Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in soft tissue sarcomas
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ABSTRACT:
ORGANISM(S): Mus musculus Canis lupus familiaris
PROVIDER: GSE218914 | GEO | 2023/03/01
REPOSITORIES: GEO
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Project description:Canine soft tissue sarcomas were analyzed for gene expression changes following intratumoral treatment with collagen-anchored IL-2 and IL-12 therapy. Tumors were surgically resected at different intervals following treatment to assess persistence of any therapy-driven gene expression changes.
2023-03-01 | GSE218912 | GEO
Project description:Mouse B16F10 melanoma tumors were analyzed for gene expression changes following intratumoral treatment with collagen-anchored IL-2 and IL-12 therapy for comparative analysis to expression changes observed in canine soft tissue sarcomas. Tumors were collected at different intervals following treatment to assess persistence of any therapy-driven gene expression changes.
2023-03-01 | GSE218913 | GEO
Project description:Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression-free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas.
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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:Background: The necroptosis and long noncoding RNA (lncRNA) are critical in the occurrence and development of malignancy, while the association between the necroptosis-related lncRNAs (NRlncRNAs) and soft tissue sarcoma (STS) remains controversial. Therefore, the present study aims to construct a novel signature based on NRlncRNAs to predict the prognosis of STS patients and investigate its possible role. Methods: The transcriptome data and clinical characteristics were extracted from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx). A novel NRlncRNA signature was established and verified by the COX regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis. Subsequently, the K-M survival analysis, ROC, univariate, multivariate Cox regression analysis, and nomogram were used to evaluate the predictive value of the signature. Also, a variety of bioinformatic analysis algorithms explored the differences between the potential mechanism, tumor immune status, and drug sensitivity in the two-risk group. Finally, the RT-qPCR was performed to evaluate the expression of signature NRlncRNAs. Results: A novel signature consisting of seven NRlncRNAs was successfully established and verified with stable prediction performance and general applicability for STS. Next, the GSEA showed that the patients in the high-risk group were mainly enriched with tumor-related pathways, while the low-risk patients were significantly involved in immune-related pathways. In parallel, we found that the STS patients in the low-risk group had a better immune status than that in the high-risk group. Additionally, there were significant differences in the sensitivity to anti-tumor agents between the two groups. Finally, the RT-qPCR results indicated that these signature NRlncRNAs were abnormally expressed in STS. Conclusion: To the best of our knowledge, it is the first study to construct an NRlncRNA signature for STS. More importantly, the novel signature displays stable value and translational potential for predicting prognosis, tumor immunogenicity, and therapeutic response in STS.
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Project description:Due to the heterogeneity of soft tissue sarcomas (STS), the choice of the proper perioperative treatment regimen is challenging. Neoadjuvant therapy has attracted increasing attention due to several advantages, particularly in patients with locally advanced disease. The number of available neoadjuvant modalities is growing continuously. We may consider radiotherapy, chemotherapy, targeted therapy, radiosensitizers, hyperthermia, and their combinations. This review discusses possible neoadjuvant treatment options in STS with an emphasis on available evidence, indications for each treatment type, and related risks. Finally, we summarize current recommendations of the STS neoadjuvant therapy response assessment.
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Project description:Soft tissue sarcomas (STS) are a rare group of mesenchymal solid tumors with heterogeneous genetic profiles and clinical features. Systemic chemotherapy is the backbone treatment for advanced STS; however, STS frequently acquire resistance to standard therapies, which highlights the need to improve treatments and identify novel therapeutic targets. Increases in the knowledge of the molecular pathways that drive sarcomas have brought to light different molecular alterations that cause tumor initiation and progression. These findings have triggered a breakthrough of targeted therapies that are being assessed in clinical trials. Cancer stem cells (CSCs) exhibit mesenchymal stem cell (MSC) features and represent a subpopulation of tumor cells that play an important role in tumor progression, chemotherapy resistance, recurrence and metastasis. In fact, CSCs phenotypes have been identified in sarcomas, allied to drug resistance and tumorigenesis. Herein, we will review the published evidence of CSCs in STS, discussing the molecular characteristic of CSCs, the commonly used isolation techniques and the new possibilities of targeting CSCs as a way to improve STS treatment and consequently patient outcome.
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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:Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.
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