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Neuroblastoma is a pediatric cancer with a five-year survival rate of merely 50% for high-risk cases. The treatment regimen is aggressive, leading to extensive side effects that significantly impact patients’ quality of life.

Targeted radionuclide therapy (TRT) involves the systemic administration of cancer-specific radioconjugates. This thesis focuses on TRT against the somatostatin receptor 2 (SSTR2) and the antigen CD44v6, two targets that are overexpressed in neuroblastoma,  

Radiosensitization renders cells more sensitive to radiation, which can improve the therapeutic efficacy and potentially reduce the radiation dose required to achieve an antitumor effect. This thesis investigates radiosensitization through the stabilization of p53 and the inhibition of heat shock protein 90 (HSP90), two proteins involved in the cellular response to DNA damage.

In papers I and II, we investigated the combination of the SSTR2-targeting radioconjugate ¹⁷⁷Lu-DOTATATE with the p53-stabilizing peptide VIP116 for neuroblastoma treatment. The combination therapy demonstrated enhanced antitumor effects in both in vitro and in vivo studies using mice bearing human neuroblastoma xenografts. Notably, the untreated and monotreated controls showed no nephrotoxicity.

In paper III, we demonstrated that combining external beam radiotherapy with the HSP90-inhibitor Onalespib produced additive or synergistic effects in vitro across a panel of neuroblastoma cell lines. Additionally, mice bearing syngeneic neuroblastoma tumor xenografts treated with this combination exhibited significantly improved therapeutic efficacy compared to control groups.

In paper IV, we developed and characterized human anti-CD44v6 antibodies for molecular radiotherapy. This work identified a lead candidate, UU-40, which demonstrated high affinity, strong tumor uptake, and favorable in vivodistribution, making it a promising candidate for future use against CD44v6-expressing cancers.

In conclusion, this thesis demonstrates that radiosensitization enhances the antitumor effects of radiation therapy in preclinical models of neuroblastoma. It is our hope that these discoveries will enable more effective and less harmful treatments for children with neuroblastoma. This thesis also produced an anti-CD44v6 antibody that holds great potential for future use in targeted radionuclide therapy, paving the way for innovative treatments for CD44v6-expressing cancers, including neuroblastoma.