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Adenovirus Expressing Sodium Iodide Symporter (NIS) Targets Pancreatic Cancer for Radioiodine Therapy and Imaging
Benjamin Eidenschink*1, Jordan Sell1, Kari Jacobsen1, John Morris2, Masato Yamamoto1, Julia Davydova1
1Surgery, University of Minnesota, Minneapolis, MN; 2Endocrinology, Mayo Clinic, Rochester, MN
Pancreatic cancer is a devastating disease that has little effective treatments due to inoperable metastasizes and resistance to normal cancer treatment. It is the fourth leading cause of cancer deaths and has a 6% five-year survival rate. New methodologies are needed to treat this cancer. Oncolytic adenovirus (OAds) is a promising methodology to target metastatic cancer and express a transgene specifically in cancer cells.
We have developed an OAd to specifically replicate in pancreatic cancer using a tumor specific promoter. This promoter controls virus replication, oncolytic activity, and transgene expression. Modifications to the virus fiber improves target cell binding. In addition, the virus has been modified to also express a transgene of interest.
The transgene is the sodium iodide symporter (NIS). NIS is a naturally expressed human thyroid protein that transports Na+ and I- across the membrane. The transgene allows for the transport of iodine into the infected cancer cells. With NIS expressed in cancer cells radioiodide therapy and diagnostics is now a possibility. Radioiodine therapy and diagnostics enhances NIS expressing cell in SPECT/CT imaging with I125 and kill the cells with I131. The safety and application of radioiodine therapy was been well established with 50 years of treating thyroid cancers.
Our OAd vector functionality is shown by virus viability, specificity ad transgene expression. Virus replication, oncolytic activity, and selectivity was exhibited in vitro with crystal violet assays to show viable cells and qPCR to quantify virus DNA. The new NIS-expressing adenovirus exhibited selective and strong oncolytic potency in S2O13, S2VP10, AsPC1, and MiaPaca2 pancreatic cancer cells. Radioiodine uptake assay was performed by infecting cells with 1vp/cell in a 12 well plate. Radioiodine was added 2,3,and 4 days after infection for 1h at 37C. After washing, the cells were measured for gamma radiation activity with Beckman 5500 gamma counter. Radioiodine uptake in Miapaca2, Panc1, and Hs766T in vitro was shown to be dependent on NIS expression.
NIS expressing OAds have promise in the future of pancreatic cancer therapy and diagnostics. However, further experimentation is needed to bring this methodology to the clinic. Future experiments will evaluate the effective of NIS OAd radioiodine therapy through imaging and therapeutic animal studies, as well as explore any interactions with current cancer treatments such as chemotherapies. Overall, this methodology intends to bring a new therapeutic and imaging standard to pancreatic cancer treatment
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