p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids
2021
Sara Lundsten | Hanna Berglund | Preeti Jha | Cecilia Krona | Mehran Hariri | Sven Nelander | David P. Lane | Marika Nestor
p53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with <sup>177</sup>Lu-DOTATATE is currently being explored as a treatment for neuroblastoma. The aim of this study was to investigate the novel p53-stabilizing peptide VIP116 in neuroblastoma, both as monotherapy and together with <sup>177</sup>Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for <sup>177</sup>Lu-DOTATATE uptake. IC<sub>50</sub> values after VIP116 treatments correlated with p53 status, ranging between 2.8–238.2 μM. IMR-32 and PDX lines LU-NB-1 and LU-NB-2 were then cultured as multicellular tumor spheroids and treated with <sup>177</sup>Lu-DOTATATE and/or VIP116. Spheroid growth was inhibited in all spheroid models for all treatment modalities. The most pronounced effects were observed for combination treatments, mediating synergistic effects in the IMR-32 model. VIP116 and combination treatment increased p53 levels with subsequent induction of p21, Bax and cleaved caspase 3. Combination treatment resulted in a 14-fold and 1.6-fold induction of MDM2 in LU-NB-2 and IMR-32 spheroids, respectively. This, together with differential MYCN signaling, may explain the varying degree of synergy. In conclusion, VIP116 inhibited neuroblastoma cell growth, potentiated <sup>177</sup>Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma.
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