Prospects for Epigenetic Targeted Therapies of Bone and Soft-Tissue Sarcomas.
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ABSTRACT:
SUBMITTER: Wang J
PROVIDER: S-EPMC8328687 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bone sarcomas include a very large number of tumour subtypes, which originate form bone and more particularly from mesenchymal stem cell lineage. Osteosarcoma, Ewing's sarcoma and chondrosarcoma, the three main bone sarcoma entities develop in a favourable microenvironment composed by bone cells, blood vessels, immune cells, based on the 'seed and soil theory'. Current therapy associates surgery and chemotherapy, however, bone sarcomas remain diseases with high morbidity and mortality especially in children and adolescents. In the past decade, various new therapeutic approaches emerged and target the tumour niche or/and directly the tumour cells by acting on signalling/metabolic pathways involved in cell proliferation, apoptosis or drug resistance. The present review gives a brief overview from basic to clinical assessment of the main targeted therapies of bone sarcoma cells.
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Project description:Primary malignant bone tumours, osteosarcomas, and Ewing sarcomas are rare diseases which occur mainly in adolescents and young adults. With the current therapies, some patients remain very difficult to treat, such as tumour with poor histological response to preoperative CT (or large initial tumour volume for Ewing sarcomas not operated), patients with multiple metastases at or those who relapsed. In order to develop new therapies against these rare tumours, we need to unveil the key driving factors and molecular abnormalities behind the malignant characteristics and to broaden our understanding of the phenomena sustaining the metastatic phenotype and treatment resistance in these tumours. In this paper, starting with the biology of these tumours, we will discuss potential therapeutic targets aimed at increasing local tumour control, limiting metastatic spread, and finally improving patient survival.
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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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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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Project description:Due to the rarity and heterogeneity of bone and soft-tissue sarcomas, investigation into molecular targets and new treatments has been particularly challenging. Although intensive chemotherapy and establishment of surgical procedures have improved the outcomes of patients with sarcoma, the curative rate of recurrent and metastatic sarcomas is still not satisfactory. Recent basic science research has revealed some of the mechanisms of progression and metastasis of malignancies including proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, invasion, and regulation of antitumor immune systems. Based on these basic studies, new anticancer drugs, including pazopanib, trabectedin, eribulin, and immune checkpoint inhibitors have been developed and the efficacies and safety of the new drugs have been assessed by clinical trials. This review summarizes new molecular therapeutic targets and advances in the treatment for bone and soft tissue sarcomas.
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Project description:Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes.
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Project description:Alveolar soft part sarcoma (ASPS) is a very rare soft tissue sarcoma which arises primarily in children and young adults. Despite its unique histology and well-characterized genetic translocation, many questions remain regarding the pathogenesis and treatment of this tumor type. Though collective clinical experience with this tumor type spans more than 60 years, there has been little progress made in treating this uncommon but frequently fatal disease. This paper focuses on the available data regarding its molecular pathogenesis and insights into targeted therapeutics as well as the results of clinical trials performed to date to hopefully improve the outcome of patients with this rare malignancy.
| S-EPMC3337503 | biostudies-literature
Project description:ObjectivesMost epidemiologic studies on soft tissue sarcomas (STS) and bone sarcomas (BS) are performed in western countries, with few in the Middle East and North Africa region. We describe the epidemiology of sarcomas in Lebanon using the medical records database at the American University of Beirut Medical Center (AUBMC).MethodsThis single-center retrospective cohort study included patients with sarcomas registered in the database between 2015 and 2019. Their charts were reviewed for baseline characteristics, tumor biology and location, treatment modalities, recurrence, metastasis, and death.ResultsThe cohort included 234 patients with STS and 99 patients with BS. Most tumors were <10 cm in size. The most common subtypes were liposarcoma for STS and osteosarcoma for BS. The most common location of STS was the thigh. The most frequent sites of STS metastasis were the lungs. Histological subtype, smoking status, and tumor size and grade were significant for progression-free survival (PFS) in patients with STS. By multivariable analysis, smoking was significantly associated with poorer PFS in STS. For BS, only tumor grade was significant for PFS.ConclusionThe epidemiology of sarcomas at AUBMC is similar to that previously reported. Smoking history was associated with poorer survival in patients with STS.
| S-EPMC8918978 | biostudies-literature
Project description:Soft tissue sarcomas (STSs) are a heterogeneous group of tumors originating from the mesenchyme. Even though they affect individuals in all age groups, the prevalence of subtypes of STSs changes significantly from childhood through adolescence into adulthood. The mainstay of therapy is surgery, with or without the addition of chemotherapy and/or radiation therapy. These treatment modalities are associated, in many cases, with significant morbidity and, given the heterogeneity of tumor histologies encompassed by the term "STS", have not uniformly improved outcomes. Moreover, some subgroups of STSs appear to be more, and others less, responsive to conventional chemotherapy agents. Over the last two decades, our understanding of the biology of STSs is slowly increasing, allowing for the development of more targeted therapies. We review the new treatment modalities that have been tested on patients with STSs, with a special focus on adolescents and young adults, a group of patients that is often underrepresented in clinical trials and has not received the dedicated attention it deserves, given the significant differences in biology and treatment response in comparison to children and adults.
| S-EPMC5384699 | biostudies-literature
Project description:IntroductionSelected patients with locally advanced or metastatic soft tissue and bone sarcomas (STBS) may benefit from intensive local treatment, such as stereotactic radiotherapy (SRT). This study aimed to summarize the utilization and outcomes of SRT in STBS and to identify predictive factors for progression and survival.Materials and methodsConsecutive patients with advanced STBS who underwent STBS in a sarcoma tertiary center were identified. We collected tumor- and treatment-related factors. Endpoints comprised time to local progression (TTLP), local progression-free survival (LPFS), time to progression, progression-free survival, and overall survival (OS). The Cox proportional-hazards model was used to identify prognostic factors.ResultsWe identified 141 patients who underwent 233 SRTs. Median follow-up was 21 months. Local and distant progression occurred after 19 and 163 SRTs, respectively. SRT for lung metastases was predictive for better TTLP and LPFS (hazard ratio, HR = 0.12, p = 0.007 and HR = 0.42, p = 0.002, respectively). Bone sarcoma (HR for TTLP = 3.18, p = 0.043; HR for LPFS = 1.99, p = 0.028) and lower administered dose (HR for TTLP = 0.98, p = 0.007; HR for LPFS = 0.99, p = 0.012) were predictive for worse TTLP and LPFS. SRT for oligometastases (HR = 0.46, p = 0.021) and lung metastases (HR = 0.55, p = 0.046) was predictive for better OS, whereas diagnosis of bone sarcoma (HR = 2.05, p = 0.029) was predictive for worse OS.ConclusionSRT provides excellent local control in STBS patients without significant toxicity. Patients with oligometastatic disease, lung metastases, and soft tissue sarcomas benefit the most from SRT. The dose escalation moderately enhances local control; however, it does not translate into better survival.
| S-EPMC8848098 | biostudies-literature