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p53-Mediated Radiosensitization of 177Lu-DOTATATE in Neuroblastoma Tumor Spheroids
Sara Lundsten1, Hanna Berglund1, Preeti Jha1,2
1Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
Abstract:
p53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with 177Lu-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 177Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for 177Lu-DOTATATE uptake. IC50 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 177Lu-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 177Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma.
Insights
The p53-stabilizing peptide VIP116 shows promise in treating neuroblastoma. It effectively inhibits cancer cell growth and enhances targeted radionuclide therapy with 177Lu-DOTATATE, suggesting a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- p53 protein plays a crucial role in DNA damage response and is a key target for cancer radiosensitization.
- Targeted radionuclide therapy using 177Lu-DOTATATE is an emerging treatment for neuroblastoma.
- The p53-stabilizing peptide VIP116 is a novel therapeutic agent under investigation.
Purpose of the Study:
- To evaluate the efficacy of VIP116 as a monotherapy and in combination with 177Lu-DOTATATE for neuroblastoma treatment.
- To assess the impact of VIP116 on neuroblastoma cell growth and its interaction with 177Lu-DOTATATE therapy.
- To investigate the molecular mechanisms underlying VIP116's effects, including p53 pathway activation.
Main Methods:
- Characterization of five neuroblastoma cell lines, including patient-derived xenografts (PDX), for 177Lu-DOTATATE uptake.
- Treatment of neuroblastoma cell lines and multicellular tumor spheroids with VIP116 and/or 177Lu-DOTATATE.
- Analysis of cell viability (IC50), spheroid growth inhibition, and molecular markers (p53, p21, Bax, cleaved caspase 3, MDM2, MYCN).
Main Results:
- VIP116 monotherapy demonstrated dose-dependent inhibition of neuroblastoma cell growth, with efficacy correlating with p53 status.
- Combined treatment with VIP116 and 177Lu-DOTATATE showed synergistic effects, particularly in the IMR-32 model.
- VIP116 and combination treatments upregulated p53, p21, Bax, and cleaved caspase 3, indicating apoptosis induction.
- Differential MDM2 induction and MYCN signaling were observed, potentially explaining varying synergistic responses.
Conclusions:
- VIP116 effectively inhibits neuroblastoma cell growth and potentiates the therapeutic effect of 177Lu-DOTATATE.
- The combination of VIP116 and 177Lu-DOTATATE represents a promising therapeutic strategy for neuroblastoma.
- Further investigation into VIP116's role in p53 stabilization and its synergistic potential is warranted for neuroblastoma treatment.
