Treating anaplastic thyroid carcinoma with an oncolytic adenovirus
Reddi, Honey V.
Copland, John A.
Grebe, Stefan K.G.
Eberhardt, Norman L.
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Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Standard therapy is rarely curative, and the tumors are resistant to radioiodine or chemotherapy. Oncolytic viruses may be used to treat ATC. ONYX-015, a modified adenovirus designed to replicate preferentially in p53-mutated cells, induces apoptosis in p53 defective ATC cell lines. However, this effect is not entirely specific to p53 deficient cells, inducing apoptosis in some normal cells. This toxicity limits ONYX-015 to topical use. ONYX-411 is a related oncolytic virus that replicates in cells with impaired function of the retinoblastoma protein (pRB) pathway. This virus exhibits higher selectivity for malignant cells, making it potentially suitable for systemic therapy. This study demonstrates the efficacy of ONYX-411 to inhibit cell growth of the ATC cell lines ARO, DRO, and BHT101, and compares its tumoricidal effects with those of ONYX-015 (1) and PPAR gamma agonist (2) treatment. Quantitation of cell death was achieved by a cell viability assay (MTT). A thyroid cell line immortalized with SV40 large T-antigen (NThy-ori3-1), which inactivates both p53 and pRb, was the positive control. Short-term cultured primary thyrocytes served as a negative control. These in vitro studies showed that ONYX-411 was most effective in BHT101, achieving 80% cell death within 72 hours at an moi of 25. This effect was less prominent in ARO and DRO cells, and the degree of cell killing correlated with the extent of pRB dysfunction quantitated by western blot. Further, unlike ONYX-015, ONYX-411 was non-toxic to normal thyrocytes.
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