Publications
DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo
Reuvers TGA, Verkaik NS, Stuurman D, de Ridder C, Groningen MCC, de Blois E, Nonnekens J.
Peptide receptor radionuclide therapy (PRRT) increases progression-free survival and quality of life of neuroendocrine tumor (NET) patients, however complete cures are rare and dose-limiting toxicity has been reported. PRRT induces DNA damage of which DNA double strand breaks (DSBs) are the most cytotoxic. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key player in DSB repair and its inhibition therefore is a potential way to enhance PRRT efficacy without increasing the dosage. We analyzed effects of combining PRRT and DNA-PKcs inhibitor AZD7648 on viability, cell death and clonogenic survival on SSTR2-expressing cell lines BON1-SSTR2, GOT1 and NCI-H69. Combining PRRT and AZD7648 significantly decreased viability of BON1-SSTR2, GOT1 and NCI-H69 cells and induced cell death in GOT1 and BON1-SSTR2 cells. A strong effect of AZD7648 on PRRT-induced DSB repair was found. In vivo, AZD7648 significantly sensitized BON1-SSTR2 and NCI-H69 xenograft models to PRRT. These results highlight that the potentiation of the therapeutic effect of PRRT by DNA-PKcs inhibition is a highly effective and well-tolerated therapeutic strategy.
A Clinical Guide to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients
Becx MN, Minczeles NS, Brabander T, de Herder WW, Nonnekens J, Hofland J.
Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-[DOTA0,Tyr3]-octreotate (177Lu-DOTATATE) has become an established second- or third-line treatment option for patients with somatostatin receptor (SSTR)-positive advanced well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Clinical evidence of the efficacy of PRRT in tumor control has been proven and lower risks of disease progression or death are seen combined with an improved quality of life. When appropriate patient selection is performed, PRRT is accompanied by limited risks for renal and hematological toxicities. Treatment of NET patients with PRRT requires dedicated clinical expertise due to the biological characteristics of PRRT and specific characteristics of NET patients. This review provides an overview for clinicians dealing with NET on the history, molecular characteristics, efficacy, toxicity and relevant clinical specifics of PRRT.
In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T.
Ruigrok EAM, Tamborino G, de Blois E, Roobol SJ, Verkaik N, De Saint-Hubert M, Konijnenberg MW, van Weerden WM, de Jong M, Nonnekens J.
Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate cancer (PCa). The efficacy of this therapy might be further improved by replacing the β-emitting lutetium-177 with the α-emitting actinium-225, due to the high linear energy transfer (LET) of the emitted α-particles. Here we evaluated the relative biological effectiveness of [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T by assessing in vitro binding characteristics, dosimetry, and therapeutic efficac. We found that labeling of PSMA-I&T with lutetium-177 or actinium-225 resulted in similar in vitro binding characteristics, indicating that the distinct biological effects observed in this study are not caused by a difference in uptake of the two tracers. The slower repair kinetics of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T correlates to the assumption that irradiation with actinium-225 causes more complex, more difficult to repair DSBs compared to lutetium-177 irradiation. Furthermore, the higher RBE of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa.
In Vivo Efficacy Testing of Peptide Receptor Radionuclide Therapy Radiosensitization Using Olaparib
Feijtel D, Reuvers TGA, van Tuyll-van Serooskerken C, de Ridder CMA, Stuurman DC, de Blois E, Verkaik NS, de Bruijn P, Koolen SLW, de Jong M, Nonnekens J.
Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [177Lu]Lu [DOTA0-Tyr3]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.
List of publications
2023
Nonnekens J, Cornelissen B, Terry SYA; European Working Group on the Radiobiology of Molecular Radiotherapy. Second Symposium of the European Working Group on the Radiobiology of Molecular Radionuclide Therapy. J Nucl Med. 2023 Nov;64(11):1788-1790. doi: 10.2967/jnumed.123.265956. Epub 2023 Jul 13. PMID: 37442600.
Ladan MM, Meijer TG, Verkaik NS, de Monye C, Koppert LB, Oomen-de Hoop E, van Deurzen CHM, Kanaar R, Nonnekens J, van Gent DC, Jager A. Proof-of-concept study linking ex vivo sensitivity testing to neoadjuvant anthracycline-based chemotherapy response in breast cancer patients. NPJ Breast Cancer. 2023 Sep 30;9(1):80. doi: 10.1038/s41523-023-00583-6. PMID: 37777518; PMCID: PMC10542784.
Reuvers TGA, Verkaik NS, Stuurman D, de Ridder C, Groningen MCC, de Blois E, Nonnekens J. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics. 2023 May 21;13(10):3117-3130. doi: 10.7150/thno.82963. PMID: 37351169; PMCID: PMC10283055.
Dijkstra BM, Nonnekens J, Nagengast W, Kruijff S, Meersma GJ, den Dunnen WFA, Kruyt FAE, Groen RJM. Feasibility of bevacizumab-IRDye800CW as a tracer for fluorescence-guided meningioma surgery. J Neurosurg. 2022 Oct 28;138(5):1263-1272. doi: 10.3171/2022.9.JNS221036. PMID: 36308486.
Feijtel D, Reuvers TGA, van Tuyll-van Serooskerken C, de Ridder CMA, Stuurman DC, de Blois E, Verkaik NS, de Bruijn P, Koolen SLW, de Jong M, Nonnekens J. In Vivo Efficacy Testing of Peptide Receptor Radionuclide Therapy Radiosensitization Using Olaparib. Cancers (Basel). 2023 Feb 1;15(3):915. doi: 10.3390/cancers15030915. PMID: 36765883; PMCID: PMC9913849.
2022
Becx MN, Minczeles NS, Brabander T, de Herder WW, Nonnekens J, Hofland J. A Clinical Guide to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients. Cancers (Basel). 2022 Nov 24;14(23):5792. doi: 10.3390/cancers14235792. PMID: 36497273; PMCID: PMC9737149.
Hooijman EL, Ntihabose CM, Reuvers TGA, Nonnekens J, Aalbersberg EA, van de Merbel JRJP, Huijmans JE, Koolen SLW, Hendrikx JJMA, de Blois E. Radiolabeling and quality control of therapeutic radiopharmaceuticals: optimization, clinical implementation and comparison of radio-TLC/HPLC analysis, demonstrated by [177Lu]Lu-PSMA. EJNMMI Radiopharm Chem. 2022 Nov 4;7(1):29. doi: 10.1186/s41181-022-00181-0. PMID: 36333648; PMCID: PMC9636342.
Koustoulidou S, Handula M, de Ridder C, Stuurman D, Beekman S, de Jong M, Nonnekens J, Seimbille Y. Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors. Pharmaceuticals (Basel). 2022 Sep 16;15(9):1155. doi: 10.3390/ph15091155. PMID: 36145375; PMCID: PMC9503898.
Ruigrok EAM, Tamborino G, de Blois E, Roobol SJ, Verkaik N, De Saint-Hubert M, Konijnenberg MW, van Weerden WM, de Jong M, Nonnekens J. Correction to: In vitro dose effect relationships of actinium‑225‑ and lutetium‑177‑labeled PSMA‑I&T. Eur J Nucl Med Mol Imaging. 2022 Sep;49(11):3956-3957. doi: 10.1007/s00259-022-05845-2. Erratum for: Eur J Nucl Med Mol Imaging. 2022 Sep;49(11):3627-3638. PMID: 35614268; PMCID: PMC9399007.
Ruigrok EAM, Tamborino G, de Blois E, Roobol SJ, Verkaik N, De Saint-Hubert M, Konijnenberg MW, van Weerden WM, de Jong M, Nonnekens J. In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T. Eur J Nucl Med Mol Imaging. 2022 Sep;49(11):3627-3638. doi: 10.1007/s00259-022-05821-w. Epub 2022 May 12. Erratum in: Eur J Nucl Med Mol Imaging. 2022 May 26;: PMID: 35556158; PMCID: PMC9399067.
Ruigrok EAM, Verkaik NS, de Blois E, de Ridder C, Stuurman D, Roobol SJ, Van Gent DC, de Jong M, Van Weerden WM, Nonnekens J. Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment. Int J Mol Sci. 2022 Jul 21;23(14):8037. doi: 10.3390/ijms23148037. PMID: 35887398; PMCID: PMC9316488.
Nonnekens J, Pouget JP, Cornelissen B, Terry SYA; European Working Group; Radiobiology of Molecular Radionuclide Therapy. Status of radiobiology in molecular radionuclide therapy - Hope for the future. Nucl Med Biol. 2022 Jul-Aug;110-111:45-46. doi: 10.1016/j.nucmedbio.2022.04.008. Epub 2022 Apr 16. PMID: 35561638.
Tamborino G, Perrot Y, De Saint-Hubert M, Struelens L, Nonnekens J, Jong M, Konijnenberg MW, Villagrasa C. Modeling Early Radiation DNA Damage Occurring During 177Lu-DOTATATE Radionuclide Therapy. J Nucl Med. 2022 May;63(5):761-769. doi: 10.2967/jnumed.121.262610. Epub 2021 Sep 9. PMID: 34503959; PMCID: PMC9051596.
Tamborino G, Nonnekens J, Struelens L, De Saint-Hubert M, Verburg FA, Konijnenberg MW. Therapeutic efficacy of heterogeneously distributed radiolabelled peptides: Influence of radionuclide choice. Phys Med. 2022 Apr;96:90-100. doi: 10.1016/j.ejmp.2022.02.021. Epub 2022 Mar 1. PMID: 35245708.
Tamborino G, Nonnekens J, De Saint-Hubert M, Struelens L, Feijtel D, de Jong M, Konijnenberg MW. Dosimetric Evaluation of the Effect of Receptor Heterogeneity on the Therapeutic Efficacy of Peptide Receptor Radionuclide Therapy: Correlation with DNA Damage Induction and In Vivo Survival. J Nucl Med. 2022 Jan;63(1):100-107. doi: 10.2967/jnumed.121.262122. Epub 2021 Apr 9. PMID: 33837068; PMCID: PMC8717202.
2021
Verburg FA, Konijnenberg MW, Nonnekens J. The limits of the "holy gray" in radioembolization and beyond : Beyond the "holy Gray". Eur J Nucl Med Mol Imaging. 2021 Dec;48(13):4118-4119. doi: 10.1007/s00259-021-05560-4. PMID: 34498110.
Geenen L, Nonnekens J, Konijnenberg M, Baatout S, De Jong M, Aerts A. Overcoming nephrotoxicity in peptide receptor radionuclide therapy using [177Lu]Lu-DOTA-TATE for the treatment of neuroendocrine tumours. Nucl Med Biol. 2021 Nov-Dec;102-103:1-11. doi: 10.1016/j.nucmedbio.2021.06.006. Epub 2021 Jul 1. PMID: 34242948.
Verburg FA, Nonnekens J, Konijnenberg MW, de Jong M. To go where no one has gone before: the necessity of radiobiology studies for exploration beyond the limits of the "Holy Gray" in radionuclide therapy. Eur J Nucl Med Mol Imaging. 2021 Aug;48(9):2680-2682. doi: 10.1007/s00259-020-05147-5. PMID: 33392716.
Cornelissen B, Terry S, Nonnekens J, Pouget JP; European Working Group on the Radiobiology of Molecular Radiotherapy. First Symposium of the European Working Group on the Radiobiology of Molecular Radiotherapy. J Nucl Med. 2021 Jul 1;62(7):14N-15N. PMID: 34244371.
Dijkstra BM, de Jong M, Stroet MCM, Andreae F, Dulfer SE, Everts M, Kruijff S, Nonnekens J, den Dunnen WFA, Kruyt FAE, Groen RJM. Correction to: Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma. J Neurooncol. 2021 Jun;153(2):223. doi: 10.1007/s11060-021-03769-9. Erratum for: J Neurooncol. 2021 Jun;153(2):211-222. PMID: 34014425; PMCID: PMC8211574.
Dijkstra BM, de Jong M, Stroet MCM, Andreae F, Dulfer SE, Everts M, Kruijff S, Nonnekens J, den Dunnen WFA, Kruyt FAE, Groen RJM. Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma. J Neurooncol. 2021 Jun;153(2):211-222. doi: 10.1007/s11060-021-03739-1. Epub 2021 Mar 26. Erratum in: J Neurooncol. 2021 May 20;: PMID: 33768405; PMCID: PMC8211583.
Ruigrok EAM, van Vliet N, Dalm SU, de Blois E, van Gent DC, Haeck J, de Ridder C, Stuurman D, Konijnenberg MW, van Weerden WM, de Jong M, Nonnekens J. Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy. Eur J Nucl Med Mol Imaging. 2021 May;48(5):1339-1350. doi: 10.1007/s00259-020-05057-6. Epub 2020 Oct 23. PMID: 33094433; PMCID: PMC8113296.
Feijtel D, Doeswijk GN, Verkaik NS, Haeck JC, Chicco D, Angotti C, Konijnenberg MW, de Jong M, Nonnekens J. Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response. Theranostics. 2021 Jan 1;11(2):491-505. doi: 10.7150/thno.51215. PMID: 33391488; PMCID: PMC7738856.
2020
Reuvers TGA, Kanaar R, Nonnekens J. DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage. Cancers (Basel). 2020 Jul 28;12(8):2098. doi: 10.3390/cancers12082098. PMID: 32731592; PMCID: PMC7463878.
O'Neill E, Kersemans V, Allen PD, Terry SYA, Torres JB, Mosley M, Smart S, Lee BQ, Falzone N, Vallis KA, Konijnenberg MW, de Jong M, Nonnekens J, Cornelissen B. Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy. J Nucl Med. 2020 May;61(5):743-750. doi: 10.2967/jnumed.119.232934. Epub 2019 Nov 22. PMID: 31757844; PMCID: PMC7198382.
Zhang W, van Gent DC, Incrocci L, van Weerden WM, Nonnekens J. Role of the DNA damage response in prostate cancer formation, progression and treatment. Prostate Cancer Prostatic Dis. 2020 Mar;23(1):24-37. doi: 10.1038/s41391-019-0153-2. Epub 2019 Jun 13. Erratum in: Prostate Cancer Prostatic Dis. 2019 Jul 17;: PMID: 31197228; PMCID: PMC8076026.
Tamborino G, De Saint-Hubert M, Struelens L, Seoane DC, Ruigrok EAM, Aerts A, van Cappellen WA, de Jong M, Konijnenberg MW, Nonnekens J. Cellular dosimetry of [177Lu]Lu-DOTA-[Tyr3]octreotate radionuclide therapy: the impact of modeling assumptions on the correlation with in vitro cytotoxicity. EJNMMI Phys. 2020 Feb 10;7(1):8. doi: 10.1186/s40658-020-0276-5. PMID: 32040783; PMCID: PMC7010903.
Feijtel D, de Jong M, Nonnekens J. Peptide Receptor Radionuclide Therapy: Looking Back, Looking Forward. Curr Top Med Chem. 2020;20(32):2959-2969. doi: 10.2174/1568026620666200226104652. PMID: 32101125; PMCID: PMC8493789.
2019
Ruigrok EAM, van Weerden WM, Nonnekens J, de Jong M. The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research. Pharmaceutics. 2019 Oct 29;11(11):560. doi: 10.3390/pharmaceutics11110560. PMID: 31671763; PMCID: PMC6921028.
Zhang W, Liao CY, Chtatou H, Incrocci L, van Gent DC, van Weerden WM, Nonnekens J. Apalutamide Sensitizes Prostate Cancer to Ionizing Radiation via Inhibition of Non-Homologous End-Joining DNA Repair. Cancers (Basel). 2019 Oct 18;11(10):1593. doi: 10.3390/cancers11101593. PMID: 31635359; PMCID: PMC6827010.
Brabander T, Nonnekens J, Hofland J. The next generation of peptide receptor radionuclide therapy. Endocr Relat Cancer. 2019 Aug;26(8):C7-C11. doi: 10.1530/ERC-19-0186. PMID: 31200364.
Terry SYA, Nonnekens J, Aerts A, Baatout S, de Jong M, Cornelissen B, Pouget JP. Call to arms: need for radiobiology in molecular radionuclide therapy. Eur J Nucl Med Mol Imaging. 2019 Jul;46(8):1588-1590. doi: 10.1007/s00259-019-04334-3. Epub 2019 May 8. PMID: 31069454.
Zhang W, van Weerden WM, de Ridder CMA, Erkens-Schulze S, Schönfeld E, Meijer TG, Kanaar R, van Gent DC, Nonnekens J. Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response. Prostate. 2019 Mar;79(4):390-402. doi: 10.1002/pros.23745. Epub 2018 Dec 5. PMID: 30520109; PMCID: PMC6587720.