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Published on: March 13, 2018
Sodium iodide symporter (NIS)-mediated radiovirotherapy for pancreatic cancer
Alan R Penheiter1, Troy R Wegman, Kelly L Classic
1Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Objective:
We have previously shown the therapeutic efficacy of an engineered oncolytic measles virus expressing the sodium iodide symporter reporter gene (MV-NIS) in mice with human pancreatic cancer xenografts. The goal of this study was to determine the synergy between MV-NIS-induced oncolysis and NIS-mediated (131)I radiotherapy in this tumor model.
Materials And Methods:
Subcutaneous human BxPC-3 pancreatic tumors were injected twice with MV-NIS. Viral infection, NIS expression, and intratumoral iodide uptake were quantitated with (123)I micro-SPECT/CT. Mice with MV-NIS-infected tumors were treated with 0, 37, or 74 MBq (131)I and monitored for tumor progression and survival. Additional studies were performed with stable NIS-expressing tumors (BxPC-3-NIS) treated with 0, 3.7, 18.5, 37, or 74 MBq of (131)I.
Results:
Mice treated with intratumoral MV-NIS exhibited significant tumor growth delay (p < 0.01) and prolonged survival (p = 0.02) compared with untreated mice. Synergy between MV-NIS-induced oncolysis and NIS-mediated (131)I ablation was not seen; however, a significant correlation was observed between NIS-mediated intratumoral iodide localization (% ID/g) and peak tumor volume reduction (p = 0.04) with combination MV-NIS and (131)I therapy. Stably transduced NIS-expressing BxPC-3 tumors exhibited rapid regression with > or = 18.5 MBq (131)I.
Conclusion:
Delivery of (131)I radiotherapy to NIS-expressing tumors can be optimized using micro-SPECT/CT imaging guidance. Significant hurdles exist for NIS as a therapeutic gene for combined radiovirotherapy in this human pancreatic cancer model. The lack of synergy observed with MV-NIS and (131)I in this model was not due to a lack of radiosensitivity but rather to a nonuniform intratumoral distribution of MV-NIS infection.
Insights
This study investigated combining oncolytic measles virus expressing the sodium iodide symporter (MV-NIS) with (131)I radiotherapy for pancreatic cancer. While not synergistic, MV-NIS showed therapeutic efficacy, and (131)I delivery to NIS-expressing tumors was optimized.
Area of Science:
- Oncolytic virotherapy
- Radiotherapy
- Gene therapy
- Pancreatic cancer research
Background:
- Engineered oncolytic measles virus expressing the sodium iodide symporter reporter gene (MV-NIS) demonstrated therapeutic efficacy in preclinical pancreatic cancer models.
- The sodium iodide symporter (NIS) facilitates iodide uptake, making it a potential target for radionuclide therapy.
Purpose of the Study:
- To evaluate the synergy between MV-NIS-induced oncolysis and NIS-mediated radioactive iodine ((131)I) radiotherapy in a human pancreatic cancer xenograft model.
- To assess the feasibility of optimizing (131)I delivery to NIS-expressing tumors using imaging guidance.
Main Methods:
- Human pancreatic cancer cells (BxPC-3) were injected subcutaneously into mice.
- Tumors were infected with MV-NIS, and viral infection and iodide uptake were assessed using (123)I micro-SPECT/CT.
- Mice received varying doses of (131)I, and tumor progression and survival were monitored.
Main Results:
- Intratumoral MV-NIS treatment led to significant tumor growth delay and prolonged survival compared to controls.
- No synergy was observed between MV-NIS and (131)I radiotherapy; however, a correlation existed between iodide uptake and tumor volume reduction.
- Stable NIS-expressing tumors showed rapid regression with doses of 18.5 MBq (131)I or higher.
Conclusions:
- Micro-SPECT/CT imaging can guide (131)I radiotherapy delivery to NIS-expressing tumors.
- Significant challenges remain for using NIS as a therapeutic gene in combined radiovirotherapy for pancreatic cancer.
- The lack of synergy was attributed to nonuniform MV-NIS infection distribution, not radiosensitivity.
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