Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review.

Zeger Rijs,Michiel A J Van De Sande,A Naweed Shifai,Judith V M G Bovée,Pieter B A A Van Driel,Stijn Keereweer,Peter J K Kuppen,Sarah E Bosma,Alexander L Vahrmeijer,Cornelis F M Sier

doi:10.3390/cancers13030557

Zeger Rijs, Michiel A J Van De Sande + Show 8 more

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https://doi.org/10.3390/cancers13030557

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Abstract

Simple SummaryNear-infrared imaging of tumors during surgery facilitates the oncologic surgeon to distinguish malignant from healthy tissue. The technique is based on fluorescent tracers binding to tumor biomarkers on malignant cells. Currently, there are no clinically available fluorescent tracers that specifically target soft tissue sarcomas. This review searched the literature to find candidate biomarkers for soft tissue sarcomas, based on clinically used therapeutic antibodies. The search revealed 7 biomarkers: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. These biomarkers are abundantly present on soft tissue sarcoma tumor cells and are already being targeted with humanized monoclonal antibodies. The conjugation of these antibodies with a fluorescent dye will yield in specific tracers for image-guided surgery of soft tissue sarcomas to improve the success rates of tumor resections.Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific imaging can facilitate complete resection by visualizing tumor tissue during surgery. Unfortunately, STS specific tracers are presently not clinically available. In this review, STS-associated cell surface-expressed biomarkers, which are currently already clinically targeted with monoclonal antibodies for therapeutic purposes, are evaluated for their use in near-infrared fluorescence (NIRF) imaging of STS. Clinically targeted biomarkers in STS were extracted from clinical trial registers and a PubMed search was performed. Data on biomarker characteristics, sample size, percentage of biomarker-positive STS samples, pattern of biomarker expression, biomarker internalization features, and previous applications of the biomarker in imaging were extracted. The biomarkers were ranked utilizing a previously described scoring system. Eleven cell surface-expressed biomarkers were identified from which 7 were selected as potential biomarkers for NIRF imaging: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. Promising biomarkers in common and aggressive STS subtypes are TEM1 for myxofibrosarcoma, TEM1, and PDGFRα for undifferentiated soft tissue sarcoma and EGFR for synovial sarcoma.

Highlights

Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors that represent 1% of all malignancies [1]
In order to select the optimal biomarkers for tumor specific nearinfrared fluorescence (NIRF) imaging in soft tissue sarcomas (STS), we developed a target selection scoring system
This review selected tumor endothelial marker 1 (TEM1), vascular endothelial growth factor receptor-1 (VEGFR-1), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor-2 (VEGFR-2), insulin-like growth factor 1 receptor (IGF-1R), platelet derived growth factor α (PDGFRα), and cluster of differentiation 40 (CD40) as the most promising cell surfaceexpressed biomarkers for tumor-specific NIRF imaging in STS, for which clinically available monoclonal antibodies are already present

Summary

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors that represent 1% of all malignancies [1]. Determining the surgical margin is challenging, when tumor tissue is surrounded by vital structures or in STS subtypes with a highly infiltrative growth pattern, such as myxofibrosarcoma (MFS), undifferentiated soft tissue sarcoma (USTS, previously called undifferentiated pleomorphic sarcoma), and synovial sarcoma (SS). In these specific tumors, preoperative surgical planning is complicated by current limitations in preoperative radiological imaging. Near-infrared fluorescence (NIRF) imaging is one of the most upcoming technologies in real-time targeted imaging as it facilitates surgeons to visualize tumor tissue during surgery It has been explored for various tumor types with promising results and is expected to play an important role in future surgery of STS [19]

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