Emerging Opportunities for c-MET Visualization in the Clinic

Pool, Martin; Dam, Gooitzen M. van; Vries, Elisabeth G.E. de

doi:10.2967/jnumed.115.169771

Cited by 4 publications

(4 citation statements)

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“…Due to the pivotal role of c-Met in cancer biology and overexpression in several cancer types, it is regarded as a promising target for molecular tumor imaging, including colorectal neoplasia. 11 , 24 Still, the numbers of this receptor per tumor cell might be lower compared to adhesion molecules like CEA and EpCAM, as reflected in the expression scores within this study. 8 …”

Section: Discussionmentioning

confidence: 64%

Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy

Boogerd¹,

Valk²,

Boonstra³

et al. 2018

OTT

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PurposeIntraoperative identification of rectal cancer (RC) can be challenging, especially because of fibrosis after treatment with preoperative chemo- and radiotherapy (CRT). Tumor-targeted fluorescence imaging can enhance the contrast between tumor and normal tissue during surgery. Promising targets for RC imaging are carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM) and the tyrosine-kinase receptor Met (c-Met). The effect of CRT on their expression determines their applicability for imaging. Therefore, we investigated whether CRT modifies expression patterns in tumors, lymph node (LN) metastases and adjacent normal rectal tissues.Patients and methodsPreoperative biopsies, primary tumor specimens and metastatic LNs were collected from 38 RC patients who did not receive CRT (cohort 1) and 34 patients who did (cohort 2). CEA, EpCAM and c-Met expression was determined using immunohistochemical staining and was semiquantified by a total immunostaining score (TIS), consisting of the percentage and intensity of stained tumor cells (0–12).ResultsIn both cohorts CEA, EpCAM and c-Met were significantly highly expressed in >60% of tumor tissues compared with adjacent normal epithelium (T/N ratio, P<0.01). EpCAM showed the most homogenous expression in tumors, whereas CEA showed the highest T/N ratio. Most importantly, CEA and EpCAM expression did not significantly change in normal or neoplastic RC tissue after CRT, whereas levels of c-Met changed (P=0.02). Tissues of eight patients with a pathological complete response after CRT showed expression of all biomarkers with TIS close to normal epithelium.ConclusionHistological evaluation shows that CEA, EpCAM and c-Met are suitable targets for RC imaging, because all three are significantly enhanced in cancer tissue from primary tumors or LN metastases compared with normal adjacent tissue. Furthermore, the expression of CEA and EpCAM is not significantly changed after CRT. These data underscore the applicability of c-Met and especially, CEA and EpCAM as targets for image-guided RC surgery, both before and after CRT.

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Section: Discussionmentioning

confidence: 64%

Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy

Boogerd¹,

Valk²,

Boonstra³

et al. 2018

OTT

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“…The effect sizes of antibody tracer uptake reduction after target protein downregulation through HSP90 inhibition and everolimus treatment are comparable to the reduction in uptake of 89 Zr-onartuzumab after c-MET downregulation found in the present study [36–39], and the results of some of these preclinical studies have been translated to successful treatments in the clinic [40, 41]. Furthermore, insight into whole-body c-MET target distribution via noninvasive 89 Zr-onartuzumab scans could potentially enlarge the patient population which might benefit from c-MET/HGF-targeted drugs [18]. …”

Section: Discussionmentioning

confidence: 79%

“…Several other antibody and antibody fragment tracers have been reported to be of value for preclinical c-MET PET imaging [18]. These studies used an immunogenic full-length murine antibody DN30 [19] or antibody fragments and other protein scaffolds such as the 89 Zr-labelled H2 cys-diabody, H2 minibody [20], and anticalin 89 Zr-PRS110 [21].…”

Section: Introductionmentioning

confidence: 99%

89Zr-Onartuzumab PET imaging of c-MET receptor dynamics

Pool

Scheltinga

Kol

et al. 2017

Eur J Nucl Med Mol Imaging

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Purposec-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of 89Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts.MethodsIn vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent 89Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent 89Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results.ResultsIn vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213 ± 44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69 ± 9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo, 89Zr-onartuzumab uptake was 26% higher (P < 0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P < 0.001) following NVP-AUY-922 treatment.ConclusionThe results show that 89Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-017-3672-x) contains supplementary material, which is available to authorized users.

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“…Other strategies which might be relevant for translation into the clinic are antibody (fragment) tracers, as companion diagnostics for their parental antibody therapies [77]. Although studies for c-MET-targeted molecular imaging have made many important advances, most of imaging agents specifically target to extracellular area of c-MET, so it can only reflect overexpression of c-MET.…”

Section: Discussionmentioning

confidence: 99%

Analysis of progress and challenges for various patterns of c-MET-targeted molecular imaging: a systematic review

Han

Wang

et al. 2017

EJNMMI Res

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BackgroundMesenchymal–epithelial transition factor also named c-MET is a receptor tyrosine kinase for the hepatocyte growth factor that plays a pivotal role in tumorigenesis. c-MET-targeted therapies have been tested in preclinical models and patients, with significant benefits for cancer treatment. In recent years, many studies have shown that the expression level and activation status of c-MET are closely correlated to c-MET-targeted therapy response and clinical prognosis, thus highlighting the importance of evaluating the c-MET status during and prior to targeted therapy. Molecular imaging allows the monitoring of abnormal alterations of c-MET in real time and in vivo.ResultsIn this review, we initially summarize the recent advances in c-MET-targeted molecular imaging, with a special focus on the development of imaging agents ranging in size from monoclonal antibody to small molecule. The aim of this review is to report the preclinical results and clinical application of all molecular imaging studies completed until now for in vivo detection of c-MET in cancer, in order to be beneficial to development of molecular probe and the combination of molecular imaging technologies for in vivo evaluation of c-MET. Various molecular probe targeted to c-MET possesses distinctive advantages and disadvantages. For example, antibody-based probes have high binding affinity but with long metabolic cycle as well as remarkable immunogenicity.ConclusionsAlthough studies for c-MET-targeted molecular imaging have made many important advances, most of imaging agents specifically target to extracellular area of c-MET receptor; however, it is difficult to reflect entirely activation of c-MET. Therefore, small molecule probes based on tyrosine kinase inhibitors, which could target to intracellular area of c-MET without any immunogenicity, should be paid more attention.

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Emerging Opportunities for c-MET Visualization in the Clinic

Cited by 4 publications

References 25 publications

Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy

Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy

89Zr-Onartuzumab PET imaging of c-MET receptor dynamics

Analysis of progress and challenges for various patterns of c-MET-targeted molecular imaging: a systematic review

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