High Prevalence of 5T4/Trophoblast Glycoprotein in Soft Tissue Sarcomas.
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ABSTRACT:
SUBMITTER: Groothuis P
PROVIDER: S-EPMC8508483 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Soft tissue sarcoma is a rare and aggressive disease with a 40 to 50% metastasis rate. The limited efficacy of traditional approaches with surgery, radiation, and chemotherapy has prompted research in novel immunotherapy for soft tissue sarcoma. Immune checkpoint inhibitors such as anti-CTLA-4 and PD-1 therapies in STS have demonstrated histologic-specific responses. Some combinations of immunotherapy with chemotherapy, TKI, and radiation were effective. STS is considered a 'cold', non-inflamed tumor. Adoptive cell therapies are actively investigated in STS to enhance immune response. Genetically modified T-cell receptor therapy targeting cancer testis antigens such as NY-ESO-1 and MAGE-A4 demonstrated durable responses, especially in synovial sarcoma. Two early HER2-CAR T-cell trials have achieved stable disease in some patients. In the future, CAR-T cell therapies will find more specific targets in STS with a reliable response. Early recognition of T-cell induced cytokine release syndrome is crucial, which can be alleviated by immunosuppression such as steroids. Further understanding of the immune subtypes and biomarkers will promote the advancement of soft tissue sarcoma treatment.
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Project description:Soft tissue sarcomas are rare neoplasms, with approximately 9000 new cases in the USA every year. Unfortunately, during the past two decades, there has been little progress in the treatment of metastatic soft tissue sarcomas beyond the standard approaches of surgery, chemotherapy and radiation. Immunotherapy is a modality complementary to conventional therapy. It is appealing because functional antitumor activity could affect both local-regional and systemic disease, and act over a prolonged period of time. In this report, we review immunotherapeutic investigative strategies that are being developed, including several tumor vaccine, antigen vaccine and dendritic cell vaccine strategies.
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Project description:Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma (STS). Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors, preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways. Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma, pazopanib was investigated in STS. A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes. The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts. At present, there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy, limiting the clinical effectiveness and cost-effectiveness of the drug. In this review, we summarize the preclinical and clinical data for pazopanib, outline the evidence base for its effect in STS and explore reported studies that have investigated putative biomarkers.
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Project description:Human soft-tissue sarcomas (STS) are rare mesenchymal tumors with a 5-year survival rate of 50%, highlighting the need for further STS research. Research has been hampered by limited human sarcoma cell line availability and the large number of STS subtypes, making development of STS cell lines and animal models representative of the diverse human STS subtypes critical. Pigs represent ideal human disease models due to their similar size, anatomy, metabolism, and genetics compared to humans. The Oncopig encodes inducible KRAS G12D and TP53 R167H transgenes, allowing for STS modeling in a spatial and temporal manner. This study utilized Oncopig STS cell line (fibroblast) and tumor (leiomyosarcoma) RNA-seq data to compare Oncopig and human STS expression profiles. Altered expression of 3,360 and 7,652 genes was identified in Oncopig STS cell lines and leiomyosarcomas, respectively. Transcriptional hallmarks of human STS were observed in Oncopig STS, including altered TP53 signaling, Wnt signaling activation, and evidence of epigenetic reprogramming. Furthermore, master regulators of Oncopig STS expression were identified, including FOSL1, which was previously identified as a potential human STS therapeutic target. These results demonstrate the Oncopig STS model's ability to mimic human STS transcriptional profiles, providing a valuable resource for sarcoma research and cell line development.
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Project description:Pediatric soft tissue sarcomas are rare tumors of childhood, frequently characterized by specific chromosome translocations. Despite improvements in treatment, their clinical management is often challenging due to the low responsiveness of metastatic forms and aggressive variants to conventional therapeutic approaches, which leads to poor overall survival. It is widely thought that soft tissue sarcomas derive from mesenchymal progenitor cells that, during embryonic life, have developed chromosomal aberrations with de-regulation of the main pathways governing tissue morphogenesis. The Notch signaling pathway is one of the most important molecular networks involved in differentiation processes. Emerging evidence highlights the role of Notch signaling de-regulation in the biology of these pediatric sarcomas. In this review, we present an outline of recently gathered evidence on the role of Notch signaling in soft tissue sarcomas, highlighting its importance in tumor cell biology. The potential challenges and opportunities of targeting Notch signaling in the treatment of pediatric soft tissue sarcomas are also discussed.
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Project description:Genomic and functional study of existing and emerging sarcoma targets, such as fusion proteins, chromosomal aberrations, reduced tumor suppressor activity, and oncogenic drivers, is broadening our understanding of sarcomagenesis. Among these mechanisms, the tumor suppressor p53 (TP53) plays significant roles in the suppression of bone and soft tissue sarcoma progression. Although mutations in TP53 were thought to be relatively low in sarcomas, modern techniques including whole-genome sequencing have recently illuminated unappreciated alterations in TP53 in osteosarcoma. In addition, oncogenic gain-of-function activities of missense mutant p53 (mutp53) have been reported in sarcomas. Moreover, new targeting strategies for TP53 have been discovered: restoration of wild-type p53 (wtp53) activity through inhibition of TP53 negative regulators, reactivation of the wtp53 activity from mutp53, depletion of mutp53, and targeting of vulnerabilities in cells with TP53 deletions or mutations. These discoveries enable development of novel therapeutic strategies for therapy-resistant sarcomas. We have outlined nine bone and soft tissue sarcomas for which TP53 plays a crucial tumor suppressive role. These include osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma (RMS), leiomyosarcoma (LMS), synovial sarcoma, liposarcoma (LPS), angiosarcoma, and undifferentiated pleomorphic sarcoma (UPS).
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