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  • Publications | Nonnekenslab

    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. Read the Paper 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. Read the Paper 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. Read the Paper 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. Read the Paper 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. Complete list

  • Research | Nonnekenslab

    Our areas of research Cellular effects of radionuclide in tumor cells Investigating the impact of radionuclide therapy on tumor cells at the cellular level. More Info Radiobiology and dosimetry of different radiation qualities Studying the radiobiological aspects and dosimetry of various radiation qualities to gain insights into their effects. More Info Radiosensitization for improved radionuclide therapy outcome Exploring strategies to enhance radiosensitivity, with the aim of improving outcomes in radionuclide therapy. More Info Vacancies&Internship Cellular effects of radionuclide in tumor cells During targeted radionuclide therapy, radiolabeled compounds are targeted to the cancer cells via specific tumor binding (e.g. via receptors). Once bound to the tumor cells, the radionuclides will induce DNA damage leading to cancer cell death. ​ In order to gain insight in the underlying radiobiological principle of this therapy, we are studying human tumor cell line and slices cultured and treated in vitro with targeted radionuclide therapy. We are investigating the internalisation of TRT, the subsequent induced DNA damage, regulation of RNA expression, survival of tumor cells, etc ​ Current projects: Tumor radiobiology of NET TRT [Danny Feijtel, Pleun Engbers , Joke Zink, Giulia Tamborino , Tijmen de Wolf ] Tumor cell radiobiology of PCa TRT [Eline Ruigrok, Mariangela Sabatella] Pathway activation analysis of NET TRT [Thom Reuvers, Mariangela Sabatella ] Immune responses activated by TRT [Justine Perrin ] Radiobiological assessment of blood of NET TRT patients [Nina Becx ] Novel TRT options for pediatric neuro oncology [Nina Overdevest ] ​ ​ Radiobiology and dosimetry of different radiation qualities Various radionuclides are being used in clinical practice or expected to be implemented in the future, including Auger, alpha and beta emitter. Different radionuclides have different cellular effects based mostly on the type of decay, half-life and range. In order to predict which radionuclide is suitable for which indication, we are investigating the difference between these radiation qualities using in vitro biological experiments en in silico dose simulations ​ In addition, we are also focusing on development of detailed dosimetric modes. At the moment, there is no accurate method to determine the dose of TRT on various cellular targets and intratumoral heterogeneous regions. Therefore, it is essential to perform dosimetry to understand radiation dose-effects and integrate them into treatment planning systems for TRT. ​ ​Current projects: Live cell imaging of DNA repair dynamics by TRT [Pleun Engbers , Tijmen de Wolf , Justine Perrin ] Radiobiological comparison of lutetium-177 and actinium-225 for PCa TRT [Eline Ruigrok, Mariangela Sabatella ] Radiobiological comparison of lutetium-177 and terbium-161 [Joke Zink] Micro- and macrodosimetry of TRT [Giulia Tamborino ] Automated image analysis of TRT fluorescent images [Tijmen de Wolf ] Radiobiological comparison of holmium-166 and yttrium-90 for radioembolization [Justine Perrin ] Radiosensitization for improved radionuclide therapy outcome Work by us and others has shown that TRT can be potentiated by combination with radiosensitizing compounds. Especially, various DDR inhibitors can function as radiosensitizers, and differentially impair DNA repair of TRT induced DNA damage and thereby vastly increase cell death, as we have shown in cells, tumor slices and xenografted tumors. ​ On key example is radiosensitization of TRT for neuroendocrine tumors using the PARP-1 inhibitor olaparib. Our preclinical work has led to the start of various clinical trials worldwide and we are now also performing our own clinical phase 1 trial (collaboration with Dr. Hans Hofland). In addition to PARP-1 inhibitors, we are using drug screens to identify other potential synergistic combinatory regimens. ​ Current projects: Radiosensitization to improve TRT outcome [Thom Reuvers, Danny Feijtel, Eline Ruigrok, Mariangela Sabatella ] Clinical phase 1 trial of NET TRT in combination with PARP inhibitors [Nina Becx ] For more details please contact: ​ Current vacacancies and internship Vacancies PhD student: unraveling the radiation biology of radioactive anticancer agents. The project focuses on investigating cellular effects of radioactive anti-cancer agents as part of a Dutch NWO-funded consortium. ​ Job description We are looking for a highly motivated PhD student to work on a project focusing on the radiation biology of targeted radionuclide therapy (TRT). This multidisciplinary project brings together expertise from the fields of nuclear medicine, molecular biology and cellular (radiation) biology. TRT is a promising novel modality to treat patients with metastasized cancer. TRTs function via systemic administration of radiolabeled molecules designed to target tumor cells. However, the biological radiation effects of TRTs are poorly understood, and rational design of new modalities based on underlying cellular mechanisms is therefore not possible, resulting in suboptimal treatment strategies. In this preclinical research project, you will perform cellular experiments to identify and quantify specific radiobiological mechanisms of TRT-radiation effects. In this project, you will be trained in using various laboratory techniques including cell culture, (fluorescent) microscopy, and different molecular biological techniques. Focus of this project will be on 2D cellular model systems and within the consortium, you will collaborate with colleagues from Radboud UMC who will work on 3D and in vivo radiobiology. contact us Internship We welcome all students for internship positions. If you are interested in doing an internship with us, please contact us via email : j.nonnekens@erasmusmc.nl Current fundings MSCA postdoctoral fellowship Justine Perrin 2024-2026 Impact of BRCA2 deficiency on the DNA damage response and immunogenicity of prostate cancer after radioligand therapy. NWO Perspectief consortium Frank Nijsen, Julie Nonnekens, Sandra Heskamp, Antonia Denkova, consortium partners 2022-2027 Understanding the radiobiology of therapeutic medical radionuclides. Research grant Cure Starts Now Foundation Sophie Veldhuijzen van Zanten, Julie Nonnekens 2022-2026 Development and optimization of targeted radiopharmaceutical therapies for pediatric brain tumors; a world-first translational study. ERC starting grant 2021 Julie Nonnekens 2022-2027 RADIOBIO: Deciphering the radiobiology of targeted radionuclide therapy: from subcellular to intra-tumoural analyses Research collaboration with Quirem Medical, Terumo Julie Nonnekens 2022-2024 Radiobiological effects of holmium-166 and yttrium-90 Research collaboration with POINT Biopharma Julie Nonnekens 2022-2024 Radiobiology of alpha and beta-PSMA targeted radionuclide therapy Oncode clinical proof of concept study Roland Kanaar, Julie Nonnekens, Hans Hofland, Ferry Eskens, Wouter de Herder, Tessa Brabander, Astrid van der Veldt, Mark Konijnenberg, Stijn Koolen 2021-2024 Oncode clinical proof of concept study. “Improving Peptide Receptor Radionuclide Therapy with PARP inhibitors: the PRRT-PARPi study”. Erasmus MC Fellowship 2019 Julie Nonnekens 2020-2024 RADIANT: cellular RADIAtion exposure effects of molecular radioNuclide Therapies

  • News | Nonnekenslab

    News&updates Find here the latest news about our lab Julie Nonnekens giving the white paper to the Dutch ambassador in London, 2024 Justine Perrin presented her talk on dose-response between TRT and immune response at the NVRO/NVRB meeting Tijmen de Wolf paper "Weakly supervised 3D image segmentation in fluorescence microscopy using maximum intensity projections" got accepted Meet us at these upcoming conferences! EACR 2024 10-13 June 2024 Rotterdam Gordon Research conference 7-12 July 2024 Maine, USA Establishing a correlation between the immune response and radionuclide therapy: towards a dose-response? Justine Perrin Radioibology: dose-effect relationship of radionuclide therapy Julie Nonnekens

  • About us | Nonnekenslab

    Julie Nonnekens Associate professor and principal investigator Julie Nonnekens received her MSc in Biotechnology at Wageningen University in 2009. She obtained her PhD in cancer biology with the focus on DNA repair mechanisms at the University of Toulouse (France) in 2013. Following, she was a postdoc at the Hubrecht Institute working on ribosome biogenesis in cancer and longevity. In 2014 Julie joined the Erasmus MC Departments of Radiology & Nuclear Medicine and Molecular Genetics and is now Associate Professor. The research of her group bridges the interests of both departments in the field of DNA damage repair mechanisms and nuclear medicine to study the radiation biology of targeted radionuclide anticancer treatment to ultimately optimize treatment regimens. ​ Julie has received several (young investigator) awards and is principal investigator on various research grants including the prestigious ERC starting grant. She is chair of the Netherlands Society of Radiobiology (www.nvrb.org ) and co-founder of the European working group on Radiobiology of Molecular Radionuclide Therapy (www.mrtradiobiology.com ). Linkedin profile Justine Perrin Post-doctoral researcher Project: My current work focuses on holmium-166 and yttrium-90, two radionuclides currently used in the clinic for the treatment of liver cancer for radioembolization. This treatment consists in the injection of radiolabeled microsphere in the liver arteria to irradiate liver tumours. However, there is currently no evidence of which radionuclide would lead to the best therapeutic response. I am therefore studying the radiobiological impact of both these radionuclides on liver cancer cells in vitro, in order to asses s which radionuclide is best suited for this therapy. Linkedin profile Mariangela Sabatella Post-doctoral researcher Project: Targeted radionuclide therapy (TRT) induces DNA damage in the tumor cells causing their death. However, not much is known about the type of DNA damage induced by the different radionuclides nor about the DNA damage response (DDR) that tumor cells activated to overcome the damage and withstand the therapy. My work aims to increase knowledge about the molecular mechanisms underlying the action and response to (novel) TRT used to treat metastatic prostate cancer and identify possible targets for combination therapies with DDR inhibitors. Linkedin profile Justine & mariangela Bio Giulia & Nina bo Giulia Tamborino Post-doctoral researcher Project My research focuses on micro-/nano- dosimetry and biophysical modeling to predict relevant in vitro and in vivo biological end-points, such as cell death, DNA damage induction and tumor volume reduction following targeted radionuclide therapy. I am developing more refined dosimetry frameworks including realistic cellular morphologies and organelles for radionuclide localization, along with the DNA content in order to score DNA damage and elucidate the mechanisms of biological damage caused by Targeted Radionuclide Therapy. I am working in a multidisciplinary environment to develop simulation tools that can effectively consider the intricate nature of DNA damage and repair caused by targeted radionuclide exposure, thereby integrating novel radiobiological information obtained from specifically designed experiments. My ultimate goal is to gain a fundamental understanding of targeted radionuclide therapy with dose-effect relationships that could be implemented in clinical practice for treatment optimization. Nina Becx PhD candidate Project: Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-[DOTA0,Tyr3]octreotate (177Lu-DOTATATE) is an effective and safe treatment for metastasized neuroendocrine tumors (NETs). 177Lu-DOTATATE has been proven to secure long-term survival. However, objective response rates are limited. The goal of my projects is to improve this therapy. We are currently working on a phase 1 clinical trial where we combine PRRT with the PARP inhibitor olaparib. We also want to get a better understanding of the radiation response of 177Lu-DOTATATE in healthy cells, looking at DNA damage induction and transcriptional effects in peripheral blood mononuclear cells. Linkedin profile Nina & Tijmn bio Pleun bio Tijmen de Wolf PhD candidate Project: My research focus is the image analysis for peptide receptor radionuclide therapy (PRRT). The project aims to understand the radiobiology of PRRT. For this purpose, live cell microscopy is used to capture the dynamics of the radionuclides and DNA damage over time. Image analysis is an essential step required for the quantification of the underlying dynamics. Especially, live cell imaging suffers from low signal to noise ratios making this a challenging task. We develop novel algorithms to improve and fully automate the analysis. Nina Overdevest PhD candidate Project: Currently, there is a lack of effective treatments available for pediatric medulloblastoma and diffuse intrinsic pontine glioma / diffuse midline glioma (DIPG/DMG). Therefore, the goal of this project is to determine through preclinical research whether targeted radionuclide therapy (TRT) is a potent treatment option for medulloblastoma and DIPG/DGM. This project includes the optimization of TRT for pediatric brain tumors using different tracers and radionuclides. Linkedin profile Pleun Engbers PhD candidate Project: Targeted radionuclide therapy (TRT) for patients with metastatic neuroendocrine tumors prolongs survival, however complete cures remain rare. Up to now, little is known about the biological effects of ionizing radiation in TRT. Gaining a better insight into the radiobiology of TRT could contribute to improving the therapeutic window of TRT. Therefore, in this project we aim to determine cell-intrinsic radiobiological parameters for TRT. We evaluate amongst others intracellular localization of the radiotracer, DNA damage kinetics, and cellular response to irradiation. Current students: Samuel Odro (Hogeschool Breda) Vincent Ribbe (TU Delft / Erasmus University) Michelle Valk (TU Delft / Erasmus University) Alumni: Stefan Roobol – postdoc 2019-2022 Thom Reuvers – PhD student (defense expected 2024) Danny Feijtel – PhD student (defense 31-1-24) Bianca Dijkstra – PhD student (UMCG, defense 16-10-23) Eline Ruigrok – PhD student (Defense 21-3-23) Giulia Tamborino – PhD student (defense 26-01-2022) Wenhao Zhang – PhD student (defense 18-02-2020) Joke Zink – Research technician 2022-2024 Nicole Verkaik – Research technician 2020-2022 Nicole van Vliet – Research technician 2018-2020

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  • nonnekens lab | research laboratory

    The Nonnekens research laboratory Research Our mission is to enhance the understanding of the molecular and cellular impacts of radioactive anti-cancer agents, leveraging this knowledge to refine existing treatments and innovate new ones. Our ultimate goal is to contribute to the improved care of patients with metastasized diseases. ​ Our research is centered around three primary themes: Cellular effects of radionuclide in tumor cells: Investigating the impact of radionuclide therapy on tumor cells at the cellular level. Radiobiology and dosimetry of different radiation qualities: Studying the radiobiological aspects and dosimetry of various radiation qualities to gain insights into their effects. Radiosensitization for improved radionuclide therapy outcome: Exploring strategies to enhance radiosensitivity, with the aim of improving outcomes in radionuclide therapy. ​ Our research spans multiple levels, encompassing studies conducted at the cellular and animal level, as well as utilizing computational models and patient-based research. This diverse approach enables us to seamlessly translate our discoveries from laboratory experimentation to real-world applications. Read More about research Vacancies&Internship The Erasmus MC Situated within the Departments of Molecular Genetics and Radiology & Nuclear Medicine at Erasmus University Medical Center in Rotterdam , our laboratory is strategically positioned at the largest academic hospital in the Netherlands. This institution facilitates high-level research, empowering us to conduct groundbreaking studies at the forefront of scientific innovation.

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