In Vivo Efficacy Testing of Peptide Receptor Radionuclide Therapy Radiosensitization Using Olaparib

SIMPLE SUMMARY: Neuroendocrine tumor (NET) patients often suffer from metastases, thereby eliminating surgery as a curative treatment option. A possible treatment strategy for these patients is peptide receptor radionuclide therapy (PRRT). PRRT is composed of a radiolabeled peptide that can bind to the NET-cells via a specific receptor. After intravenous injection of the radiolabeled peptide and binding to the NET cells, the radionuclide induces DNA damage upon radioactive decay, leading to cell death. However, the majority of patients will not be cured with the current regimen. Therefore, there is an urgent need for therapy improvement. Previously, it was shown, in cell models, that the combination treatment of PRRT with a poly(ADP-ribose)-polymerase (PARP) inhibitor, which inhibits DNA damage repair, can be effective. As the next step towards patients, we have tested this combination treatment in animal models and showed that, in mice, the combination of PRRT with PARP inhibitors is more effective than PRRT alone, however not in all the tested models. This discrepancy is of importance for the translation of this type of therapy towards the clinic. ABSTRACT: Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [(177)Lu]Lu [DOTA(0)-Tyr(3)]octreotate, is used to treat patients with metastasized neuroendocrine tumors (NETs). Even though PRRT is now the second line of treatment for patients with metastasized NETs, the majority of patients will not be cured by the treatment. PRRT functions by inducing DNA damage upon radioactive decay and inhibition of DNA damage repair proteins could therefore be used as a strategy to potentiate PRRT. Previous work has shown promising results on the combination of PRRT with the PARP inhibitor olaparib in cell lines and mice and we have been taken the next step for further in vivo validation using two different xenografted mouse models. We observed that this combination therapy resulted in increased therapeutic efficacy only in one model and not the other. Overall, our findings indicate a tumor-type dependent anti-tumor response to the combination of PRRT and olaparib. These data emphasize the unmet need for the molecular stratification of tumors to predetermine the potential clinical value of combining PARP inhibition with PRRT.