Preclinical efficacy of the oncolytic measles virus expressing the sodium iodide symporter in iodine non-avid anaplastic thyroid cancer: a novel therapeutic agent allowing noninvasive imaging and radioiodine therapy

Abstract

Anaplastic thyroid cancer is an extremely aggressive disease resistant to radioiodine treatment because of loss of sodium iodide symporter (NIS) expression. To enhance prognosis of this fatal cancer, we validated the preclinical efficacy of measles virus (MV)-NIS, the vaccine strain of the oncolytic MV (MV-Edm), modified to include the NIS gene. Western blotting analysis confirmed that a panel of eight anaplastic thyroid cancer (ATC)-derived cell lines do not express NIS protein, but do express CD46, the MV receptor. In vitro cell death assays and in vivo xenograft studies demonstrate the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines. Radioactive iodine uptake along with single-photon emission computed tomography (SPECT)-computed tomography imaging of KTC-3 xenografts after 99 Tc m administration confirmed NIS expression in vitro and in vivo, respectively, after virus treatment. Adjuvant administration of RAI, to MV-NIS-treated KTC-3 tumors showed a trend for increased tumor cell killing. As current treatment for ATC is only palliative, and MV-NIS is currently Food and Drug Administration approved for human clinical trials in myeloma, our data indicate that targeting ATC with MV-NIS could prove to be a novel therapeutic strategy for effective treatment of iodine-resistant ATC and will expedite its testing in clinical trials for this aggressive disease.

Progress in oncolytic virotherapy for treatment of thyroid malignant neoplasm

“…There is a study that utilizes MV-Edm, which was modified to include the NIS gene to be combined with radiology treatment. This study demonstrated the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines and mouse model [87].…”

Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities

“…83 Oncolytic viruses (measles, vaccinia, and lentiviruses) expressing the NIS gene have been used to induce cell death as well as facilitate noninvasive imaging and radioiodine therapy. 69,86,94 Combinatorial therapeutic options using small molecule inhibitors such as paclitaxel, 84 bevacizumab, 89 gancliclovir, 95 and aurora kinase inhibitor AZD1152, 82 along with independent virus treatments, have also been evaluated preclinically.…”

“…[66][67][68][69] In the recent past, a number of transgenic mice have been developed that mimic ATC in vivo [70][71][72][73] and serve as much more clinically relevant models for preclinical testing. These models have primarily been used to elucidate the hypothesis that ATCs arise as a progression from PTC or FTC due to hits to multiple signaling pathways and therefore provide the closest simulation environment reflective of direct in human testing.…”

“…Conditionally replicative viruses include those that target cells with specific tumor suppressor pathways that have been [88][89][90] or are directed to negatively impact tumor growth such as targeting of angiogenesis. 91 Non-replicative adenoviruses, used as vectors to replace tumor suppressor genes such as TP53, 92 TTF1,93 or to express genes with therapeutic potential such as the sodium iodide symporter (NIS) to enable dual targeting, 69,86 have also been evaluated ( Table 3). As single-modality therapy has been shown to have a limited effect on ATC, multimodality therapy has become the treatment of choice in recent years.…”

“…Adeno 82,83 measles, 69 herpes simplex, 84,85 and vaccinia viruses 86,87 have been tested in vitro as well as in vivo in mouse explant models (Table 3). Conditionally replicative viruses include those that target cells with specific tumor suppressor pathways that have been [88][89][90] or are directed to negatively impact tumor growth such as targeting of angiogenesis.…”