Prospective Phase II Trial of Prognostication by <sup>68</sup>Ga-NOTA-AE105 uPAR PET in Patients with Neuroendocrine Neoplasms: Implications for uPAR-Targeted Therapy

Carlsen, Esben Andreas; Loft, Mathias; Loft, Annika; Berthelsen, Anne Kiil; Langer, Seppo W.; Knigge, Ulrich; Kjær, Andreas

doi:10.2967/jnumed.121.263177

Cited by 14 publications

(8 citation statements)

References 25 publications

(34 reference statements)

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“…7 ). In the clinic, most uPAR-targeted PET imaging platforms are presently conducted with [ 68 Ga]Ga-NOTA–AE105 for logistic reasons 38 – 40 , 72 , but if the improved resolution provided by 64 Cu is preferred, our studies suggest that [ 64 Cu]Cu-CB-TE2A-PA– (9) would be an obvious candidate. The cross-bridged CB-TE2A-PA chelator would limit nonspecific tracer accumulation in the liver 75 while the cyclic core of AE105 would diminish negative impacts from the chelator on uPAR affinity.…”

Section: Discussionmentioning

confidence: 96%

“…Parallel to those new attempts to design cytotoxic uPAR-targeted therapies, others developed several non-invasive imaging approaches to visualize uPAR expression in vivo—thus completing a possible theranostic pipeline for uPAR in clinical oncology 30 – 36 . The virtue of these uPAR-specific imaging platforms is that they (i) can aid patient stratification, (ii) can follow treatment responses using positron emission tomography (PET) scanning 31 , 37 – 40 , and (iii) can potentially be used to increase cancer surgery precision by fluorescence-guided intraoperative imaging 33 , 34 , 41 , 42 . Furthermore, the elevated expression of uPAR in chronically inflamed tumor-stroma microenvironments makes it an ideal candidate for fluorescence-guided intraoperative imaging during cancer resection 30 .…”

Section: Introductionmentioning

confidence: 99%

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Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

Leth,

Newcombe,

Grønnemose

et al. 2023

Sci Rep

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A comprehensive literature reports on the correlation between elevated levels of urokinase-type plasminogen activator receptor (uPAR) and the severity of diseases with chronic inflammation including solid cancers. Molecular imaging is widely used as a non-invasive method to locate disease dissemination via full body scans and to stratify patients for targeted treatment. To date, the only imaging probe targeting uPAR that has reached clinical phase-II testing relies on a high-affinity 9-mer peptide (AE105), and several studies by positron emission tomography (PET) scanning or near-infra red (NIR) fluorescence imaging have validated its utility and specificity in vivo. While our previous studies focused on applying various reporter groups, the current study aims to improve uPAR-targeting properties of AE105. We successfully stabilized the small uPAR-targeting core of AE105 by constraining its conformational landscape by disulfide-mediated cyclization. Importantly, this modification mitigated the penalty on uPAR-affinity typically observed after conjugation to macrocyclic chelators. Cyclization did not impair tumor targeting efficiency of AE105 in vivo as assessed by PET imaging and a trend towards increased tracer uptake was observed. In future studies, we predict that this knowledge will aid development of new fluorescent AE105 derivatives with a view to optical imaging of uPAR to assist precision guided cancer surgery.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

Leth,

Newcombe,

Grønnemose

et al. 2023

Sci Rep

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“…Different molecular imaging modalities have been explored for uPAR. In clinical trials, uPAR-targeted PET imaging using a peptide-based tracer has been studied for several cancers including OSCC, where a prognostic value was demonstrated [ 40 , 41 , 42 , 43 ]. No studies have yet investigated the diagnostic potential of uPAR-targeted PET imaging in OSCC, but a Phase II clinical trial is currently underway (NCT02960724).…”

Section: Discussionmentioning

confidence: 99%

Potential of uPAR, αvβ6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry

Lawaetz

Christensen

Juhl

et al. 2023

IJMS

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No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high and homogenous expression in tumor tissue and minimal expression in normal tissue is essential for the development of new molecular imaging targets in head and neck cancer. We investigated the expression of nine imaging targets in both primary tumor and matched metastatic tissue of 41 patients with oral squamous cell carcinoma (OSCC) to assess their potential as targets for molecular imaging. The intensity, proportion, and homogeneity in the tumor and the reaction in neighboring non-cancerous tissue was scored. The intensity and proportion were multiplied to obtain a total immunohistochemical (IHC) score ranging from 0–12. The mean intensity in the tumor tissue and normal epithelium were compared. The expression rate was high for the urokinase-type plasminogen activator receptor (uPAR) (97%), integrin αvβ6 (97%), and tissue factor (86%) with a median total immunostaining score (interquartile range) for primary tumors of 6 (6–9), 12 (12–12), and 6 (2.5–7.5), respectively. For the uPAR and tissue factor, the mean staining intensity score was significantly higher in tumors compared to normal epithelium. The uPAR, integrin αvβ6, and tissue factor are promising imaging targets for OSCC primary tumors, lymph node metastases, and recurrences.

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“…Other potential theragnostic targets being explored in high-grade NENs include C-X-C motif chemokine receptor-4 and urokinase plasminogen activator receptor (uPAR) ( 52 , 53 ). Overexpression of CXCR4 has been documented in SST2-negative, high-grade NENs.…”

Section: Theragnostics In Necs: Does It Play Any Role?mentioning

confidence: 99%

Advances in the Treatment of Gastroenteropancreatic Neuroendocrine Carcinomas: Are we Moving Forward?

et al. 2023

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Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small-cell lung cancer (SCLC), a far more common G3 NEN, although emerging molecular and clinical data increasingly question this approach. In this manuscript we will briefly summarize epidemiology and prognosis of GEP NECs to emphasize the very low incidence, aggressive nature and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background as compared to SCLC, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum-doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors) and additional treatment strategies targeting other tumor vulnerabilities (i.e. Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient’s care and prognosis.

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Prospective Phase II Trial of Prognostication by ⁶⁸Ga-NOTA-AE105 uPAR PET in Patients with Neuroendocrine Neoplasms: Implications for uPAR-Targeted Therapy

Cited by 14 publications

References 25 publications

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

Potential of uPAR, αvβ6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry

Advances in the Treatment of Gastroenteropancreatic Neuroendocrine Carcinomas: Are we Moving Forward?

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Prospective Phase II Trial of Prognostication by 68Ga-NOTA-AE105 uPAR PET in Patients with Neuroendocrine Neoplasms: Implications for uPAR-Targeted Therapy

Cited by 14 publications

References 25 publications

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

Potential of uPAR, αvβ6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry

Advances in the Treatment of Gastroenteropancreatic Neuroendocrine Carcinomas: Are we Moving Forward?

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Prospective Phase II Trial of Prognostication by ⁶⁸Ga-NOTA-AE105 uPAR PET in Patients with Neuroendocrine Neoplasms: Implications for uPAR-Targeted Therapy