The evolving management of epithelioid sarcoma.
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ABSTRACT:
SUBMITTER: Alves A
PROVIDER: S-EPMC9285437 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
Publications
The evolving management of epithelioid sarcoma.
Alves Anneke A Constantinidou Anastasia A Thway Khin K Fisher Cyril C Huang Paul P Jones Robin L RL
European journal of cancer care 20210718 6
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Project description:BackgroundEpithelioid sarcoma (EpS) is a high-grade malignant soft-tissue sarcoma characterized by local recurrences and distant metastases. Effective treatments for EpS have not been established and thus novel therapeutic approaches against EpS are urgently required. mTOR inhibitors exert antitumor effects on several malignancies but AKT reactivation by mTOR inhibition attenuates the antitumor effects of mTOR inhibitors. This reactivation is receptor tyrosine kinase (RTK)-dependent due to a release of negative feedback inhibition. We found that c-MET was the most highly activated RTK in two human EpS cell lines, Asra-EPS and VAESBJ. Here we investigated the functional and therapeutic relevance of mTOR and/or c-MET signaling pathways in EpS both in vitro and in vivo.MethodsWe first examined the effects of an mTOR inhibitor, RAD001 (everolimus), on cell proliferation, cell cycle, AKT/mTOR signaling, and xenograft tumor growth in EpS cell lines. Next, we determined whether RAD001-induced AKT reactivation was blocked by silencing of c-MET or treatment with a selective c-MET inhibitor, INC280. Finally, we evaluated the antitumor effects of RAD001 combined with INC280 on EpS cell lines compared with either single agent or control in vitro and in vivo.ResultsConstitutive AKT phosphorylation was observed in Asra-EPS and VAESBJ cells. RAD001 suppressed EpS cell growth by inducing cell cycle arrest but enhanced AKT phosphorylation, which resulted in intrinsic resistance to mTOR inhibitors. In both EpS cell lines, RAD001-induced AKT phosphorylation was dependent on c-MET signaling. INC280 inhibited phosphorylation of c-MET and its downstream molecules, and decreased RAD001-induced phosphorylation of both AKT and ERK in EpS. Compared with a single agent or control, the combination of RAD001 and INC280 exerted superior antitumor effects on the growth of EpS cell lines in vitro and in vivo.ConclusionsTargeting of mTOR and c-MET signaling pathways significantly abrogates the growth of EpS in preclinical models and may be a promising therapeutic approach for patients with EpS.
| S-EPMC4249599 | biostudies-literature
Project description:Epithelioid sarcoma is a mesenchymal soft tissue sarcoma often arising in the extremities, usually in young adults with a pick of incidence at 35 years of age. Epithelioid sarcoma (ES) is characterized by the loss of SMARCB1/INI1 (integrase interactor 1) or other proteins of the SWI/SNF complex. Two distinct types, proximal and distal, with varying biology and treatment outcomes, are distinguished. ES is known for aggressive behavior, including a high recurrence rate and regional lymph node metastases. An optimal long-term management strategy is still to be defined. The best treatment of localized ES is wide surgical resection. Neo-adjuvant or adjuvant radiotherapy may be recommended, as it reduces the local recurrence rate. Sentinel lymph node biopsy should be considered in ES patients. Patients with metastatic ES have a poor prognosis with an expected median overall survival of about a year. Doxorubicin-based regimens are recommended for advanced ES. Tazemetostat, an EZH2 methyltransferase, has shown promising results in ES patients. Novel therapies, including immunotherapy, are still needed.
| S-EPMC7463637 | biostudies-literature
Project description:Epithelioid sarcoma is a rare and aggressive mesenchymal tumour, the genetic hallmark of which is the loss of expression of SMARCB1, a key member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelling complex. Hampered by its rarity, epithelioid sarcoma has received little research attention and therapeutic options for this disease remain limited. SMARCB1-deficient tumours also include malignant rhabdoid tumour, atypical teratoid and rhabdoid tumour, epithelioid malignant peripheral nerve sheath tumour, and poorly differentiated chordoma. Histologically, it can be challenging to distinguish epithelioid sarcoma from malignant rhabdoid tumour and other SMARCB1-deficient tumours, whereas methylation profiling shows that they represent distinct entities and facilitates their classification. Methylation studies on SMARCB1-deficient tumours, although not including epithelioid sarcomas, reported methylation subgroups which resulted in new clinical stratification and therapeutic approaches. In addition, emerging evidence indicates that immunotherapy, including immune checkpoint inhibitors, represents a promising therapeutic strategy for SMARCB1-deficient tumours. Here, we show that some epithelioid sarcomas share methylation patterns of malignant rhabdoid tumours indicating that this could help to distinguish these entities and guide treatment. Using gene expression data, we also showed that the immune environment of epithelioid sarcoma is characterised by a predominance of CD8+ lymphocytes and M2 macrophages. These findings have potential implications for the management of patients with epithelioid sarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
| S-EPMC10952852 | biostudies-literature
Project description:BackgroundMetachronous osteosarcoma is a rare form of osteosarcoma. The occurrence of metachronous tumor in soft tissue is exceedingly rare. The pathogenesis of metachronous osteosarcoma, as to whether it represents multiple true primaries or metastatic disease, is still obscure.Case presentationA 49-year-old Indian man presented with progressively increasing swelling in his left hand of 2 months' duration. An X-ray showed a soft tissue lesion. Contrast-enhanced computed tomography showed a soft tissue mass lesion, with peripheral enhancement and central necrotic areas in radial palmar soft tissue overlying second metacarpophalangeal region with no obvious bony osteolysis. Possibilities of acute abscess, resolving hematoma, or aggressive soft tissue mass lesion were suggested. An incision biopsy showed morphological features of epithelioid osteosarcoma, which was confirmed on immunohistochemistry. A detailed history revealed that our patient was diagnosed as having osteosarcoma of his right leg 3 years previously. Based on history, radiology, morphology, and immunohistochemistry, a final diagnosis of extraskeletal (soft tissue) epithelioid osteogenic sarcoma of the left hand occurring as a metachronous tumor 3 years after diagnosis of primary osteosarcoma in the right leg was given.ConclusionThis is probably the first reported case of extraskeletal (soft tissue) epithelioid osteosarcoma occurring as a metachronous tumor 3 years after diagnosis of primary osteosarcoma in the right leg. The prognosis of metachronous skeletal osteosarcoma is poor as compared to that of relapse limited to lungs. In late metachronous osteosarcoma, combined-modality therapy comprising surgery and aggressive chemotherapy may affect long-term survival. Lifelong follow-up of surviving patients with osteosarcoma is necessary and if metachronous osteosarcoma is discovered, it should be treated with curative intent.
| S-EPMC6507060 | biostudies-literature
Project description:Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is overexpressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition.EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti-EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models.EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration.EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.
| S-EPMC3176924 | biostudies-literature
Project description:Epithelioid sarcoma (ES) is a very rare and aggressive mesenchymal tumor of unclear origin and uncertain lineage characterized by a prevalent epithelioid morphology. The only recurrent genetic alteration reported in ES as yet is the functional inactivation of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), a key component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes. How SMARCB1 deficiency dictates the clinicopathological characteristics of ES and what other molecular defects concur to its malignant progression is still poorly understood. This review summarizes the recent findings about ES pathobiology, including defects in chromatin remodeling and other signaling pathways and their role as therapeutic vulnerabilities.
| S-EPMC9454995 | biostudies-literature
Project description:Epithelioid sarcoma is a rare malignant mesenchymal tumor that represents less than 1% of soft-tissue sarcomas. Despite its slow growth, the overall prognosis is poor with a high rate of local recurrence, lymph-node spread, and hematogenous metastasis. Primary epithelioid sarcoma arising from the spine is extremely rare, with limited data in the literature. We review the existing literature regarding spinal epithelioid sarcoma and report a case of epithelioid sarcoma arising from the spinal cord. A 54 year old male presented with a 1-month history of progressive left upper-limb weakness and numbness. Magnetic resonance imaging (MRI) of the spine showed an enhancing intramedullary mass at the level of T1 also involving the left T1 nerve root. Systemic radiological examination revealed no other lesion at presentation. Surgical excision of the mass was performed, and histology was consistent with epithelioid sarcoma of the spine. Despite adjuvant radiotherapy, there was aggressive local recurrence and development of intracranial metastatic spread. The patient died of the disease within 5 months from presentation. To the best of our knowledge, spinal epithelioid sarcoma arising from the spinal cord has not yet been reported. We review the challenges in diagnosis, surgical treatment, and oncologic outcome of this case.
| S-EPMC10488709 | biostudies-literature
Project description:ImportanceEpithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease.ObjectiveTo report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES.Design, setting, and participantsSeventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria.ExposuresAll patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib.Main outcome and measuresResponse was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines).ResultsOverall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months.Conclusions and relevanceThis is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.
| S-EPMC6143006 | biostudies-literature
Project description:BackgroundEpithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients.MethodsWe retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People's Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021.ResultsA total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated.ConclusionsThe combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma.Trial registrationThis study was approved in the Medical Ethics Committee of Peking University People's Hospital on October 28, 2022 (No.: 2022PHD015-002). The study was registered in Clinicaltrials.gov with identifier no. NCT05656222.
| S-EPMC10838420 | biostudies-literature
Project description:Epithelioid sarcoma (ES) is rare and aggressive soft tissue neoplasm characterized by tumor cells showing epithelioid morphology and immunohistochemically, characteristic loss of INI1/ SMARCB1 in most cases. The proximal-type ES usually involves the deeper soft tissues of the vulva or perineum is an extremely rare entity with diagnostic challenges. Surgery is the mainstay of treatment in localized diseases. Radiation and chemotherapy are used in the advanced and metastatic setting, however, their role in the adjuvant setting is uncertain. Anthracycline and gemcitabine-based chemotherapy are given in metastatic and recurrent tumors. We report 4 cases of ES treated over a period of 6 years at our center. All the cases initially presented at a local hospital with vulvar swelling with a benign mimic (3/4) or squamous cell carcinoma (1/4). The median age of diagnosis was 34 years (range 17-80). The diagnosis was established with epithelioid morphology of tumor cells and immunohistochemically characteristic loss of INI1/SMARCB1 in all cases. 3 cases were treated with upfront surgery and two of them received adjuvant radiotherapy. One case received upfront palliative therapy due to lung metastasis at the time of presentation. On median follow-up of 24 months (2-63), 2 cases were disease-free. One case had a recurrence in the lungs and chest wall after a disease-free interval of 63 months. She underwent surgical excision of metastatic deposits, however developed second lung recurrence after 3 months and is being treated with Adriamycin-based chemotherapy. All patients are alive at the last follow-up.
| S-EPMC8760413 | biostudies-literature