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Theranostics 2018; 8(12):3380-3391. doi:10.7150/thno.24017 This issue Cite

Research Paper

Somatostatin receptor type 2 as a radiotheranostic PET reporter gene for oncologic interventions

Pedram Heidari^*, Anchisa Kunawudhi^*, Jordi Martinez-Quintanilla, Alicia Szretter, Khalid Shah, Umar Mahmood^✉

Department of Radiology, Massachusetts General Hospital, Boston, MA
*Equal contribution

✉ Corresponding author: Umar Mahmood, M.D., Ph.D., Center for Precision Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114. Tel: 617-726-6477; Fax: 617-726-7422; Email: umahmoodharvard.edu

Abstract

Reporter gene systems can serve as therapy targets. However, the therapeutic use of reporters has been limited by the challenges of transgene delivery to a majority of cancer cells. This study specifically assesses the efficacy of targeting human somatostatin receptor subtype 2 (hSSTR2) with peptide receptor radionuclide therapy (PRRT) when a small subpopulation of cells bears the transgene.

Methods: The hSSTR2 transgene was delivered to A549 and Panc-1tumors using the lentiviral vector, LV-hSSTR2-IRES-GFP or murine mesenchymal stem cells (mMSC)s using a retroviral vector. SSTR2 expression was assessed using Western blot and correlated to GFP fluorescence and ⁶⁸Ga-DOTATOC uptake. Wild type (WT), transduced (TD), and mixed population A549 or Panc-1 xenografts were implanted in nude mice. Separate groups with A549_WT and Panc-1_WT tumors received intratumoral injection of SSTR2-expressing mMSCs. Tumor-bearing mice were treated with ⁹⁰Y-DOTATOC or saline and evaluated with ⁶⁸Ga-DOTATOC PET before and after treatment.

Results: Cell studies showed a strong correlation between ⁶⁸Ga-DOTATOC uptake and SSTR2 expression in A549 (p < 0.004) and Panc-1 cells (p < 0.01). ⁶⁸Ga-DOTATOC PET SUVmean was 8- and 5-fold higher in TD compared to WT A549 and Panc-1 tumors, respectively (p < 0.001). After ⁹⁰Y-DOTATOC treatment, 100% TD and mixed population TD xenografts showed growth cessation while the WT xenografts did not. A549_WT and Panc-1_WT tumors with SSTR2-expressing mMSCs treated with ⁹⁰Y-DOTATOC showed significantly lower tumor volumes compared to controls (p < 0.05). ⁶⁸Ga-DOTATOC PET SUVmean of treated TD tumors monotonically declined and was significantly lower than that of non-treated xenografts.

Conclusions: We showed that SSTR2 delivery to a small population of cells in tumor in conjunction with PRRT is effective in tumor growth cessation. The availability of various transgene delivery methods for hSSTR2 and radiotherpaeutic somatostatin analogs highlights the direct translational potential of this paradigm in the treatment of various cancers.

Keywords: somatostatin receptor, theranostic, peptide receptor radionuclide therapy (PRRT), ⁶⁸Ga-DOTATOC, reporter gene

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