Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.

Peptide receptor scintigraphy and peptide receptor radionuclide therapy using radiolabeled somatostatin receptor (SSTR) agonists are successfully used in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated the superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic antitumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of 177 Lu-DOTA-octreotate, an SSTR agonist, and 177 Lu-DOTA-JR11, an SSTR antagonist. Methods: We analyzed radiotracer uptake (both membrane-bound and internalized fractions) and the produced DNA double-strand breaks, by determining the number of p53 binding protein 1 foci, after incubating SSTR2-positive cells with 177 Lu-diethylene triamine pentaacetic acid, 177 Lu-DOTA-octreotate, or 177 Lu-DOTA-JR11. Also, biodistribution studies were performed in tumor-xenografted mice to determine the optimal dose for therapy experiments. Afterward, in vivo therapy experiments comparing the effect of 177 Lu-DOTA-octreotate and 177 Lu-DOTA-JR11 were performed in this same animal model. Results: We found a 5-times-higher uptake of 177 Lu-DOTA-JR11 than of 177 Lu-DOTA-octreotate. The major part (88% ± 1%) of the antagonist uptake was membranebound, whereas 74% ± 3% of the total receptor agonist uptake was internalized. Cells treated with 177 Lu-DOTA-JR11 showed 2 times more p53-binding protein 1 foci than cells treated with 177 Lu-DOTAoctreotate. Biodistribution studies with 177 Lu-DOTA-JR11 (0.5 μg/ 30 MBq) resulted in the highest tumor radiation dose of 1.8 ± 0.7 Gy/ MBq, 4.4 times higher than the highest tumor radiation dose found for 177 Lu-DOTA-octreotate. In vivo therapy studies with 177 Lu-DOTAoctreotate and 177 Lu-DOTA-JR11 resulted in a tumor growth delay time of 18 ± 5 and 26 ± 7 d, respectively. Median survival rates were 43.5, 61, and 71 d for the control group, 177 Lu-DOTA-octreotate group, and the 177 Lu-DOTA-JR11-treated group, respectively. Conclusion: On the basis of these results, we concluded that the use of radiolabeled SSTR antagonists such as JR11 might enhance peptide receptor scintigraphy and peptide receptor radionuclide therapy of neuroendocrine tumors and provide successful imaging and therapeutic strategies for cancer types with relatively low SSTR expression. Radi olabeled somatostatin (SST) analogs targeting SST receptors (SSTRs), especially SSTR2, overexpressed on tumor cells are successfully used for imaging and treatment of neuroendocrine tumors. These applications are referred to as peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT), respectively. PRS using radiolabeled SST analogs was first described in the late 1980s by Krenning et al. (1), and soon after the first...

Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA has shown to be an excellent target for PCa theranostics because of its high expression on the membrane of PCa cells and the increase in expression during disease progression. Therefore, numerous PSMA-targeting tracers have been developed and (pre)clinically studied with promising results. However, many of these PSMA-targeting tracers show uptake in healthy organs such as the salivary glands, causing radiotoxicity. Furthermore, not all patients respond to PSMA-targeted radionuclide therapy (TRT). This created the necessity of additional preclinical research studies in which existing tracers are reevaluated and new tracers are developed in order to improve PSMA-TRT by protecting the (PSMA-expressing) healthy organs and improving tumor uptake. In this review we will give an overview of the recent preclinical research projects regarding PCa-TRT using PSMA-specific radiotracers, which will give an indication of where the PSMA-TRT research movement is going and what we can expect in future clinical trials.