beta-catenin pathway, are susceptible to cell killing by HILMI. Furthermore, viral replication in ATC cells as xenograft tumors in nude mice was observed, and prolonged survival of mice with ATC tumors was observed following administration of the HILMI therapeutic vector. The results warrant further development of this therapeutic approach for ATC patients.