WNT/β-Catenin Pathway in Soft Tissue Sarcomas: New Therapeutic Opportunities?

Abstract

Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be a largely unmatched goal. The WNT/β-catenin signaling pathway is involved in various fundamental processes for embryogenic development, including the proliferation and differentiation of mesenchymal stem cells. Although the role of this pathway has been widely researched in neoplasms of epithelial origin, little is known about its relevance for mesenchymal neoplasms. This review covers the most important molecular alterations of the WNT signaling pathway in STS. The detection of these alterations and the understanding of their functional consequences for those pathways controlling sarcomagenesis development and progression are crucial to broaden the current knowledge about STS as well as to identify novel drug targets. In this regard, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are also discussed.

Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need

“…Therefore, these data are suggestive of poor differentiation and increased cell migration, which are consistent with the clinical–pathological features of UPS. Moreover, even though the success of the blockade of Wnt signaling as a cancer treatment has been hampered by consequent severe side effects such as alteration of tissue homeostasis and regeneration, recently several Wnt signaling inhibitors have been developed and are currently being used in clinical trials, opening new therapeutic options also for STS [ 17 ].…”

Complex Elucidation of Cells-of-Origin in Pediatric Soft Tissue Sarcoma: From Concepts to Real Life, Hide-and-Seek through Epigenetic and Transcriptional Reprogramming

“…However, although major in case of chromosomal translocation affecting transcription factors, oncogenic transcriptional reprogramming also exists in STS without fusion transcripts, and can be induced by single gene mutations. This notably holds true when mutation affects transcriptions factors, such as the L122R gain-of-function mutation in MYOD1 observed in spindle cell/sclerosing rhabdomyosarcoma, or in the CTNBB1 mutations that are recurrent in desmoid tumors for example [ 45 , 46 ]. These particular signatures can serve as a guide to improve the molecular classification of this complex entity.…”

Role of Tumor Microenvironment in Cancer Stem Cell and Clinical Application

“…as single agents or part of combination regimens. For instance, peptidomimetic drug CWP232291 activates caspases, which leads to β-catenin degradation, therefore reducing β-catenin target genes survivin and cyclin D1 expression [100]. It is currently being tested as monotherapy for patients with recurrent and/or refractory myeloid malignancies (NCT01398462) and in combination with lenalidomide and dexamethasone in patients with Multiple Myeloma (NCT02426723).101…”