ORCID Profile
0000-0001-7581-3303
Current Organisations
University Medical Center Groningen
,
University of Oxford
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Ivyspring International Publisher
Date: 2023
DOI: 10.7150/THNO.82101
Publisher: Elsevier BV
Date: 2023
Publisher: Society of Nuclear Medicine
Date: 22-11-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2005
DOI: 10.1097/00006231-200502000-00012
Abstract: The goal of this study was to develop a 99mTc labelled human epidermal growth factor (hEGF) for the in-vivo prediction of cancer cell response to farnesyltransferase inhibitor (FTI) therapy. This is based on the observation that internalization of EGF receptors is inhibited by FTIs. We describe the radiolabelling of 99mTc-hEGF using the hydrazinonicotinamide (HYNIC) linker. Binding characteristics of 99mTc-HYNIC-hEGF to the EGF receptor are explored using an in-vitro binding assay. Biodistribution data of the compound in mice and tumour uptake in LoVo tumour bearing athymic mice before and after farnesyltransferase inhibitor therapy are presented. No colloid formation was observed. Binding parameters and LoVo tumour uptake of 99mTc-HYNIC-hEGF did not differ significantly from directly labelled 123I-hEGF values. However, the biodistribution data of the 99mTc-HYNIC-hEGF showed higher uptake in liver and intestines and decreased stomach uptake compared to its 123I analogue. Eight hours after farnesyltransferase inhibitor therapy with R115777, LoVo tumour uptake of 99mTc-HYNIC-hEGF decreased significantly, as shown using planar gamma scintigraphy (the ratio tumour vs. thigh dropped from 2.54+/-0.83 to 0.99+/-0.18). These data confirm the results obtained using 123I-hEGF. These data suggest that 99mTc-HYNIC-hEGF is a promising and selective new radiotracer for in-vivo monitoring of the EGF receptor with SPECT. Moreover, 99mTc-HYNIC-hEGF is a possible tool for early therapy response prediction of farnesyltransferase inhibitors.
Publisher: Society of Nuclear Medicine
Date: 28-09-2023
Publisher: Society of Nuclear Medicine
Date: 31-03-2021
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 09-10-2022
DOI: 10.1186/S13550-022-00940-9
Abstract: Radiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [ 18 F]olaparib and the injected mass of [ Total F]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models. [ 18 F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [ Total F]olaparib (varying injected mass: 0.04–8.0 µg, and molar activity: 1–320 GBq/μmol). Selective uptake of [ 18 F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [ Total F]olaparib (µg) but not the molar activity. An injected mass of 1 μg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [ Total F]olaparib resulted in lower relative tumour uptake (%ID/g P 0.05). Ex vivo analysis of U87MG xenograft sections showed that the heterogeneity in [ 18 F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [ Total F]olaparib ( 0.5 µg). Our findings show that the injected mass of [ Total F]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.
Publisher: American Chemical Society (ACS)
Date: 30-08-2021
DOI: 10.1021/ACS.ORGLETT.1C02770
Abstract: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is used in the clinic to treat
Publisher: Springer Science and Business Media LLC
Date: 26-05-2022
DOI: 10.1007/S00259-022-05835-4
Abstract: Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA -mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [ 18 F]rucaparib, an 18 F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [ 18 F]rucaparib in human pancreatic cancer models. We incorporated the positron-emitting 18 F isotope into rucaparib, enabling its use as a PET imaging agent. [ 18 F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. Uptake of [ 18 F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [ 18 F]rucaparib. In vivo studies revealed relatively fast blood clearance of [ 18 F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [ 18 F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. Taken together, we demonstrate the potential of [ 18 F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.
Publisher: Springer Science and Business Media LLC
Date: 13-08-2022
DOI: 10.1186/S13550-022-00920-Z
Abstract: Ataxia telangiectasia mutated (ATM) is a key mediator of the DNA damage response, and several ATM inhibitors (ATMi) are currently undergoing early phase clinical trials for the treatment of cancer. A radiolabelled ATMi to determine drug pharmacokinetics could assist patient selection in a move towards more personalised medicine. The aim of this study was to synthesise and investigate the first 18 F-labelled ATM inhibitor [ 18 F] 1 for non-invasive imaging of ATM protein and ATMi pharmacokinetics. Radiofluorination of a confirmed selective ATM inhibitor ( 1 ) was achieved through substitution of a nitro-precursor with [ 18 F]fluoride. Uptake of [ 18 F] 1 was assessed in vitro in H1299 lung cancer cells stably transfected with shRNA to reduce expression of ATM. Blocking studies using several non-radioactive ATM inhibitors assessed binding specificity to ATM. In vivo biodistribution studies were performed in wild-type and ATM-knockout C57BL/6 mice using PET/CT and ex vivo analysis. Uptake of [ 18 F] 1 in H1299 tumour xenografts was assessed in BALB/c nu / nu mice. Nitro-precursor 2 was synthesised with an overall yield of 12%. Radiofluorination of 2 achieved radiochemically pure [ 18 F] 1 in 80 ± 13 min with a radiochemical yield of 20 ± 13% (decay-corrected) and molar activities up to 79.5 GBq/μmol ( n = 11). In vitro, cell-associated activity of [ 18 F] 1 increased over 1 h, and retention of [ 18 F] 1 dropped to 50% over 2 h. [ 18 F] 1 uptake did not correlate with ATM expression, but could be reduced significantly with an excess of known ATM inhibitors, demonstrating specific binding of [ 18 F] 1 to ATM. In vivo, fast hepatobiliary clearance was observed with tumour uptake ranging 0.13–0.90%ID/g after 1 h. Here, we report the first radiofluorination of an ATM inhibitor and its in vitro and in vivo biological evaluations, revealing the benefits but also some limitations of 18 F-labelled ATM inhibitors.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.NUCMEDBIO.2022.02.004
Abstract: Molecular radionuclide therapy (MRT) is an effective treatment for both localised and disseminated tumours. Biomarkers can be used to identify potential subtypes of tumours that are known to respond better to standard MRT protocols. These enrolment-based biomarkers can further be used to develop dose-response relationships using image-based dosimetry within these defined subtypes. However, the biological identity of the cancers treated with MRT are commonly not well-defined, particularly for neuroendocrine neoplasms. The biological heterogeneity of such cancers has hindered the establishment of dose-responses and minimum tumour dose thresholds. Biomarkers could also be used to determine normal tissue MRT dose limits and permit greater injected doses of MRT in patients. An alternative approach is to understand the repair capacity limits of tumours using radiobiology-based biomarkers within and outside patient cohorts currently treated with MRT. It is hoped that by knowing more about tumours and how they respond to MRT, biomarkers can provide needed dimensionality to image-based biodosimetry to improve MRT with optimized protocols and personalised therapies.
Publisher: Ivyspring International Publisher
Date: 2020
DOI: 10.7150/THNO.44772
Publisher: Society of Nuclear Medicine
Date: 09-10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2005
DOI: 10.1158/1078-0432.CCR-04-2503
Abstract: Purpose: The monoclonal antibody (mAb) 14C5 is a murine IgG1 directed against a yet undefined molecule involved in cell substrate adhesion found on the surface of malignant breast cancer tissue. mAb 14C5 is able to inhibit cell substrate adhesion and invasion of breast cancer cells in vitro. In normal tissues as well as in the stroma surrounding in situ carcinomas of the breast, no expression of the antigen 14C5 occurs. The aim of this study was to investigate the in vitro and in vivo targeting properties of 123I- and 131I-labeled mAb 14C5 as a novel agent for radioimmunodetection and radioimmunotherapy. Experimental Design: Internalization of mAb 14C5 was investigated with 125I-labeled mAb 14C5 and by confocal laser scanning microscopy. Biodistribution studies of 131I-labeled mAb 14C5 and planar gamma imaging were done in nude mice bearing an A549 (non–small cell lung carcinoma) or a LoVo (colon carcinoma) tumor. Results: Internalization studies with both A549 and LoVo cells showed that 125I-labeled mAb 14C5 is slowly internalized with ∼30% of the initially bound mAb 14C5 internalized after 2 hours at 37°C. Internalization of mAb 14C5 could be visualized with confocal laser scanning microscopy. In vivo, radioisotope uptake peaked at 24 hours for both tumor models (n = 5) with no significant difference in percentage of injected dose/g tissue (A549 10.4 ± 0.8 and LoVo 9.3 ± 0.8). Via planar gamma camera imaging, A549 lung tumors as well as LoVo colon tumors could be clearly visualized. Conclusions: The in vitro and in vivo targeting properties of 123I- and 131I-labeled mAb 14C5 are promising and could provide a new antibody-based agent for radioimmunodetection and radioimmunotherapy of patients bearing antigen 14C5–expressing tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 20-10-2020
DOI: 10.1158/1078-0432.CCR-20-2766
Abstract: Targeting of PARP enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination signaling. Currently used to treat BRCA-mutated cancers, PARP inhibitors (PARPi) have demonstrated improved outcome in various cancer types as single agents. Ongoing efforts have seen the exploitation of PARPi combination therapies, boosting patient responses as a result of drug synergisms. Despite great successes using PARPi therapy, selecting those patients who will benefit from single agent or combination therapy remains one of the major challenges. Numerous reports have demonstrated that the presence of a BRCA mutation does not always result in synthetic lethality with PARPi therapy in treatment-naïve tumors. Cancer cells can also develop resistance to PARPi therapy. Hence, combination therapy may significantly affect the treatment outcomes. In this review, we discuss the development and utilization of PARPi in different cancer types from preclinical models to clinical trials, provide a current overview of the potential uses of PARP imaging agents in cancer therapy, and discuss the use of radiolabeled PARPi as radionuclide therapies.
Publisher: EMBO
Date: 24-05-2019
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Bart Cornelissen.