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12 pages, 2180 KiB

Open AccessArticle

Immunohistochemical Evaluation of Candidate Biomarkers for Fluorescence-Guided Surgery of Myxofibrosarcoma Using an Objective Scoring Method

by Zeger Rijs, Esther Belt, Gijsbert M. Kalisvaart, Cornelis F. M. Sier, Peter J. K. Kuppen, Arjen H. G. Cleven, Alexander L. Vahrmeijer, Michiel A. J. van de Sande and Pieter B. A. A. van Driel

Biomedicines 2023, 11(3), 982; https://doi.org/10.3390/biomedicines11030982 - 22 Mar 2023

Cited by 3 | Viewed by 1519

Abstract

Introduction: Myxofibrosarcoma (MFS) is the most common soft-tissue sarcoma subtype in elderly patients. Local recurrence (LR) remains a major concern as the lack of intraoperative guidance and an infiltrative growth pattern with long, slender tails hamper surgeons’ ability to achieve adequate resection margins [...] Read more.

Introduction: Myxofibrosarcoma (MFS) is the most common soft-tissue sarcoma subtype in elderly patients. Local recurrence (LR) remains a major concern as the lack of intraoperative guidance and an infiltrative growth pattern with long, slender tails hamper surgeons’ ability to achieve adequate resection margins for MFS. Fluorescence-guided surgery (FGS) could overcome this concern by delineating tumor tissue during surgery. One of the most important steps to successful FGS is to define a tumor-specific biomarker that is highly overexpressed in tumor tissue while low or absent in adjacent healthy tissue. The aim of this study is to evaluate the expression of eight previously selected promising biomarkers for FGS in MFS tissue samples with adjacent healthy tissue using immunohistochemistry (IHC). Methods: The following eight biomarkers were stained in seventeen paraffin-embedded MFS samples: tumor endothelial marker-1 (TEM-1, also known as endosialin/CD248), vascular endothelial growth factor receptor-1 (VEGFR-1, also known as Flt-1), vascular endothelial growth factor receptor-2 (VEGFR-2, also known as Flk1), vascular endothelial growth factor-A (VEGF-A), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), platelet derived growth factor receptor-α (PDGFR-α), and cluster of differentiation 40 (CD40, also known as TNFRSF5). A pathologist specializing in sarcoma annotated the margin between the tumor and adjacent healthy tissue in each MFS tissue sample. Subsequently, we used an objective IHC scoring method to assess and compare the difference in staining intensity between the tumor and adjacent healthy tissue, which is crucial for the use of FGS. Results: TEM-1, VEGF-A, and PDGFR-α stained all MFS tumors, while the other biomarkers did not show expression in all MFS tumors. Ultimately, TEM-1 was identified as the most suitable biomarker for FGS in MFS based on higher tumor-to-background (TBR) staining intensity compared to VEGF-A and PDGFR-α, regardless of preoperative therapy. Conclusion: TEM-1-targeted FGS tracers should be further investigated to optimize MFS treatment. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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14 pages, 1955 KiB

Open AccessArticle

Myogenetic Oligodeoxynucleotides as Anti-Nucleolin Aptamers Inhibit the Growth of Embryonal Rhabdomyosarcoma Cells

by Naoki Nohira, Sayaka Shinji, Shunichi Nakamura, Yuma Nihashi, Takeshi Shimosato and Tomohide Takaya

Biomedicines 2022, 10(11), 2691; https://doi.org/10.3390/biomedicines10112691 - 25 Oct 2022

Cited by 3 | Viewed by 1271

Abstract

Embryonal rhabdomyosarcoma (ERMS) is the muscle-derived tumor retaining myogenic ability. iSN04 and AS1411, which are myogenetic oligodeoxynucleotides (myoDNs) serving as anti-nucleolin aptamers, have been reported to inhibit the proliferation and induce the differentiation of myoblasts. The present study investigated the effects of iSN04 [...] Read more.

Embryonal rhabdomyosarcoma (ERMS) is the muscle-derived tumor retaining myogenic ability. iSN04 and AS1411, which are myogenetic oligodeoxynucleotides (myoDNs) serving as anti-nucleolin aptamers, have been reported to inhibit the proliferation and induce the differentiation of myoblasts. The present study investigated the effects of iSN04 and AS1411 in vitro on the growth of multiple patient-derived ERMS cell lines, ERMS1, KYM1, and RD. RT-PCR and immunostaining revealed that nucleolin was abundantly expressed and localized in nucleoplasm and nucleoli in all ERMS cell lines, similar to myoblasts. Both iSN04 and AS1411 at final concentrations of 10–30 μM significantly decreased the number of all ERMS cells; however, their optimal conditions were different among the cell lines. In all ERMS cell lines, iSN04 at a final concentration of 10 μM markedly reduced the ratio of EdU⁺ cells, indicating the inhibition of cell proliferation. Quantitative RT-PCR or immunostaining of phosphorylated histone H3 and myosin heavy chain demonstrated that iSN04 suppressed the cell cycle and partially promoted myogenesis but did not induce apoptosis in ERMS cells. Finally, both iSN04 and AS1411 at final concentrations of 10–30 μM disrupted the formation and outgrowth of RD tumorspheres in three-dimensional culture mimicking in vivo tumorigenesis. In conclusion, ERMS cells expressed nucleolin, and their growth was inhibited by the anti-nucleolin aptamers, iSN04 and AS1411, which modulates several cell cycle-related and myogenic gene expression. The present study provides evidence that anti-nucleolin aptamers can be used as nucleic acid drugs for chemotherapy against ERMS. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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13 pages, 1635 KiB

Open AccessArticle

In Vivo Evaluation of Fibroblast Growth Factor Receptor Inhibition in Mouse Xenograft Models of Gastrointestinal Stromal Tumor

by Patrick Schöffski, Yemarshet Gebreyohannes, Thomas Van Looy, Paul Manley, Joseph D. Growney, Matthew Squires and Agnieszka Wozniak

Biomedicines 2022, 10(5), 1135; https://doi.org/10.3390/biomedicines10051135 - 13 May 2022

Cited by 4 | Viewed by 2101

Abstract

Advanced gastrointestinal stromal tumors (GIST) are typically treated with tyrosine kinase inhibitors, and imatinib is the most commonly used standard of care in first line treatments. The use of this and other tyrosine kinase inhibitors is associated with objective tumor responses and prolongation [...] Read more.

Advanced gastrointestinal stromal tumors (GIST) are typically treated with tyrosine kinase inhibitors, and imatinib is the most commonly used standard of care in first line treatments. The use of this and other tyrosine kinase inhibitors is associated with objective tumor responses and prolongation of progression-free and overall survival, but the treatment of metastatic disease is non-curative due to the selection or acquisition of secondary mutations and the activation of alternative kinase signaling pathways, leading to resistance and disease progression after an initial response. The present preclinical study evaluated the potential use of the fibroblast growth factor receptor inhibitors infigratinib and dovitinib alone or in combination with the mitogen-activated protein kinase inhibitor binimetinib in mouse models of GIST with different sensitivity or resistance to imatinib. Patient- and cell-line-derived GIST xenografts were established by bilateral, subcutaneous transplantation of human GIST tissue in female adult nu/nu NMRI mice. The mice were treated with dovitinib, infigratinib, or binimetinib, either alone or in combination with imatinib. The safety of treated animals was assessed by well-being inspection and body weight measurement. Antitumor effects were assessed by caliper-based tumor measurement. H&E staining and immunohistochemistry were used for assessing anti-mitotic and pro-apoptotic activity of the experimental treatments. Western blotting was used for assessing effects of the agents on kinase signaling pathways. Anti-angiogenic activity was assessed by measuring tumor vessel density. Dovitinib was found to have antitumor efficacy in GIST xenografts characterized by different imatinib resistance patterns. Dovitinib had better efficacy than imatinib (both at standard and increased dose) and was found to be well tolerated. Dovitinib had better efficacy in a KIT exon 9 mutant model, highlighting a role of patient selection in clinical GIST trials with the agent. In a model with KIT exon 11 and 17 mutations, dovitinib induced tumor necrosis, most likely due to anti-angiogenic effects. Additive effects combining dovitinib with binimetinib were limited. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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14 pages, 5163 KiB

Open AccessArticle

Enhanced Antitumor Efficacy of PhAc-ALGP-Dox, an Enzyme-Activated Doxorubicin Prodrug, in a Panel of THOP1-Expressing Patient-Derived Xenografts of Soft Tissue Sarcoma

by Britt Van Renterghem, Agnieszka Wozniak, Ludovica Tarantola, Andrea Casazza, Jasmien Wellens, Madita Nysen, Ulla Vanleeuw, Che-Jui Lee, Geert Reyns, Raf Sciot, Nele Kindt and Patrick Schöffski

Biomedicines 2022, 10(4), 862; https://doi.org/10.3390/biomedicines10040862 - 06 Apr 2022

Cited by 1 | Viewed by 2311

Abstract

Despite poor response rates and dose-limiting cardiotoxicity, doxorubicin (doxo) remains the standard-of-care for patients with advanced soft tissue sarcoma. We evaluated the efficacy of two tetrapeptidic doxo prodrugs (PhAc-ALGP-Dox or CBR-049 and CBR-050) that are locally activated by enzymes expressed in the tumor [...] Read more.

Despite poor response rates and dose-limiting cardiotoxicity, doxorubicin (doxo) remains the standard-of-care for patients with advanced soft tissue sarcoma. We evaluated the efficacy of two tetrapeptidic doxo prodrugs (PhAc-ALGP-Dox or CBR-049 and CBR-050) that are locally activated by enzymes expressed in the tumor environment, in ten sarcoma patient-derived xenografts. Xenograft models were selected based on expression of the main activating enzyme, i.e., thimet oligopeptidase (THOP1). Mice were either randomized to vehicle, doxo, CBR-049 and CBR-050 or control, doxo, aldoxorubicin (aldoxo) and CBR-049. Treatment efficacy was assessed by tumor volume measurement and histological assessment of ex-mouse tumors. CBR-049 showed significant tumor growth delay compared to control in all xenografts investigated and was superior compared to doxo in all but one. At the same time, CBR-049 showed comparable efficacy to aldoxo but the latter was found to have a complex safety profile in mice. CBR-050 demonstrated tumor growth delay compared to control in one xenograft but was not superior to doxo. For both experimental prodrugs, strong immunostaining for THOP1 was found to predict better antitumor efficacy. The prodrugs were well tolerated without any adverse events, even though molar doses were 17-fold higher than those administered and tolerated for doxo. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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Review

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17 pages, 976 KiB

Open AccessReview

Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments

by Carine Ngo and Sophie Postel-Vinay

Biomedicines 2022, 10(3), 650; https://doi.org/10.3390/biomedicines10030650 - 11 Mar 2022

Cited by 25 | Viewed by 4254

Abstract

Mutations in subunits of the SWItch Sucrose Non-Fermentable (SWI/SNF) complex occur in 20% of all human tumors. Among these, the core subunit SMARCB1 is the most frequently mutated, and SMARCB1 loss represents a founder driver event in several malignancies, such as malignant rhabdoid [...] Read more.

Mutations in subunits of the SWItch Sucrose Non-Fermentable (SWI/SNF) complex occur in 20% of all human tumors. Among these, the core subunit SMARCB1 is the most frequently mutated, and SMARCB1 loss represents a founder driver event in several malignancies, such as malignant rhabdoid tumors (MRT), epithelioid sarcoma, poorly differentiated chordoma, and renal medullary carcinoma (RMC). Intriguingly, SMARCB1-deficient pediatric MRT and RMC have recently been reported to be immunogenic, despite their very simple genome and low tumor mutational burden. Responses to immune checkpoint inhibitors have further been reported in some SMARCB1-deficient diseases. Here, we will review the preclinical data and clinical data that suggest that immunotherapy, including immune checkpoint inhibitors, may represent a promising therapeutic strategy for SMARCB1-defective tumors. We notably discuss the heterogeneity that exists among the spectrum of malignancies driven by SMARCB1-loss, and highlight challenges that are at stake for developing a personalized immunotherapy for these tumors, notably using molecular profiling of the tumor and of its microenvironment. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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25 pages, 945 KiB

Open AccessReview

Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas

by William G. J. Kerrison, Alexander T. J. Lee, Khin Thway, Robin L. Jones and Paul H. Huang

Biomedicines 2022, 10(3), 573; https://doi.org/10.3390/biomedicines10030573 - 28 Feb 2022

Cited by 8 | Viewed by 3395

Abstract

Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have [...] Read more.

Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have demonstrated promising responses in a select number of STS subtypes, including rarer subtypes, such as alveolar soft part sarcoma, SWI/SNF-deficient sarcomas, clear cell sarcoma, and angiosarcoma. Multiple pan-subtype sarcoma trials have facilitated the study of possible predictive biomarkers of the CPI response. It has also become apparent that certain therapies, when combined with CPIs, can enhance response rates, although the specific mechanisms of this possible synergy remain unconfirmed in STS. In addition to CPIs, several other immune targeting agents, including anti-tumour-associated macrophage and antigen-directed therapies, are now under assessment in STS with promising efficacy in some subtypes. In this article, we review the state of the art in immunotherapy in STS, highlighting the pre-clinical and clinical data available for this promising therapeutic strategy. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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20 pages, 310 KiB

Open AccessReview

Enhancing the Potential of Immunotherapy in Paediatric Sarcomas: Breaking the Immunosuppressive Barrier with Receptor Tyrosine Kinase Inhibitors

by Emmy D. G. Fleuren, Rachael L. Terry, Deborah Meyran, Natacha Omer, Joseph A. Trapani, Michelle Haber, Paul J. Neeson and Paul G. Ekert

Biomedicines 2021, 9(12), 1798; https://doi.org/10.3390/biomedicines9121798 - 30 Nov 2021

Cited by 6 | Viewed by 1812

Abstract

Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment [...] Read more.

Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

17 pages, 341 KiB

Open AccessReview

Introducing Fluorescence-Guided Surgery for Pediatric Ewing, Osteo-, and Rhabdomyosarcomas: A Literature Review

by Zeger Rijs, Bernadette Jeremiasse, Naweed Shifai, Hans Gelderblom, Cornelis F. M. Sier, Alexander L. Vahrmeijer, Fijs W. B. van Leeuwen, Alida F. W. van der Steeg and Michiel A. J. van de Sande

Biomedicines 2021, 9(10), 1388; https://doi.org/10.3390/biomedicines9101388 - 04 Oct 2021

Cited by 14 | Viewed by 4818

Abstract

Sarcomas are a rare heterogeneous group of malignant neoplasms of mesenchymal origin which represent approximately 13% of all cancers in pediatric patients. The most prevalent pediatric bone sarcomas are osteosarcoma (OS) and Ewing sarcoma (ES). Rhabdomyosarcoma (RMS) is the most frequently occurring pediatric [...] Read more.

Sarcomas are a rare heterogeneous group of malignant neoplasms of mesenchymal origin which represent approximately 13% of all cancers in pediatric patients. The most prevalent pediatric bone sarcomas are osteosarcoma (OS) and Ewing sarcoma (ES). Rhabdomyosarcoma (RMS) is the most frequently occurring pediatric soft tissue sarcoma. The median age of OS and ES is approximately 17 years, so this disease is also commonly seen in adults while non-pleiomorphic RMS is rare in the adult population. The mainstay of all treatment regimens is multimodal treatment containing chemotherapy, surgical resection, and sometimes (neo)adjuvant radiotherapy. A clear resection margin improves both local control and overall survival and should be the goal during surgery with a curative intent. Real-time intraoperative fluorescence-guided imaging could facilitate complete resections by visualizing tumor tissue during surgery. This review evaluates whether non-targeted and targeted fluorescence-guided surgery (FGS) could be beneficial for pediatric OS, ES, and RMS patients. Necessities for clinical implementation, current literature, and the positive as well as negative aspects of non-targeted FGS using the NIR dye Indocyanine Green (ICG) were evaluated. In addition, we provide an overview of targets that could potentially be used for FGS in OS, ES, and RMS. Then, due to the time- and cost-efficient translational perspective, we elaborate on the use of antibody-based tracers as well as their disadvantages and alternatives. Finally, we conclude with recommendations for the experiments needed before FGS can be implemented for pediatric OS, ES, and RMS patients. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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16 pages, 328 KiB

Open AccessReview

Liquid Biopsies in Sarcoma Clinical Practice: Where Do We Stand?

by Pia van der Laan, Winan J. van Houdt, Daan van den Broek, Neeltje Steeghs and Winette T. A. van der Graaf

Biomedicines 2021, 9(10), 1315; https://doi.org/10.3390/biomedicines9101315 - 26 Sep 2021

Cited by 9 | Viewed by 2545

Abstract

Sarcomas are rare tumors of bone and soft tissue with a mesenchymal origin. This uncommon type of cancer is marked by a high heterogeneity, consisting of over 70 subtypes. Because of this broad spectrum, their treatment requires a subtype-specific therapeutic approach. Tissue biopsy [...] Read more.

Sarcomas are rare tumors of bone and soft tissue with a mesenchymal origin. This uncommon type of cancer is marked by a high heterogeneity, consisting of over 70 subtypes. Because of this broad spectrum, their treatment requires a subtype-specific therapeutic approach. Tissue biopsy is currently the golden standard for sarcoma diagnosis, but it has its limitations. Over the recent years, methods to detect, characterize, and monitor cancer through liquid biopsy have evolved rapidly. The analysis of circulating biomarkers in peripheral blood, such as circulating tumor cells (CTC) or circulating tumor DNA (ctDNA), could provide real-time information on tumor genetics, disease state, and resistance mechanisms. Furthermore, it traces tumor evolution and can assess tumor heterogeneity. Although the first results in sarcomas are encouraging, there are technical challenges that need to be addressed for implementation in clinical practice. Here, we summarize current knowledge about liquid biopsies in sarcomas and elaborate on different strategies to integrate liquid biopsy into sarcoma clinical care. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

19 pages, 1800 KiB

Open AccessReview

Linking Immunity with Genomics in Sarcomas: Is Genomic Complexity an Immunogenic Trigger?

by Siddh van Oost, Debora M. Meijer, Marieke L. Kuijjer, Judith V. M. G. Bovée and Noel F. C. C. de Miranda

Biomedicines 2021, 9(8), 1048; https://doi.org/10.3390/biomedicines9081048 - 19 Aug 2021

Cited by 4 | Viewed by 3738

Abstract

Sarcomas comprise a collection of highly heterogeneous malignancies that can be grossly grouped in the categories of sarcomas with simple or complex genomes. Since the outcome for most sarcoma patients has barely improved in the last decades, there is an urgent need for [...] Read more.

Sarcomas comprise a collection of highly heterogeneous malignancies that can be grossly grouped in the categories of sarcomas with simple or complex genomes. Since the outcome for most sarcoma patients has barely improved in the last decades, there is an urgent need for improved therapies. Immunotherapy, and especially T cell checkpoint blockade, has recently been a game-changer in cancer therapy as it produced significant and durable treatment responses in several cancer types. Currently, only a small fraction of sarcoma patients benefit from immunotherapy, supposedly due to a general lack of somatically mutated antigens (neoantigens) and spontaneous T cell immunity in most cancers. However, genomic events resulting from chromosomal instability are frequent in sarcomas with complex genomes and could drive immunity in those tumors. Improving our understanding of the mechanisms that shape the immune landscape of sarcomas will be crucial to overcoming the current challenges of sarcoma immunotherapy. This review focuses on what is currently known about the tumor microenvironment in sarcomas and how this relates to their genomic features. Moreover, we discuss novel therapeutic strategies that leverage the tumor microenvironment to increase the clinical efficacy of immunotherapy, and which could provide new avenues for the treatment of sarcomas. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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