Bart Cornelissen

University Medical Center Groningen · Nuclear Medicine and Molecular Imaging

Purpose: Late-stage, unresectable pancreatic ductal adenocarcinoma (PDAC) is largely resistant to chemotherapy and consequently has a very poor 5-year survival rate of < 5%. The ability to assess the efficacy of a treatment soon after its initiation would enable rapid switching to potentially more effective therapies if the current treatment is fou...

PARP inhibitors are increasingly being studied as cancer drugs, as single agents or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Here, via t...

Purpose: Increased activity of matrix metalloproteinases (MMPs) is associated with worse prognosis in different cancer types. The protective antigen (PA-WT) of the binary anthrax lethal toxin was modified to form a pore in cell membranes only when cleaved by MMPs (PA-L1). Anthrax lethal factor (LF) is then able to translocate through these pores. H...

Purpose: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has been shown to extend survival in men with advanced prostate cancer (PCa). Novel radiohybrid (rh) PSMA-targeted 177Lu-rhPSMA-10.1 has shown promising preclinical efficacy and advantageous radiation dosimetry in humans. We conducted an in vitro screen to identif...

Poly(adenosine diphosphate ribose) polymerase (PARP) has emerged as an effective therapeutic strategy against cancer that targets the DNA damage repair enzyme. PARP-targeting compounds radiolabeled with an Auger electron-emitting radionuclide can be trapped close to damaged DNA in tumor tissue, where high ionizing potential and short range lead Aug...

Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense...

Imaging water pathways in the human body provides an excellent way of measuring accurately the blood flow directed to different organs. This makes it a powerful diagnostic tool for a wide range of diseases that are related to perfusion and oxygenation. Although water PET has a long history, its true potential has not made it into regular clinical p...

Rationale: An effective absorbed dose response relationship is yet to be established for Lutetium-177 based radionuclide therapies such as ¹⁷⁷Lu-DOTATATE and ¹⁷⁷Lu-PSMA. The inherent biological heterogeneity of neuroendocrine and prostate cancers may make the prospect of establishing cohort-based dose-response relationships unobtainable. Instead, a...

Introduction: Radioligand therapy (RLT) is an expanding field that has shown great potential in the fight against cancer. Radionuclides that can be carried by selective ligands such as antibodies, peptides, and small molecules targeting cancerous cells have demonstrated a clear improvement in the move towards precision medicine. Poly (ADP-ribose)...

Introduction: Radioligand therapy (RLT) is an expanding field that has shown great potential in the fight against cancer. Radionuclides that can be carried by selective ligands such as antibodies, peptides, and small molecules targeting cancerous cells have demonstrated a clear improvement in the move towards precision medicine. Poly (ADP-ribose) p...

Purpose 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 inh...

1,8-Bis(boronic ester) derivatives of naphthalene, 1,8-C10H6{B(OR)2}2, present an attractive target as receptors for the fluoride ion via B-F-B chelation, but are synthetically challenging to access due to the competing formation of a very stable anhydride containing a B-O-B motif. By contrast, unsymmetrical systems of the type 1,8-C10H6{B(OR)2}(BR...

Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body This commentary of highlights has resulted in 21 different topics selected by each coauthoring Editorial Board member addressing a variety of asp...

Purpose 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 se...

Purpose 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...

Approval of B-cell-depleting therapies signifies an important advance in the treatment of multiple sclerosis (MS). However, it is unclear whether the administration route of anti-CD20 monoclonal antibodies (mAbs) alters tissue distribution patterns and subsequent downstream effects. This study aimed to investigate the distribution and efficacy of r...

The colony formation assay is the gold-standard technique to assess cell viability after treatment with cytotoxic reagents, ionizing radiation, and cytotoxic combinatorial treatments. This protocol describes a high-throughput automated and high-content imaging approach to screen siRNA molecular libraries in HeLa cervical cancer cells in 96-well for...

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 dosimet...

Purpose: 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...

Purpose 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 inh...

Positron emission tomography (PET) has become an invaluable tool for drug discovery and diagnosis. The positron-emitting radionuclide fluorine-18 is frequently used in PET radiopharmaceuticals due to its advantageous characteristics; hence, methods streamlining access to ¹⁸ F-labelled radiotracers can make a direct impact in medicine. For many year...

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results: This commentary of highlights has resulted in 21 different topics selected by each member of the Editorial Board addressing a variety of aspects r...

Glioblastoma multiforme (GBM) is the most common primary brain cancer. GBMs commonly acquire resistance to standard-of-care therapies. Among the novel means to sensitize GBM to DNA-damaging therapies, a promising strategy is to combine them with inhibitors of the DNA damage repair (DDR) machinery, such as inhibitors for poly(ADP-ribose) polymerase...

Chelators are necessary in nuclear medicine imaging to direct an inorganic radionuclide, a radiometal, to a desired target; unfortunately, there is no ‘one-size-fits-all’ chelator. As the toolbox of radiometals is expanding, new chelators are required to prevent off-target side effects. 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA...

PURPOSE: Imaging of intranuclear epitopes using antibodies tagged to cell penetrating peptides (CPPs) has great potential given its versatility, specificity and sensitivity. However, this process is technically challenging because of the location of the target. Previous research has demonstrated a variety of intranuclear epitopes that can be target...

In recent years, targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. In contrast to conventional radiotherapy, TRT delivers ionizing radiation to tumors in a targeted manner, reducing the dose that healthy tissues are exposed to. Existing TRT strategies include the use of 177Lu-DOTATATE, 131I-metaiodobenzyl...

Targeting of poly(ADP-ribose)polymerase (PARP) enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination (HR) signaling. Currently used to treat BRCA-mutated cancers, PARP inhibitors (PARPi) have demonstrated improved outcome in various cancer types as single agents. On...

Insufficient apoptosis is a recognised hallmark of cancer. A strategy to quantitatively measure apoptosis in vivo would be of immense value in both drug discovery and routine patient management. The first irreversible step in the apoptosis cascade is activation of the “executioner” caspase-3 enzyme to commence cleavage of key structural proteins. O...

Introduction: Overexpression of tight junction protein claudin-4 has been detected in primary and metastatic pancreatic cancer tissue, and is associated with better prognosis in patients. Non-invasive measurement of claudin-4 expression by imaging methods could provide a means for accelerating detection and stratifying patients into risk groups. Cl...

Background Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1–3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP...

Rationale: The evaluation of early treatment response is critical for patient prognosis and treatment planning. When the current methods rely on invasive protocols that evaluate the expression of DNA damage markers on patient biopsy samples, we aim to evaluate a non-invasive PET imaging approach to monitor the early expression of the phosphorylated...

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., ¹⁸F). In recent years, new reactions have appeared for the ¹⁸F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those...

Purpose: Molecular imaging of cancer cells' reaction to radiation damage can provide a non-invasive measure of tumour response to treatment. The cell surface glycoprotein ICAM-1 (CD54) was identified as a potential radiation response marker. SPECT imaging using an 111In-radiolabelled anti-ICAM-1 antibody was explored. Methods: PSN-1 cells were i...

18F-Labeling strategies for unmodified peptides with [18F]fluoride require 18F-prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here, we explore selective radical chemistry to target aromatic residues applying C–H 18F-trifluoromethylation. We report a one-step route to [18F]CF3SO2NH4 from [18F]fluoride, and its appli...

Rationale: Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-i...

Purpose: Molecular Radiotherapy (MRT) using 177Lu-DOTATATE is a most effective therapy for the treatment of somatostatin receptor expressing neuroendocrine tumors (NETs). Despite its frequent and successful use in the clinic, little or no radiobiological considerations are taken into account at the time of treatment planning or delivery, and upon p...

Site-selective labelling of antibodies (Abs) can circumvent problems from heterogeneity of conventional conjugation. Here, we evaluate the industrially-applied chemoenzymatic 'Q-tag' strategy based on transglutaminase-mediated (TGase) amide-bond formation in the generation of 89Zr-radiolabelled antibody conjugates. We show that, despite previously...

Introduction: Increased activity of matrix metalloproteases (MMPs) is associated with reduced survival in several cancer subtypes. Aiming to produce an MMP tumour cell-selective cytotoxin, we genetically modified both components of the AB-type lethal toxin from Bacillus anthracis. Component A, Protective Antigen (PA-WT), was re-engineered to form...

A magnetic resonance (MR)-, computed tomography (CT)-, single-photon emission computed tomography (SPECT)-, and positron emission tomography (PET)-compatible carbon-fiber sheet resistor for temperature maintenance in small animals where space limitations prevent the use of circulating fluids was developed. A 250 Ω carbon-fiber sheet resistor was mo...

Due to compromised homologous recombination (HR) repair, BRCA1‐ and BRCA2‐mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2‐deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctiona...

For any chemist embarking on the synthesis of a particular compound, the prospect of using a chemical reaction which will very rapidly form the desired product in high yields without any fuss is highly attractive. Click chemistry reactions are the embodiment of this concept and are now widely used as efficient and versatile methods for the synthesi...

While radiolabelled antibodies have found great utility as PET and SPECT imaging agents in oncological investigations, a notable shortcoming of these agents is their propensity to accumulate non-specifically within tumour tissue. The degree of this non-specific contribution to overall tumour uptake is highly variable and can ultimately lead to fals...

Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the incre...

Click chemistry reactions have had a considerable impact in the effort to develop efficient synthetic strategies towards new radiopharmaceutical agents. This is largely due to the ability of these reactions to proceed rapidly under ambient conditions, resulting in an easily isolated product. These reaction properties are particularly desirable in t...

Given the increasing exploration of fluorescent tracers in the field of nuclear medicine, a need has risen for practical development guidelines that can help improve the translation aspects of fluorescent tracers. This editorial discusses the does and don’ts in developing fluorescence tracers. It has been put forward by the European Association of...

Purpose: Despite its widespread use, the positron emission tomography (PET) radiotracer 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) has been shown in clinical settings to be ineffective for improving early diagnosis of pancreatic ductal adenocarcinoma (PDAC). A promising biomarker for PDAC detection is the tight junction protein claudin-4. The...

DNA integrity is constantly challenged by endogenous and exogenous factors that can alter the DNA sequence, leading to mutagenesis, aberrant transcriptional activity, and cytotoxicity. Left unrepaired, damaged DNA can ultimately lead to the development of cancer. To overcome this threat, a series of complex mechanisms collectively known as the DNA...

Background The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of 111In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin.Spec...

A novel pretargeted SPECT imaging strategy based on the HaloTag enzyme has been evaluated for the first time in a living system. To determine the efficacy of this approach, two clinically relevant cancer biomarkers, HER2 and TAG-72, were selected to represent models of internalizing and non-internalizing antigens, respectively. In MDA-MB-231/H2N (H...

The tumor suppressor p53 is widely dysregulated in cancer and represents an attractive target for immunotherapy. Due to its intracellular localization, p53 is inaccessible to classical therapeutic monoclonal antibodies, an increasingly successful class of anti-cancer drugs. However, peptides derived from intracellular antigens are presented on the...

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welco...

The most widely cited procedures for radiolabeling antibodies with zirconium-89 for immuno-PET require multi-milligram amounts of antibody which can be cost-prohibitive, particularly during the research and development process. We therefore sought to develop a reliable 89Zr-radiolabeling procedure that provides high radiochemical yields at the micr...

DNA double-strand breaks (DSBs) are formed as a result of genotoxic insults, such as exogenous ionizing radiation, and are among the most serious types of DNA damage. One of the earliest molecular responses following DSB formation is the phosphorylation of the histone H2AX, giving rise to gH2AX. Many copies of gH2AX are generated at DSBs and can be...

Lead-compound optimization is an iterative process in the cancer drug development pipeline, in which small molecule inhibitors or biological compounds that are selected for their ability to bind specific targets are synthesised, tested and optimised. This process can be accelerated significantly using molecular imaging with nuclear medicine techniq...

The efficacy of most anticancer treatments, including radiotherapy, depends on an ability to cause DNA double-strand breaks (DSBs). Very early during the DNA damage signalling process, the histone isoform H2AX is phosphorylated to form γH2AX. With the aim of positron emission tomography (PET) imaging of DSBs, we synthesized a (89)Zr-labelled anti-γ...

Expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in a number of premalignant precursor lesions, including those of cancers of the breast, pancreas and prostate, and is associated with poor survival. A non-cytotoxic c-terminal fragment of Clostridiu...

Copper(II)bis(thiosemicarbazonato) complexes such as 64Cu-ATSM continue to be investigated for positron emission tomography (PET) imaging of tumour hypoxia. However, the currently proposed mechanisms for the mode of action of these complexes are unable to account fully for their observed biological behaviour. In order to examine the roles of the co...

A pretargeted imaging strategy based on the HaloTag dehalogenase enzyme is described. Here, a HaloTag-Trastuzumab conjugate has been used as the primary agent targeting HER2 expression, and three new radiolabelled HaloTag ligands have been used as secondary agents, two of which offer dual-modality (SPECT/optical) imaging capability.

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC DNA damage is an early event after exposure of cells to many anti-cancer agents. Auger electron-emitting radiopharmaceuticals that localize at sites of DNA-double strand breaks (dsb) cause added damage, thus stimulating the formation of their own target and converting su...

Unlabelled: A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, γH2AX, a DNA damage signaling protein, is possible using (111)In-labeled anti-γH2AX antibody conjugate...

Expression of Claudin-4, a member of the Claudin protein family that is integral in adherens and tight junction complexes, is widely dysregulated in epithelial malignancies and is overexpressed in a number of premalignant precursor lesions, including those of cancers of the breast, pancreas and prostate. Increased Claudin-4 expression in breast can...

Due to their rapid and highly selective nature, bioorthogonal chemistry reactions are attracting a significant amount of recent interest in the radiopharmaceutical community. Over the last few years, reactions of this type have found tremendous utility in the construction of new radiopharmaceuticals and as a method of bioconjugation. Furthermore, r...

The safety, pharmacokinetics, biodistribution and radiation dosimetry of (111)In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, were evaluated in a first-in-human trial. Dose escalation was performed in patients with EGFR-positive metastatic breast cancer who had received ≥2 prior courses of systemic treatment. (111)In-DTPA-hEGF (0.25 m...

Molecular imaging of tumour tissue focusses mainly on extracellular epitopes such as tumour angiogenesis or signal transduction receptors expressed on the cell membrane. However, most biological processes that define tumour phenotype occur within the cell. In this mini-review, an overview is given of the various techniques to interrogate intracellu...

Radioimmunotherapy (RIT) agents that incorporate short-range particle-emitting radionuclides exploit the high linear energy transfer of α-particles and Auger electrons. Both are densely ionizing, generate complex DNA double-strand breaks and so are profoundly cytotoxic. Internalizing RIT agents enter tumor cells through receptor-mediated endocytosi...

(64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazonate), (64)Cu-ATSM, continues to be investigated clinically as a PET agent both for delineation of tumor hypoxia and as an effective indicator of patient prognosis, but there are still aspects of the mechanism of action that are not fully understood. The retention of radioactivity in tumors after admini...

Many cancer therapeutics, including radiation therapy, damage DNA eliciting the DNA Damage Response (DDR). Clinical assays that characterise the DDR could be used to personalise cancer treatment by indicating the extent of damage to tumour and normal tissues and the nature of the cellular response to that damage. The phosphorylated histone γH2AX is...

Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases. BALB/c mice were injected intracardially to induce brain metastases. After metastasis induc...