Targeting EZH2 for the treatment of soft tissue sarcomas

Karolak, Magdalena; Tracy, Ian; Shipley, Janet; Walters, Zoë S.

doi:10.20517/2394-4722.2021.05

Cited by 4 publications

(5 citation statements)

References 68 publications

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“…EZH2 catalyses the trimethylation of histone H3 at Lysine 27, leading to the silencing of differentiation effectors and to the preservation of the ability of self-renewal in the tumour cell. SS is characterised by an overexpression of both EZH2, due to the alteration in the dynamic balance of the BAF-PRC interaction generated by the SS18-SSX fusion proteins, and the consequently increased production of the H3K27me3 motif and repression of tumour suppressors 16,24 Consistently, the expression of EZH2 correlates with tumour aggressiveness and stage in SS, supporting the role of this protein for disease progression, [25][26][27] but also as a potential therapeutic target.…”

Section: Histology and Molecular Biologymentioning

confidence: 77%

Treatment at Relapse for Synovial Sarcoma of Children, Adolescents and Young Adults: From the State of Art to Future Clinical Perspectives

Ferrari,

Berlanga,

Gatz

et al. 2023

CMAR

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While the overall prognosis is generally quite satisfactory in children, adolescents and young adults with localised synovial sarcoma at first diagnosis, the outcome remains poor for patients after relapse. Conversely to the front-line standardised treatment options, patients with relapse generally have an individualised approach and to date, there is still a lack of consensus regarding standard treatment approaches. Studies on relapsed synovial sarcoma were able to identify some prognostic variables that influence post-relapse survival, in order to plan risk-adapted salvage protocols. Treatment proposals must consider previous first-line treatments, potential toxicities, and the possibility of achieving an adequate local treatment by new surgery and/or re-irradiation. Effective second-line drug therapies are urgently needed. Notably, experimental treatments such as adoptive engineered TCR-T cell immunotherapy seem promising in adults and are currently under validation also in paediatric patients.

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Section: Histology and Molecular Biologymentioning

confidence: 77%

Treatment at Relapse for Synovial Sarcoma of Children, Adolescents and Young Adults: From the State of Art to Future Clinical Perspectives

Ferrari,

Berlanga,

Gatz

et al. 2023

CMAR

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“…In sarcomas, upregulation of PRC2 components-in particular EZH2-has been correlated with metastases and lower survival [128][129][130]. In PF− RMS, aberrant PRC2 activityincluding aberrant EZH2 activity-has been shown to block skeletal muscle differentiation by repressing the transcription of myogenic genes (refer to Figure 4 for a schematic representation of epigenetic enzymes involved in aberrant myogenic differentiation in RMS) [131,132].…”

Section: Chromatin Regulatory Complex Prc2mentioning

confidence: 99%

“…The PRC2 component EZH2 has emerged as an important regulator of muscle differentiation and a candidate treatment target in RMS [128][129][130]. Various inhibitors of EZH2 have been used in preclinical studies.…”

Section: Hdac and Ezh2 Inhibitorsmentioning

confidence: 99%

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Pomella

Danielli

Alaggio

et al. 2023

Cancers

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Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention.

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“…EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is also crucial for maintaining the epigenetic state of the cells, thanks to the modulation of the chromatin structure and, consequently, the regulation of gene expression [ 54 ].…”

Section: The Epigenomic Landscape Of Esmentioning

confidence: 99%

Shifting from a Biological-Agnostic Approach to a Molecular-Driven Strategy in Rare Cancers: Ewing Sarcoma Archetype

et al. 2023

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Sarcomas of the thoracic cavity are rare entities that predominantly affect children and young adults. They can be very heterogeneous encompassing several different histological entities. Ewing Sarcoma (ES) can potentially arise from every bone, soft tissue, or visceral site in the body. However, it represents an extremely rare finding when it affects the thoracic cavity. It represents the second most frequent type of thoracic sarcoma, after chondrosarcoma. ES arises more frequently in sites that differ from the thoracic cavity, but it displays the same biological features and behavior of extra-thoracic ones. Current management of ES often requires a multidisciplinary treatment approach including surgery, radiotherapy, and systemic therapy, as it can guarantee local and distant disease control, at least transiently, although the long-term outcome remains poor. Unfortunately, due to the paucity of clinical trials purposely designed for this rare malignancy, there are no optimal strategies that can be used for disease recurrence. As a result of its complex biological features, ES might be suitable for emerging biology-based therapeutic strategies. However, a deeper understanding of the molecular mechanisms driving tumor growth and treatment resistance, including those related to oncogenic pathways, epigenetic landscape, and immune microenvironment, is necessary in order to develop new valid therapeutic opportunities. Here, we provide an overview of the most recent therapeutic advances for ES in both the preclinical and clinical settings. We performed a review of the current available literature and of the ongoing clinical trials focusing on new treatment strategies, after failure of conventional multimodal treatments.

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Targeting EZH2 for the treatment of soft tissue sarcomas

Cited by 4 publications

References 68 publications

Treatment at Relapse for Synovial Sarcoma of Children, Adolescents and Young Adults: From the State of Art to Future Clinical Perspectives

Treatment at Relapse for Synovial Sarcoma of Children, Adolescents and Young Adults: From the State of Art to Future Clinical Perspectives

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Shifting from a Biological-Agnostic Approach to a Molecular-Driven Strategy in Rare Cancers: Ewing Sarcoma Archetype

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