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Open Access 20-02-2024 | Targeted Therapy | REVIEW

Integrated Molecular and Histological Insights for Targeted Therapies in Mesenchymal Sinonasal Tract Tumors

Authors: Cosima C. Hoch, Leonard Knoedler, Samuel Knoedler, Ali Bashiri Dezfouli, Benedikt Schmidl, Anskar Trill, Jennifer E. Douglas, Nithin D. Adappa, Fabian Stögbauer, Barbara Wollenberg

Published in: Current Oncology Reports | Issue 3/2024

Abstract

Purpose of Review

This review aims to provide a comprehensive overview of mesenchymal sinonasal tract tumors (STTs), a distinct subset of STTs. Despite their rarity, mesenchymal STTs represent a unique clinical challenge, characterized by their rarity, often slow progression, and frequently subtle or overlooked symptoms. The complex anatomy of the sinonasal area, which includes critical structures such as the orbit, brain, and cranial nerves, further complicates surgical treatment options. This underscores an urgent need for more advanced and specialized therapeutic approaches.

Recent Findings

Advancements in molecular diagnostics, particularly in next-generation sequencing, have significantly enhanced our understanding of STTs. Consequently, the World Health Organization has updated its tumor classification to better reflect the distinct histological and molecular profiles of these tumors, as well as to categorize mesenchymal STTs with greater accuracy. The growing understanding of the molecular characteristics of mesenchymal STTs opens new possibilities for targeted therapeutic interventions, marking a significant shift in treatment paradigms.

Summary

This review article concentrates on mesenchymal STTs, specifically addressing sinonasal tract angiofibroma, sinonasal glomangiopericytoma, biphenotypic sinonasal sarcoma, and skull base chordoma. These entities are marked by unique histopathological and molecular features, which challenge conventional treatment approaches and simultaneously open avenues for novel targeted therapies. Our discussion is geared towards delineating the molecular underpinnings of mesenchymal STTs, with the objective of enhancing therapeutic strategies and addressing the existing shortcomings in the management of these intricate tumors.

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Makise N, et al. Loss of H3K27 trimethylation in a distinct group of de-differentiated chordoma of the skull base. Histopathology. 2023;82(3):420–30. https://doi.org/10.1111/his.14823.CrossRefPubMed

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Duan ZJ, et al. Pediatric SMARCB1/INI1-deficient poorly differentiated chordoma of the skull base: report of five cases and review of literature. Zhonghua Bing Li Xue Za Zhi. 2022;51(1):33–8. https://doi.org/10.3760/cma.j.cn112151-20210705-00482.CrossRefPubMed

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Jambhekar NA, et al. Revisiting chordoma with brachyury, a “new age” marker: analysis of a validation study on 51 cases. Arch Pathol Lab Med. 2010;134(8):1181–7. https://doi.org/10.5858/2009-0476-oa.1.CrossRefPubMed

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•• Bai J, et al. Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival. Nat Commun. 2021;12(1):757. https://doi.org/10.1038/s41467-021-21026-5. This paper is crucial for its findings from whole genome sequencing of 80 SBC, identifying PBRM1 as a significantly mutated driver gene and revealing its strong association with poor survival and high recurrence rates in chordoma patients. The study also highlights the prevalence of genomic alterations like homozygous deletions of the CDKN2A/2B locus and chromosome 22q deletions involving another SWI/SNF gene (SMARCB1). These insights provide a deeper understanding of the genetic landscape of chordoma, emphasizing the role of somatic copy number alterations in tumor initiation and progression, and could guide future therapeutic strategies.ADSCrossRefPubMedPubMedCentral

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Eisenberg MB, et al. Loss of heterozygosity in the retinoblastoma tumor suppressor gene in skull base chordomas and chondrosarcomas. Surg Neurol. 1997;47(2):156–60. https://doi.org/10.1016/s0090-3019(96)00432-6. (discussion 160-1).CrossRefPubMed

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• Bai J, et al. Gene expression profiling identifies two chordoma subtypes associated with distinct molecular mechanisms and clinical outcomes. Clin Cancer Res. 2023;29(1):261–70. https://doi.org/10.1158/1078-0432.Ccr-22-1865. This study is pivotal in identifying two major molecular subtypes of chordoma through RNA sequencing and NanoString panel analysis. The association of these subtypes with survival outcomes, as indicated by IHC staining, enhances the understanding of chordoma tumorigenesis and has potential implications for clinical prognostication and developing targeted treatment options for this rare bone tumorCrossRefPubMed

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Baluszek S, et al. DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment. Acta Neuropathol Commun. 2023;11(1):113. https://doi.org/10.1186/s40478-023-01610-0.CrossRefPubMedPubMedCentral

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Miao D, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018;359(6377):801–6. https://doi.org/10.1126/science.aan5951.ADSCrossRefPubMedPubMedCentral

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• Righi A, et al. SMARCB1/INI1 loss in skull base conventional chordomas: a clinicopathological and molecular analysis. Front Oncol. 2023;13:1160764. https://doi.org/10.3389/fonc.2023.1160764. This study is significant for its retrospective analysis of SMARCB1/INI1 expression in conventional skull base chordomas, including the chondroid subtype. Importantly, this variable protein expression did not correlate with various clinicopathological parameters or survival outcomes. However, the findings highlight the potential of SMARCB1/INI1 as a biomarker and its possible therapeutic implications in chordoma, a critical insight given the aggressive nature of this rare disease variant.CrossRefPubMedPubMedCentral

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Rekhi B, et al. Poorly differentiated chordoma showing loss of SMARCB1/INI1: clinicopathological and radiological spectrum of nine cases, including uncommon features of a relatively under-recognized entity. Ann Diagn Pathol. 2021;55:151809. https://doi.org/10.1016/j.anndiagpath.2021.151809.CrossRefPubMed

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Presneau N, et al. Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study. J Pathol. 2011;223(3):327–35. https://doi.org/10.1002/path.2816.CrossRefPubMed

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Hung YP, et al. Dedifferentiated chordoma: clinicopathologic and molecular characteristics with integrative analysis. Am J Surg Pathol. 2020;44(9):1213–23. https://doi.org/10.1097/pas.0000000000001501.CrossRefPubMed

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Amary MF, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–43. https://doi.org/10.1002/path.2913.CrossRefPubMed

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Arai M, et al. Frequent IDH1/2 mutations in intracranial chondrosarcoma: a possible diagnostic clue for its differentiation from chordoma. Brain Tumor Pathol. 2012;29(4):201–6. https://doi.org/10.1007/s10014-012-0085-1.CrossRefPubMed

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Kuang L, et al. Overexpression of adenosine deaminase acting on RNA 1 in chordoma tissues is associated with chordoma pathogenesis by reducing miR-125a and miR-10a expression. Mol Med Rep. 2015;12(1):93–8. https://doi.org/10.3892/mmr.2015.3341.MathSciNetCrossRefPubMedPubMedCentral

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Bayrak OF, et al. MicroRNA expression profiling reveals the potential function of microRNA-31 in chordomas. J Neurooncol. 2013;115(2):143–51. https://doi.org/10.1007/s11060-013-1211-6.CrossRefPubMed

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Deniz ML, et al. Expression of growth factors and structural proteins in chordomas: basic fibroblast growth factor, transforming growth factor α, and fibronectin are correlated with recurrence. Neurosurgery. 2002;51(3):753–60.PubMed

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Weinberger PM, et al. Differential expression of epidermal growth factor receptor, c-Met, and HER2/neu in chordoma compared with 17 other malignancies. Arch Otolaryngol Head Neck Surg. 2005;131(8):707–11.CrossRefPubMed

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Shalaby A, et al. The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target. J Pathol. 2011;223(3):336–46.MathSciNetCrossRefPubMed

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Fasig JH, et al. Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma. Neuropathol Appl Neurobiol. 2008;34(1):95–104. https://doi.org/10.1111/j.1365-2990.2007.00873.x.CrossRefPubMed

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Tamborini E, et al. Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas. Clin Cancer Res. 2006;12(23):6920–8. https://doi.org/10.1158/1078-0432.Ccr-06-1584.CrossRefPubMed

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Casali PG, et al. Imatinib mesylate in chordoma. Cancer. 2004;101(9):2086–97.CrossRefPubMed

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Naka T, et al. Immunohistochemical analysis of E-cadherin, α-catenin, β-catenin, γ-catenin, and neural cell adhesion molecule (NCAM) in chordoma. J Clin Pathol. 2001;54(12):945–50.CrossRefPubMedPubMedCentral

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Horiguchi H, et al. Expression of cell adhesion molecules in chordomas: an immunohistochemical study of 16 cases. Acta Neuropathol. 2004;107(2):91–6. https://doi.org/10.1007/s00401-003-0770-6.CrossRefPubMed

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•• Zhang Q, et al. Single-cell transcriptome reveals cellular hierarchies and guides p-EMT-targeted trial in skull base chordoma. Cell Discov. 2022;8(1):94. https://doi.org/10.1038/s41421-022-00459-2. This study is groundbreaking for its comprehensive profiling of the transcriptomes of 90,691 single cells from SBC, providing a detailed understanding of SBC cellular hierarchies and identifying novel treatment targets. Key findings include the identification of a stem-like cell cluster potentially responsible for radioresistance and significant partial EMT signatures in malignant cells associated with invasion and poor prognosis. The study also reports the promising clinical application of YL-13027, a partial EMT inhibitor, in a phase I trial, demonstrating its potential as a precision treatment for SBC.CrossRefPubMedPubMedCentral

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Naka T, et al. Expression of matrix metalloproteinases-1,-2, and-9; tissue inhibitors of matrix metalloproteinases-1 and-2; cathepsin B; urokinase plasminogen activator; and plasminogen activator inhibitor, type I in skull base chordoma. Hum Pathol. 2008;39(2):217–23.CrossRefPubMed

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de Castro CV, et al. Tyrosine kinase receptor expression in chordomas: phosphorylated AKT correlates inversely with outcome. Hum Pathol. 2013;44(9):1747–55. https://doi.org/10.1016/j.humpath.2012.11.024.CrossRefPubMed

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Stacchiotti S, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol. 2012;30(9):914–20. https://doi.org/10.1200/jco.2011.35.3656.CrossRefPubMed

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Hindi N, et al. Imatinib in advanced chordoma: a retrospective case series analysis. Eur J Cancer. 2015;51(17):2609–14. https://doi.org/10.1016/j.ejca.2015.07.038.CrossRefPubMed

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Stacchiotti S, et al. Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol. 2009;20(11):1886–94. https://doi.org/10.1093/annonc/mdp210.CrossRefPubMed

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Stacchiotti S, et al. Phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol. 2013;24(7):1931–6. https://doi.org/10.1093/annonc/mdt117.CrossRefPubMed

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Schuetze SM, et al. Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor. Cancer. 2017;123(1):90–7.CrossRefPubMed

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Launay SG, et al. Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review. BMC Cancer. 2011;11:423. https://doi.org/10.1186/1471-2407-11-423.CrossRefPubMedPubMedCentral

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Di Maio S, et al. Novel targeted therapies in chordoma: an update. Ther Clin Risk Manag. 2015;11:873–83. https://doi.org/10.2147/tcrm.S50526.CrossRefPubMedPubMedCentral

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Magnaghi P, et al. Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and brachyury. Mol Cancer Ther. 2018;17(3):603–13. https://doi.org/10.1158/1535-7163.Mct-17-0324.CrossRefPubMed

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•• Anderson E, et al. Synergistic drug combinations and machine learning for drug repurposing in chordoma. Sci Rep. 2020;10(1):12982. https://doi.org/10.1038/s41598-020-70026-w. This study is pivotal for its approach to repurposing existing drugs for chordoma treatment, utilizing machine learning to identify potential inhibitors and testing combinations of approved kinase inhibitors. It highlights the effectiveness of the mTOR inhibitor AZD2014 against chordoma cell lines and suggests potential synergies with FDA-approved drugs like afatinib and palbociclib. This innovative strategy accelerates the development of treatments for chordoma and potentially other rare cancers.ADSCrossRefPubMedPubMedCentral

192.

•• Scheipl S, et al. Drug combination screening as a translational approach toward an improved drug therapy for chordoma. Cell Oncol (Dordr). 2021;44(6):1231–42. https://doi.org/10.1007/s13402-021-00632-x. This paper is significant for its investigation of potential therapeutic combinations with epidermal growth factor receptor inhibitors (EGFRis) for treating chordoma, a malignant bone tumor. This research suggests novel treatment avenues, such as combining EGFRis with drugs like crizotinib, panobinostat, or doxorubicin, which could be instrumental in overcoming resistance to tyrosine kinase inhibitor monotherapies.CrossRefPubMed

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Rodrigues DA, Pinheiro PSM, Fraga CAM. Multitarget inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol-3-kinase (PI3K): current and future prospects. ChemMedChem. 2021;16(3):448–57. https://doi.org/10.1002/cmdc.202000643.CrossRefPubMed

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Lee DH, et al. Combined PDGFR and HDAC inhibition overcomes PTEN disruption in chordoma. PLoS ONE. 2015;10(8):e0134426. https://doi.org/10.1371/journal.pone.0134426.CrossRefPubMedPubMedCentral

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Title: Integrated Molecular and Histological Insights for Targeted Therapies in Mesenchymal Sinonasal Tract Tumors
Authors: Cosima C. Hoch
Leonard Knoedler
Samuel Knoedler
Ali Bashiri Dezfouli
Benedikt Schmidl
Anskar Trill
Jennifer E. Douglas
Nithin D. Adappa
Fabian Stögbauer
Barbara Wollenberg
Publication date: 20-02-2024
Publisher: Springer US
Keywords: Targeted Therapy
Sarcoma
Published in: Current Oncology Reports / Issue 3/2024
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI: https://doi.org/10.1007/s11912-024-01506-9

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