Targeting glutamine metabolism slows soft tissue sarcoma growth.
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ABSTRACT:
SUBMITTER: Lee P
PROVIDER: S-EPMC6981153 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sirtuins are NAD+ dependent deacetylases and/or ADP-ribosyl transferases active on histone and non-histone substrates. The first sirtuin was discovered as a transcriptional repressor of the mating-type-loci (Silent Information Regulator sir2) in the budding yeast, where it was shown to extend yeast lifespan. Seven mammalian sirtuins (SIRT1-7) have been now identified with distinct subcellular localization, enzymatic activities and substrates. These enzymes regulate cellular processes such as metabolism, cell survival, differentiation, DNA repair and they are implicated in the pathogenesis of solid tumors and leukemias. The purpose of the present study was to investigate the role of sirtuin expression, activity and inhibition in the survival of pediatric sarcoma cell lines.We have analyzed the expression of SIRT1 and SIRT2 in a series of pediatric sarcoma tumor cell lines and normal cells, and we have evaluated the activity of the sirtuin inhibitor and p53 activator tenovin-6 (Tv6) in synovial sarcoma and rhabdomyosarcoma cell lines. We show that SIRT1 is overexpressed in synovial sarcoma biopsies and cell lines in comparison with normal mesenchymal cells. Tv6 induced apoptosis as well as impaired autophagy flux. Using siRNA to knock down SIRT1 and SIRT2, we show that the expression of both proteins is crucial for the survival of rhabdomyosarcoma cells and that the loss of SIRT1 expression results in a decreased LC3II expression. Our results show that SIRT1 and SIRT2 expressions are crucial for the survival of synovial sarcomas and rhabdomyosarcomas, and demonstrate that the pharmacological inhibition of sirtuins impairs the autophagy process and induces tumor cell death.
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Project description:Soft-tissue sarcoma (sts) is a rare mesenchymal malignancy that accounts for less than 1% of all adult tumours. Despite the successful advancement of localized therapies such as surgery and radiotherapy, these tumours can, for many, recur-often with metastatic disease. In the advanced setting, the role of systemic therapies is modest and is associated with poor survival. With the discovery of immunotherapies in other tumour types such as melanoma and lung cancer, interest has been renewed in exploring immunotherapy in sts. The biology of some stss makes them ripe for immunotherapy intervention; for example, some stss might have chromosomal translocations resulting in pathognomonic fusion products that have been shown to express cancer/testis antigens. Here, we present a targeted review of the published data and ongoing clinical trials for immunotherapies in patients with sarcoma, which comprise immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines.
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Project description:Soft tissue sarcomas remain one of the rarest malignancies with numerous subtypes that go undiagnosed. The PDGFRα antagonist Olaratumab (Lartruvo) was withdrawn from the market due to disappointing findings in the phase III studies. We share our experience with this medication in a tertiary care center in the Middle East and North Africa region. Monitor the effect of Olaratumab on sarcomas when it was used prior to its withdrawal, and compare our findings with the literature. We performed a retrospective analysis of adult patients with advanced-/metastatic soft tissue sarcomas treated with at least two cycles of Olaratumab at a tertiary care center in Lebanon during the period from January 1, 2017 to December 31, 2018. Fifteen patients were included in the study. The mean age was 49 with a range of 26-75 years. The median duration of the use of Olaratumab was 21.3 months with a range of 7.3-37 months. The average number of number of cycles received per patient was four. Five patients were deceased. Median PFS was 7.87 months (95% CI 5.28-10.45), and mean OS was 12.26 months (95% CI 8.47-16.05) Median OS was 9.8 months (95% CI 6.07-13.53). Olaratumab has been withdrawn from the market, and it is currently being investigated as part of the phase II ANNOUNCE 2 trial. Our experience from a tertiary care center shows results similar to those reported in the literature. The immunogenicity and heterogeneity of soft tissue sarcomas pose a challenge to the treatment of soft tissue sarcomas, but they also allow a wide array of possible management solutions.
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Project description:N6-methyladenosine (m6A) RNA methylation has been shown to have prognostic value in cancer. Nonetheless, its potential role regarding immunity, metabolism, and stemness in soft tissue sarcoma (STS) remains unknown. We comprehensively estimated the m6A modification patterns and corresponding immunity, metabolism, and stemness characteristics based on 568 STS samples and 21 m6A regulators. The m6Ascore was constructed to quantify m6A modification patterns in individuals using machine learning algorithms. Two distinct m6A modification patterns among the STS patients were identified, which exhibited differences in prognosis, immune cell infiltration, metabolic pathways, stemness, somatic mutation, and copy number variation. Thereafter, immunity-, metabolism-, and stemness phenotype-related genes associated with m6A modification were identified. Furthermore, patients with lower m6Ascores had increased antitumor immune responses, survival benefit under immunotherapy, tumor mutation burden, immunogenicity, and response to anti-PD-1/L1 immunotherapy. Immunotherapy sensitivity was validated using the IMvigor210 dataset. STS patients with lower m6Ascore might be more sensitive to docetaxel and gemcitabine. Finally, pan-cancer analysis illustrated the significant correlations of m6Ascore with clinical outcomes, immune cell infiltration, metabolism, and stemness. This study revealed that m6A modification plays an important role in immunity, metabolism, and stemness in STS. Evaluating the m6A modification pattern and development of m6Ascore may help to guide more effective immunotherapy and chemotherapy strategies.
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Project description:Soft tissue sarcoma (STS) with an infiltrative histologic growth pattern, when compared to STS with an expansile pattern, may pose difficulties in local control. Preoperative assessment of the presence of infiltrative histologic growth pattern would be helpful in deciding treatment strategies. A review of 144 patients who underwent surgery for extremity STS was performed. Microscopically, the histologic growth pattern was defined as infiltrative if the penetration of the tumor cells into the surrounding tissue was observed. Possible clinicopathologic factors that might be associated with infiltrative histologic growth pattern were investigated with regard to patient demographics, tumor characteristics, and MRI findings. Of the 144 tumors, 71 (49%) showed infiltrative histologic growth pattern. On multivariate analysis, histological subtypes other than liposarcoma (OR = 4.57, p = 0.02) and infiltrative border on MRI (OR = 2.48, p = 0.01) were independent factors associated with infiltrative histologic growth pattern. Predictive index based on these two factors showed a significant improved accuracy (ROC-AUC = 0.647) for predicting infiltrative histologic growth pattern compared to either factor alone. Our data suggests that liposarcoma histology and tumor border on MRI can predict histologic growth pattern in extremity STS.
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Project description:Soft tissue sarcomas (STS) are heterogeneous rare malignancies comprising ~1% of all solid cancers in adults and including more than 70 histological and molecular subtypes with different pathological and clinical development characteristics. Over the last two decades, the increased knowledge of the new molecular and genomic mechanisms of different STS histotypes allowed for a reclassification of these tumors and consequently to the development of novel chemotherapeutic agents. Generally, surgery, in combination with radiotherapy only in selected cases of localized disease, represents the most common treatment of primary STS, whereas the principal treatment modality for locally advanced or metastatic disease is first-line chemotherapy. The principal treatment for the preponderance of STS patients is usually an anthracycline (epirubicin and doxorubicin) in monotherapy or in combination with other drug novel chemotherapeutic agents. However, survival for treated patients with metastatic disease is poor, and a 2-years survival rate is about 30%. In this scenario, Pharmacogenomics (PGx) biomarkers that can predict drug response play an important role in the improvement of molecular diagnostics in clinical routines and contribute to elucidating the genetic basis for the differences in treatment efficacy and toxicity among STS patients. This review focuses on recent insight in the PGx biomarkers that have been described to modulate responsiveness and toxicity parameters of conventional and new chemotherapeutics drugs in several STS histotypes.
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