RARE DISEASE
Bone sarcoma
Bone sarcoma
Bone sarcoma
Drug discovery
2
drugs
With orphan designations
Overview
Bone Sarcoma Overview
Bone sarcoma encompasses rare malignancies arising from bone, notably osteosarcoma and undifferentiated pleomorphic sarcoma (UPS). Primary tumors often originate in long bones, with osteosarcoma exhibiting a bimodal age distribution (peaks in adolescence/young adulthood and older adults). Diagnosis relies on imaging, biopsy, and staging. Treatment combines neoadjuvant/adjuvant chemotherapy (e.g., methotrexate, doxorubicin, cisplatin), surgical resection, and radiotherapy for unresectable tumors. Prognosis depends on histology, stage, and response to therapy, with 5-year survival rates ranging from ~50% to 70% in localized disease [1][3][7].
Burden
Incidence: ~1.0/100k annually worldwide; osteosarcoma accounts for 39% of primary bone malignancies [12][17].
Survival: 5-year relative survival 52.9% (bone sarcoma) vs. 66.4% (soft tissue); worse in metastatic/recurrent cases [4][17].
Trends: Rising age-standardized incidence (+14% in the UK since 1990s), driven by older adults [12][14].
Therapies
Chemotherapy: Multi-agent regimens (MAP: methotrexate, doxorubicin, cisplatin) ± ifosfamide for localized disease; samarium-153 or L-MTP-PE for metastasis/palliation [3][5][13].
Surgery: Limb-sparing resection preferred; amputation reserved for complex cases [1][5].
Radiotherapy: Adjuvant/SBRT for unresectable tumors or incomplete margins [10][13].
Categories: rare bone diseases, rare neoplastic diseases
Research Papers
2,134 drug discovery papers about Bone sarcoma, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,134 drug discovery papers about Bone sarcoma, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | High-Grade Undifferentiated Pleomorphic Sarcoma of the Distal Tibia Presenting as a Radiographically Benign-Appearing Lesion: A Case Report and Review of the Literature.
Background: Undifferentiated pleomorphic sarcoma (UPS) of the bone is a rare, high-grade malignancy of uncertain origin, most commonly affecting the extremities of adults. Its diagnosis may be challenging, particularly when clinical and radiological findings are confounded by trauma-related conditions. Case presentation: In this paper, the case of a 51-year-old man who sustained a high-energy trauma resulting in a diaphyseal fracture of the left tibia and fibula, initially treated with intramedullary nailing. Preoperative radiographs raised suspicion of an osteolytic lesion in the distal tibia; however, second-level imaging was performed postoperatively, suggesting a benign process. At initial evaluation at a primary Musculoskeletal Oncology Centre, strict clinical and radiological follow-up was recommended, but the patient failed to adhere. Over the following years, persistent symptoms were attributed to post-traumatic and inflammatory conditions, including suspected complex regional pain syndrome. Progressive clinical deterioration led to repeat imaging, revealing an aggressive lesion. A biopsy (March 2025) ultimately confirmed a primary bone high-grade UPS with no metastasis. Following multidisciplinary discussion, below-knee amputation was performed, achieving clear surgical margins. At one-year CT imaging follow-up, the patient remained disease-free and was able to ambulate with a prosthesis. Conclusions: High-energy trauma and later attribution of symptoms to post-traumatic conditions may complicate the diagnostic process, contributing to diagnostic delay. Early referral to specialised Musculoskeletal Oncology Centres, strict adherence to follow-up, and timely histological confirmation are essential to optimise outcomes. Suspicious bone lesions should always be fully characterised prior to surgical intervention.
2026-09-18 | Epidemiology and treatment outcomes of bone and soft tissue sarcoma in pediatric and adolescent and young adult patients in Japan: data from population-based National Cancer Registry 2016-2019.
This Japanese population-based retrospective study using National Cancer Registry data (2016-2019) revealed age-specific disparities in treatment and outcomes of bone and soft tissue sarcomas in patients under 40 years. A total of 1,209 bone sarcoma (BS) and 3,096 soft tissue sarcoma (STS) cases were analyzed for demographics, treatment modalities, survival rates, and prognostic factors. Osteosarcoma (53%) and Ewing sarcoma (15%) were the most common BS subtypes. Pediatric patients presented more frequently with metastases and received more chemotherapy, while surgery was performed in 80% of BS cases. For STS, fibrosarcoma (19%) and rhabdomyosarcoma (13%) predominated. AYA (adolescent and young adult) patients underwent more surgeries, whereas pediatric patients received more chemotherapy/radiotherapy. Three-year overall survival rates were 67% for BS and 79% for STS. Prognosis was significantly influenced by disease extent and surgical intervention. Age was an adverse prognostic factor for STS but not for BS. This first comprehensive Japanese population-based study demonstrates treatment disparities across age groups in sarcoma care. We revealed that pediatric and AYA sarcoma care in Japan shows clear age-related disparities.
2026-09-01 | Real-World Efficacy and Safety of Tyrosine Kinase Inhibitors in Patients With Advanced Bone Sarcomas: The TOGBONE Study of the Turkish Oncology Group
PURPOSE: Primary bone sarcomas, including osteosarcoma, chondrosarcoma, and Ewing sarcoma, have poor prognoses, with 5-year overall survival (OS) rates of < 20%-30% in metastatic or recurrent disease. Although tyrosine kinase inhibitors (TKIs) targeting angiogenic and oncogenic pathways have shown efficacy in phase II trials, there is a lack of supporting real-world data. This study aimed to evaluate the efficacy and safety of TKI use in patients with advanced bone sarcomas in a real-world setting. MATERIALS AND METHODS: This multicenter, retrospective study included 72 patients with advanced or metastatic osteosarcoma, chondrosarcoma, or Ewing sarcoma who received at least one TKI (regorafenib, pazopanib, sorafenib, or cabozantinib) at multiple centers in Türkiye. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Adverse events were recorded and graded according to standard criteria. RESULTS: The median age was 28.5 years (range, 17-72 years), and 62.5% (n = 45) of the patients were male. The most frequently used TKIs were regorafenib (n = 31, 43.1%) and pazopanib (n = 22, 30.6%); in the majority of patients (n = 68, 94.4%), TKIs were used as second-line or subsequent treatment. The median PFS for the entire cohort was 4.8 months (95% CI, 3.05 to 6.48), and the median OS was 9.9 months (95% CI, 6.48 to 13.25). In histologic subgroup analyses, the median PFS was 4.4 months for osteosarcoma, 4.8 months for chondrosarcoma, and 5.4 months for Ewing sarcoma. Adverse events were observed in 50% (n = 36) of patients, and 89.2% (n = 58) of these were grade 1-2. Dose reduction was required in 27.8% (n = 20) of patients, and permanent treatment discontinuation due to toxicity was necessary in 6.9% (n = 5) of patients. CONCLUSION: In this real-world cohort, although TKIs were associated with limited survival outcomes, they had an acceptable safety profile in patients with advanced bone sarcomas. These findings are consistent with the results of phase II studies and suggest that TKIs may be a treatment option for patients who have disease progression after standard therapies.
2026-08-27 | Emerging Treatments in Bone Tumors: Lessons Learned from the ESMO Annual Meeting.
Primary bone sarcomas are rare, heterogeneous malignancies with limited therapeutic options, particularly in metastatic disease where outcomes remain poor. This study synthesizes current literature to evaluate emerging therapeutic strategies and biological determinants of response across osteosarcoma, Ewing sarcoma, and chondrosarcoma, as presented at the ESMO Annual Meeting, 2025. Key approaches reviewed include VEGFR-targeted tyrosine kinase inhibitors (TKIs), DNA damage response (DDR) inhibition, MYC targeting, immune checkpoint inhibitors (ICIs), and surfaceome-directed therapies such as antibody-drug conjugates (ADCs) and chimeric antigen receptor T cell therapy. Across studies, TKIs demonstrated short lasting activity as monotherapy but improved outcomes in some of the studies when combined with ICIs or chemotherapy, reflecting their role in remodeling the tumor microenvironment (TME); importantly, controlled studies with TKI and chemotherapy upfront are ongoing. DDR- and MYC-targeted therapies have shown strong preclinical rationale but limited clinical efficacy, highlighting challenges in translation. Immune-based therapies exhibited variable responses, with dedifferentiated chondrosarcoma (DDCS) emerging as a responsive histotype. Surfaceome-targeting strategies, particularly ADCs, demonstrated promising early clinical activity. Overall, bone sarcoma rarity, tumor heterogeneity, immunosuppressive TME, and lack of predictive factors challenge drug discovery for bone sarcoma patients. These findings underscore the importance of combination strategies and biomarker-driven patient selection and suggest that continued integration of targeted and immunotherapeutic approaches will be critical to improving outcomes in bone sarcoma.
2026-07-17 | Systemic therapy of bone sarcomas: current evidence and emerging strategies
Summary Bone sarcomas are rare, biologically heterogeneous malignancies in which progress in systemic therapy has historically been slow. In Ewing sarcoma, dose-dense VDC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide) has become the global induction standard, with EURO-EWING 2012 and AEWS0031 demonstrating survival benefits through interval compression. Contemporary international platforms, including INTER-EWING and iEuroEwing, now provide harmonized, biomarker-integrated frameworks to evaluate novel agents, radiotherapy optimization, and maintenance strategies. In relapsed disease, the rEECur trial has redefined standards by identifying high-dose ifosfamide as the most active salvage regimen, while deprioritizing less effective combinations; additional rational combinations such as ifosfamide plus lenvatinib and trabectedin plus irinotecan are under active investigation. In osteosarcoma, MAP (high-dose methotrexate, doxorubicin, cisplatin) chemotherapy remains the first-line standard, and postoperative intensification with MAPIE (MAP, ifosfamide, etoposide) has not improved outcomes. Targeted multikinase inhibitors (TKIs), including cabozantinib and regorafenib, provide meaningful but time-limited activity in refractory disease. A large ongoing National Cancer Institute (NCI) phase II/III trial is currently evaluating the addition of cabozantinib to frontline MAP in newly diagnosed patients. Antibody–drug conjugates (ADCs) targeting LRRC15 and B7-H3 represent further promising strategies. Chondrosarcoma remains largely chemoresistant, but targeted approaches are beginning to alter the therapeutic landscape. Isocitrate dehydrogenase (IDH) 1 inhibition with ivosidenib has shown durable disease control, and death receptor (DR) 5 agonism with INBRX-109 has delivered the first positive randomized systemic therapy signal in conventional chondrosarcoma. Continued international collaboration and biomarker-driven trial design are essential to translate these advances into clinical practice.
cell therapies
2026-09-24 | Beyond Implant Design: Surgical Principles and Early Outcomes of Patient-Specific Scapular Reconstruction After Total Scapulectomy.
Background/Objectives: Total scapulectomy for malignant scapular tumors remains a major reconstructive challenge because resection removes the osseous framework, muscular insertions, and biomechanical support required for shoulder function. Patient-specific three-dimensional (3D)-printed implants may improve anatomical reconstruction, but the indications and surgical principles underlying successful total scapular replacement remain poorly defined. Methods: This retrospective single-center case series included the first three consecutive patients who underwent total scapulectomy followed by immediate reconstruction using a patient-specific 3D-printed scapular prosthesis between January 2024 and December 2025. Clinical, radiographic, oncological, and functional outcomes were reviewed. Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) score and active shoulder range of motion. Results: The cohort included two women and one man with a median age of 53 years (range, 43-58 years). Diagnoses were chondrosarcoma in two patients and osteosarcoma in one. All tumors were Enneking stage IIB. Negative margins were achieved in all patients, and the axillary nerve and principal shoulder-girdle stabilizers were preserved in every case. Median follow-up was 13 months (range, 12-27 months). At latest follow-up, two patients had no evidence of disease and one was alive with disease after developing pulmonary metastases. The median MSTS score was 25/30 (range, 21-26). Median active elbow flexion, abduction, and forward flexion measured 88°, 80°, and 80°, respectively. Two patients experienced complications: one clavicular fracture and one aseptic wound dehiscence; neither resulted in implant failure or required revision of the reconstruction. Conclusions: Patient-specific total scapular reconstruction may provide satisfactory early radiographic and functional outcomes in carefully selected patients, although outcomes remain variable depending on individual patient and tumor characteristics. Implant design, patient selection, preservation of the axillary nerve and viable innervated shoulder-girdle musculature, and soft-tissue reconstruction should be considered complementary components of this reconstructive strategy.
2026-08-25 | Navigating CAR-T translation in Australia: lessons from an academic program.
Adoptive cell therapies utilizing both gene-modified and unmodified immune cells have revolutionized treatments for cancer and infection. Seven Chimeric antigen receptor (CAR) T cell products have been approved as therapies, providing the momentum to expand their clinical benefit to several cancer types. Many novel receptor-expressing cell therapies remain in preclinical development and require robust clinical testing Translating these into early-phase clinical trials requires navigating manufacturing, quality, and regulatory systems that are often not documented explicitly for academic investigators. This manuscript provides a stage-by-stage roadmap for translating academic CAR T-cell research into an investigator-led Phase I clinical trial in the Australian public sector. It draws on the E2CAR program, the first clinical translation of an EphA2-directed CAR T-cell product into pediatric bone sarcoma, conducted at the Children's Hospital at Westmead. We present our experience across six stages: construct finalization and vector strategy, manufacturing process development, quality infrastructure, assay development and validation, multi-entity operational coordination, and CTA regulatory engagement and provide recommendations for researchers at each stage. We also present a consolidated program timeline, minimum personnel requirements, and indicative costs to support grant applications and institutional planning. While the operational framework described here was developed specifically for our Health Precinct some of the recommendations we provide are likely to benefit academic groups navigating constraints in comparable settings.
2026-08-24 | Biological reconstruction in the growing child after tumour resection: long-term outcomes of vascularized fibular epiphyseal transfer.
Paediatric limb-salvage surgery after tumour resection is challenging because reconstruction must account for small skeletal dimensions, immature bone, and residual growth. This study aimed to evaluate the long-term clinical, radiological, functional, and oncological outcomes of vascularized fibular epiphyseal transfer (VFET) after paediatric oncological resection. We retrospectively reviewed nine children who underwent VFET between 1995 and 2025 at two institutions. Surgical techniques, bone union, graft hypertrophy, neo-joint remodelling, growth-related changes, complications, functional outcomes, and oncological status were analysed. The mean age at surgery was 6.8 years (range, 2-14), and the mean follow-up was 105 months (range, 7-330). Reconstruction sites included the proximal humerus, proximal radius, proximal femur, and distal tibia. Mean resection length was 12.25 cm. Bone union was achieved in seven patients after a mean of 22 months. Graft hypertrophy was observed in all patients at one year, with a mean increase of 34%. Neo-joint remodelling occurred in three patients. Two patients developed proximal humeral graft overgrowth with instability and dislocation. Mechanical complications occurred in eight patients, mainly non-union and graft fracture. One-year complication-free survival was 33 ± 16%. Functional outcomes were better in the upper limb than in the lower limb. Three-year overall survival was 71 ± 18%. VFET is a demanding biological reconstruction option in growing children after tumour resection. Although graft hypertrophy and selected joint remodelling may occur, growth behaviour is unpredictable and mechanical complications are frequent.
2026-07-28 | Bridging the Gap: Biological Reconstruction with Vascularised Fibula, Massive Allograft, or Capanna Technique After Intercalary Resection in Children and Young Adults with Lower Limb Bone Sarcoma.
Background. When free margins can be achieved and adjacent joints can be preserved, limb salvage surgery is the preferred treatment for intercalary paediatric bone tumours in the lower extremity. Biological reconstruction techniques include allograft, free vascularised fibular graft (FVFG), and allograft combined with FVGF (Capanna technique). This review summarises current evidence on outcomes and complications, and proposes directions for future research to refine patient selection. Methods. A systematic review was conducted using PubMed, Scopus, Embase, and Cochrane Library. Eligible studies reported outcomes of allograft, FVFG, or combined techniques for intercalary lower limb reconstruction in children or adolescents. Results. Twenty-five articles met the inclusion criteria (8 allograft, 7 FVFG, 14 Capanna); four studies reported two techniques. In total, 391 patients were included (allograft 147, FVFG 51, Capanna 193). Mean defect lengths were 14.9 cm (allograft), 14.5 cm (FVFG), and 14.7 cm (Capanna). Time to union was 8.5 months for allografts, 11.4 for Capanna, and 12.5 for FVFG. Non-union occurred in 14.7%, 13.2%, and 10.3%, and delayed union in 13.6%, 4.8%, and 7.9% for FVFG, allograft, and Capanna, respectively. Fractures were 40.5% for FVFG, 18.4% for allograft, and 23.5% for Capanna. Infections were least common with FVFG (2.7%). Conclusions. The reconstruction strategy should be tailored to anatomical location, defect size, and patient-specific factors. Although infections rates were lowest with FVFG, time to union was longer and the postoperative fracture rate was higher compared to the allograft or Capanna technique. Allografts demonstrated the shortest time to union and lowest fracture risk. The Capanna technique may be beneficial when factors including chemotherapy, poor host bone quality, or high mechanical load are present, but comes at a cost of morbidity and complexity.
2026-07-22 | Biological Reconstruction of Proximal Humerus Primary Malignant Tumors with Free Vascularized Fibular Epiphyseal Autograft.
Primary malignant bone tumors of the proximal humerus in skeletally immature patients pose complex challenges due to the need for resection with safe margins while preserving joint function and growth potential. This study aims to evaluate the functional, radiological, and oncological outcomes, along with the complications, of biological reconstruction using free vascularized epiphyseal fibular autograft (FVEFG) following resection of proximal humerus primary malignant tumors in pediatric patients. Ten patients (mean age: 10 years; range: 5-14) who underwent proximal humeral reconstruction with FVEFG between 2001 and 2022 were retrospectively analyzed. All patients had a minimum of 24 months of follow-up (mean: 39 months). Radiological outcomes were evaluated using the ISOLS scoring system, Boer and Wood index, and the annual graft growth rate. Functional results were assessed with the MSTS and TESS scoring systems. Oncological status and complications were also recorded. The mean ISOLS radiographic score was 85%, Boer and Wood hypertrophy index was 68%, and the mean annual longitudinal growth was 4.7 mm/year. The average MSTS and TESS scores were 76.9% and 83%, respectively. One patient developed local recurrence, and one died of distant metastasis. No infections or non-unions were observed. Graft fracture occurred in 3 patients (30%), with successful healing in all. Peroneal nerve palsy (transient) occurred in two cases. No patient required conversion to non-biological reconstruction or amputation. FVEFG is a reliable biological reconstruction technique for proximal humerus osteoarticular defects following resection of primary malignant tumors in skeletally immature patients, yielding favorable functional and radiological outcomes with a relatively low complication rate. The technique preserves longitudinal growth potential and articular surface function. Meticulous graft harvesting and fixation techniques are essential for minimizing complications.
antibodies
2026-09-11 | Exploring New Frontiers in Osteosarcoma Treatment: Clinical Trial Insights.
Osteosarcoma (OS) is a common bone malignancy in adolescents and older adults and typically develops in the long bones. Outcomes in advanced cases remain poor despite the use of chemotherapeutic drugs like doxorubicin, methotrexate, and cisplatin, underscoring the urgent need for safer, more focused treatments. A comprehensive review of clinical trials and literature identified emerging OS therapies targeting DNA repair, immune pathways, and tumor-specific markers. The EMA's approval of Mepact for nonmetastatic OS underscores the shift toward precision treatments and the evolving landscape of OS management. Patent protection can influence the pricing and accessibility of innovative medicines for OS by affecting market exclusivity and competition. According to recent research, bone morphogenetic protein (BMP), RB, and TP53 gene alterations both contribute to the development of OS. These results highlight the importance of conducting further proteomic and genomic research in order to develop focused and efficient treatment plans. Furthermore, patent protection stimulates innovative drug development by encouraging research investment and faster launches, but restricts affordability due to exclusivity, posing a policy dilemma. Treatment for OS is still challenging, particularly in high-grade and metastatic cases when conventional chemotherapy is frequently harmful and unsuccessful. While new targeted medicines and advances in understanding bone cell dynamics and genetic abnormalities such as TP53, RB, and BMPs offer hope for more accurate, less invasive treatments, the approval of Mapact represents progress. The necessity for integrated therapies combining immunotherapy, targeted delivery, and molecular insights to enhance OS treatment results is highlighted by developments in genomics and bone remodeling.
2026-08-04 | GD2-targeted immunotherapy in pediatric bone sarcomas: a systematic review of emerging strategies and combination approaches
Introduction Primary bone sarcomas, including Osteosarcoma (OS) and Ewing sarcoma (ES), are rare pediatric malignancies with limited therapeutic advances over recent decades and poor outcomes, especially for patients with metastatic and refractory/relapsed disease. Disialoganglioside 2 (GD2) has emerged as a promising immunotherapeutic target due to its high expression in pediatric bone sarcomas and its role in tumor progression and treatment resistance. This systematic review summarizes current evidence on GD2-targeted therapies and combination strategies in pediatric bone sarcomas. Methods A systematic review was conducted according to PRISMA 2020 guidelines using PubMed, Embase, Web of Science, and ClinicalTrials.gov. Preclinical and clinical studies investigating GD2-targeted therapies in pediatric bone sarcomas were included, together with registered clinical trials. Results Twenty-six studies met inclusion criteria, including 17 preclinical and 9 clinical studies, alongside 15 ongoing clinical trials. Preclinical evidence consistently demonstrated antitumor activity of GD2-directed approaches, including monoclonal antibodies (mAbs), CAR-T cells, bispecific antibodies, and radio-immunotherapy. Combination strategies, particularly anti-GD2 mAbs with chemotherapy, enhanced antitumor efficacy through induction of apoptosis, activation of endoplasmic reticulum stress pathways, and inhibition of tumor invasiveness. Clinical evidence, although limited and heterogeneous, suggested encouraging activity of Dinutuximab beta-based chemo-immunotherapy, especially in ES. Several clinical trials are ongoing, mainly early-phase and focusing on relapsed or refractory diseases. Discussion GD2 represents a biologically relevant and clinically promising target in pediatric bone sarcomas. However, major translational challenges remain, including limited clinical data, heterogeneous study designs, and the lack of standardized assays for GD2 expression assessment. Further collaborative international studies are needed to optimize patient selection and accelerate the development of GD2-targeted combination immunotherapy strategies.
2026-06-26 | Exploring the Role of CD44 in the Progression and Invasion of Chondrosarcoma.
Objectives: Chondrosarcoma is the most common type of primary bone sarcoma in adults with a high risk of local recurrence and metastasis. Chondrosarcomas are largely resistant to chemotherapy and radiotherapy, meaning that surgery is the mainstay of treatment for most patients. Therefore, new therapeutic targets are required. Cluster of differentiation 44 (CD44) is a transmembrane protein that has roles in cell proliferation, adhesion and migration and is shown to be overexpressed in several cancer types. Consequently, this work was undertaken to understand whether CD44 could be a potential therapeutic target in chondrosarcoma. Methods: In this study, tissue sections from chondrosarcoma patients were evaluated for CD44 expression using immunohistochemical analysis. The relationship between CD44 expression in the patient tissue and overall and event-free survival was investigated. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing was used to generate a CD44 knockout chondrosarcoma cell line which was used for a spheroid invasion assay to understand the role of CD44 in chondrosarcoma cell invasion. Results: Cox multivariate analysis of CD44 expression in chondrosarcoma patient tissue revealed that high CD44 expression was linked to decreased overall (p < 0.01) and event-free survival (p < 0.01). The observed invasion of CD44 knockout cells in the spheroid assay was less than that of the wild type cells (p < 0.001). Conclusions: The increased expression of CD44 in intermediate and high grade chondrosarcomas, as well as reduced invasion of CD44 knockout cells suggests that CD44 plays an important role in chondrosarcoma progression and metastasis. These findings support further investigation of CD44 as an imaging and/or therapeutic target for the management of chondrosarcoma.
2026-06-07 | B7-H3 membranous expression correlates with histological grading in a two-center cohort of 133 pre-treatment bone and soft tissue sarcoma samples.
B7-H3 targeted therapies are an upcoming promising treatment option for a variety of solid tumors. High levels of B7-H3 expression have only been reported for a few sarcoma subtypes in previous studies, but a systematic analysis in an untreated sarcoma cohort and across many different sarcoma subtypes has not yet been conducted. One hundred thirty-three sarcoma samples of previously untreated patients from different sarcoma entities including soft tissue sarcoma (STS, n = 103) and bone sarcoma (BS, n = 30) were collected from two sarcoma centers in South-West Germany. Samples were centrally immunohistochemically stained and assessed for membranous B7-H3 expression. For further analysis of B7-H3 expression, H-Scores were calculated. Baseline characteristics such as sex, age, histology, grading, staging as well as outcome data like treatments, event-free and overall survival were collected. B7-H3 was found to be broadly expressed (97%) across all tested sarcoma subtypes, with only four samples (3%) without B7-H3 expression. 45% of all samples had low (H-Score 1-100), 33% intermediate (H-Score 101-200) and 19% high (H-Score 201-300) membranous B7-H3 expression. Highest expression was found in pleomorphic liposarcoma (median 202.5), osteosarcoma (median 175) and angiosarcoma (median 167.5), whereas expression was lowest in myxoid and well differentiated liposarcoma (medians 44.5 & 62.5) and chondrosarcoma (median 60). H-Scores were found to significantly correlate positive with histological grading irrespective of histological sarcoma subtype. Pre-treatment B7-H3 H-Scores did predict event-free but not overall survival. B7-H3 is a promising treatment target in sarcomas as it is highly expressed particular in high grade bone and soft tissue sarcomas, such as pleomorphic liposarcomas and osteosarcomas.
2026-05-27 | Overall survival analysis of a heavily pretreated population of patients with bone sarcomas treated with mecbotamab vedotin, a conditionally binding ADC targeting AXL.
11511 Background: Patients with metastatic bone sarcomas continue to lack effective therapies. AXL, a cell-surface receptor tyrosine kinase, is highly expressed in bone sarcoma subtypes and has been shown to drive increased metastasis, resistance to chemotherapy, and poor outcomes. Mecbotamab vedotin (Mec-V, BA3011, Conditionally Active Biologic CAB-AXL-ADC) is designed to reduce off-tumor toxicity and improve pharmacokinetics by conditionally binding to AXL under low-pH conditions (pH<6.7) of the tumor microenvironment. Methods: A phase 1/2 open-label study evaluated Mec-V among adult and adolescent patients with AXL-expressing locally advanced, unresectable, or metastatic osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma with measurable disease by RECIST v1.1. Patients received Mec-V monotherapy intravenously 1.8 mg/kg every 2 weeks (Q2W). Results: This report focuses upon the long term follow up among 33 patients treated with Mec-V with osteosarcoma (n=13), Ewing (n=9), chondrosarcoma (n=8) or chordoma (n=3). Patients received a median of 2 prior lines of treatment. Most related treatment-related adverse events (TEAE) in patients with bone sarcomas were low grade (64%) and reversible; the most common related grade 3/4 TEAE of special interest was neutropenia (18%). No grade 5 TEAE were observed. As of March 25, 2025, disease control rate (DCR) was 100% among patients with chondrosarcoma and chordoma. In patients with osteosarcoma and Ewing sarcoma, DCR was 50% with 3 confirmed responses (14%; osteosarcoma n=2, Ewing n=1). The median OS with Mec-V for all bone sarcoma patients was 17.6 months. Observed median OS by tumor type in months: osteosarcoma (11.9 [95% CI: 3.2-Not Estimable (NE)]), Ewing sarcoma (19.4 [95% CI: 5.2–NE]), chondrosarcoma (NE [95% CI: 16.3-NE]), and chordoma (15.1 [95% CI: 7.2-NE]). Conclusions: Patients with treatment refractory bone sarcomas treated with Mec-V monotherapy achieved a median OS of 17.6 months which compares favorably to reported outcomes with other therapies including combination therapies. Mec-V monotherapy holds considerable promise for these high unmet need indications with potential increased benefit when used in combination. Clinical trial information: NCT03425279 .
oligonucleotides
2024-07-03 | miR-488-3p Represses Malignant Behaviors and Facilitates Autophagy of Osteosarcoma Cells by Targeting Neurensin-2.
Osteosarcoma (OS) is a primary bone sarcoma that primarily affects children and adolescents and poses significant challenges in terms of treatment. microRNAs (miRNAs) have been implicated in OS cell growth and regulation. This study sought to investigate the role of hsa-miR-488-3p in autophagy and apoptosis of OS cells. The expression of miR-488-3p was examined in normal human osteoblasts and OS cell lines (U2OS, Saos2, and OS 99-1) using RT-qPCR. U2OS cells were transfected with miR-488- 3p-mimic, and cell viability, apoptosis, migration, and invasion were assessed using CCK-8, flow cytometry, and Transwell assays, respectively. Western blotting and immunofluorescence were employed to measure apoptosis- and autophagy-related protein levels, as well as the autophagosome marker LC3. The binding sites between miR-488-3p and neurensin-2 (NRSN2) were predicted using online bioinformatics tools and confirmed by a dual-luciferase assay. Functional rescue experiments were conducted by co-transfecting miR-488-3p-mimic and pcDNA3.1-NRSN2 into U2OS cells to validate the effects of the miR-488-3p/NRSN2 axis on OS cell behaviors. Additionally, 3-MA, an autophagy inhibitor, was used to investigate the relationship between miR- 488-3p/NRSN2 and cell apoptosis and autophagy. miR-488-3p was found to be downregulated in OS cell lines, and its over-expression inhibited the viability, migration, and invasion while promoting apoptosis of U2OS cells. NRSN2 was identified as a direct target of miR-488-3p. Over-expression of NRSN2 partially counteracted the inhibitory effects of miR-488-3p on malignant behaviors of U2OS cells. Furthermore, miR- 488-3p induced autophagy in U2OS cells through NRSN2-mediated mechanisms. The autophagy inhibitor 3-MA partially reversed the effects of the miR-488-3p/NRSN2 axis in U2OS cells. Our findings demonstrate that miR-488-3p suppresses malignant behaviors and promotes autophagy in OS cells by targeting NRSN2. This study provides insights into the role of miR-488-3p in OS pathogenesis and suggests its potential as a therapeutic target for OS treatment.
2024-03-29 | MicroRNAs as Prognostic Biomarkers and Therapeutic Targets in Chondrosarcoma.
Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes.
2023-08-31 | MiR-4270 acts as a tumor suppressor by directly targeting Bcl-xL in human osteosarcoma cells
Chondrosarcomas and osteosarcomas are malignant bone tumors with a poor prognosis when unresectable or metastasized. Moreover, radiotherapy and chemotherapy could be ineffective. MiRNAs represent an alternative therapeutic approach. Based on high-throughput functional screening, we identified four miRNAs with a potential antiproliferative effect on SW1353 chondrosarcoma cells. Individual functional validations were then performed in SW1353 cells, as well as in three osteosarcoma cell lines. The antiproliferative and cytotoxic effects of miRNAs were evaluated in comparison with a positive control, miR-342-5p. The cytotoxic effect of four selected miRNAs was not confirmed on SW1353 cells, but we unambiguously revealed that miR-4270 had a potent cytotoxic effect on HOS and MG-63 osteosarcoma cell lines, but not on SaOS-2 cell line. Furthermore, like miR-342-5p, miR-4270 induced apoptosis in these two cell lines. In addition, we provided the first report of Bcl-xL as a direct target of miR-4270. MiR-4270 also decreased the expression of the anti-apoptotic protein Mcl-1, and increased the expression of the pro-apoptotic protein Bak. Our findings demonstrated that miR-4270 has tumor suppressive activity in osteosarcoma cells, particularly through Bcl-xL downregulation.
2023-06-30 | Functional Role of RBP in Osteosarcoma: Regulatory Mechanism and Clinical Therapy
Malignant bone neoplasms can be represented by osteosarcoma (OS), which accounts for 36% of all sarcomas. To reduce tumor malignancy, extensive efforts have been devoted to find an ideal target from numerous candidates, among which RNA-binding proteins (RBPs) have shown their unparalleled competitiveness. With the special structure of RNA-binding domains, RBPs have the potential to establish relationships with RNAs or small molecules and are considered regulators of different sections of RNA processes, including splicing, transport, translation, and degradation of RNAs. RBPs have considerable significant roles in various cancers, and experiments revealed that there was a strong association of RBPs with tumorigenesis and tumor cell progression. Regarding OS, RBPs are a new orientation, but achievements in hand are noteworthy. Higher or lower expression of RBPs was first found in tumor cells compared to normal tissue. By binding to different molecules, RBPs are capable of influencing tumor cell phenotypes through different signaling pathways or other axes, and researches on medical treatment have been largely inspired. Exploring the prognostic and therapeutic values of RBPs in OS is a hotspot where diverse avenues on regulating RBPs have achieved dramatical effects. In this review, we briefly summarize the contribution of RBPs and their binding molecules to OS oncogenicity and generally introduce distinctive RBPs as samples. Moreover, we focus on the attempts to differentiate RBP’s opposite functions in predicting prognosis and collect possible strategies for treatment. Our review provides forwards insight into improving the understanding of OS and suggests RBPs as potential biomarkers for therapies.
2023-05-29 | The promising roles of exosomal microRNAs in osteosarcoma: A new insight into the clinical therapy.
Osteosarcoma is the most common malignant bone sarcoma in children. Chemotherapy drugs resistance significantly hinders the overall survival of patients. Due to high biocompatibility and immunocompatibility, exosomes have been explored extensively. Multiple parent cells can actively secrete numerous exosomes, and the membrane structure of exosomes can protect miRNAs from degradation. Based on these characteristics, exosomal miRNAs play an important role in the occurrence, development, drug resistance. Therefore, in-depth exploration of exosome biogenesis and role of exosomal miRNAs will provide new strategies and targets for understanding the pathogenesis of osteosarcoma and overcoming chemotherapy drug resistance. Moreover, advancing evidences have showed that engineering modification could attribute stronger targeting to exosomes to deliver cargos to recipient cells more effectively. In this review, we focus on the mechanisms of exosomal miRNAs on the occurrence and development of osteosarcoma and the potential to function as tumor biomarkers for diagnosis and prognosis prediction. In addition, we also summarize recent advances in the clinical application values of engineering exosomes to provide novel ideas and directions for overcoming the chemotherapy resistance in osteosarcoma.
other
2026-05-27 | First-in-human dose escalation trial of an engineered salmonella delivering L-methioninase in advanced bone and soft tissue sarcomas.
11530 Background: Advanced bone and soft-tissue sarcomas have limited treatment options. Tumor-selective methionine dependency is a known metabolic vulnerability. SGN1 is designed to deplete methionine locally within tumors via intratumoral colonization of an attenuated Salmonella vector expressing L-methioninase. Preclinical studies have demonstrated safety and targeted antitumor activity. Here, we report the results from the escalation and expansion phases of the Phase I study in patients (pts) with advanced bone and soft-tissue sarcomas. Methods: The Phase I study includes a dose-escalation phase where pts received intravenous (IV) (2.0×10⁸ to 4.0×10⁸ CFU) or intra-arterial (IA) infusion (2.0×10⁸ to 6.0×10⁸ CFU) once a week (QW) in 28-day cycles, followed by an expansion phase with the putative recommended Phase 2 dose (RP2D) (2.0×10⁸ CFU for IV or 6.0×10⁸ CFU for IA QW) in 6 cohorts, including pts with recurrent either bone or soft tissue sarcoma after at least 2 lines of chemo therapies. SGN1 was administered in combination with physician's choice systemic therapy. Administration of SGN1 was via one of three routes: IV, IA, or a combined IV/IA regimen. Efficacy was assessed by RECIST version 1.1. Results: At the cut-off of Aug 19, 2024, 25 pts with advanced bone and soft-tissue sarcomas were enrolled in the escalation and expansion phases (median follow-up of 5.6 months; range, 0.5-18.2), including pts with bone sarcoma (n=10) and soft tissue sarcoma (n=15). Treatment was administered via IV (n=13), IA (n=8), or a combined IV/IA (n=4) route. The disease control rate (DCR) was 76.0% (95% CI: 56.5, 93.0) in all, 70.0% (95% CI: 34.8, 93.3) in bone sarcoma, 80.0% (95% CI: 52.0, 95.6) in soft tissue sarcoma pts, and 69.2% (95% CI: 38.5, 90.9) in IV, 75.0% (95% CI: 34.8, 93.3) in IA, 100% in combined IV/IA route. Quantitative PCR analysis confirmed significant intra-tumoral colonization by SGN1 post-treatment. The median progression-free survival (mPFS) was 11.5 months (95% CI: 11.1, NE) in all, 11.1 months (95% CI: 1.1, NE) in bone sarcoma, not reached (NR) (95% CI: 3.2, NE) in soft tissue sarcoma pts, and NR (95% CI: 2.7, NE) in IV, 11.5 months (95% CI: 1.3, NE) in IA, NR (95% CI: 11.1, NE) in combined IV/IA route. Complete tumor necrosis was observed in at least two soft tissue sarcoma patients. In all pts, the most frequent treatment-related adverse events (TRAEs) were pyrexia (32.0%) and elevation of blood LDH increased (20.0%). No TRAEs leading to temporary drug discontinuation, no serious TRAEs resulting in withdrawal from the study, and no treatment-related deaths occurred. Conclusions: SGN1 exhibits a manageable safety profile, and showed encouraging clinical benefit in advanced bone and soft-tissue sarcoma, as evidenced by mPFS and DCR. The promising data from this phase I study supports further testing of SGN1 in Phase II studies. Clinical trial information: ChiCTR2400085361.
2026-03-14 | Vasculogenic Mimicry: A Potential Therapeutic Target for Chondrosarcoma Therapy.
Chondrosarcomas (ChSs) are mesenchymal chemo- and radiation-resistant tumors, representing the second most frequently diagnosed bone sarcoma after osteosarcoma and 20% of all bone sarcomas. Most of ChS patients have a good prognosis after complete surgical resection. Conversely, patients with inoperable disease, due to the tumor location or metastatic dissemination, represent a great clinical challenge due to the lack of effective therapeutic options. In this study, to the best of our knowledge, we document, for the first time in human ChS tissues, the existence of CD-31- and Podoplanin-negative vascular-like channels containing red blood cells, allowing us to hypothesize the occurrence of vasculogenic mimicry (VM) in ChSs. By using patient-derived ChS cells and a stabilized ChS cell line, we demonstrate that ChS cells are able to form in vitro tubules apparently similar to those formed by endothelial cells. Further characterization of these vessels revealed the pivotal role of the Urokinase Plasminogen Activator Receptor (uPAR) in mediating the capability of ChS cells to form VM. Finally, we provide evidence that, unlike bevacizumab, which did not exert any effect, the uPAR-derived antiangiogenic peptide RI-3 behaves as a potent inhibitor of VM.
2026-02-25 | Molecular epidemiology of the expression of urokinase plasminogen activator receptor-associated protein (uPARAP) in mesenchymal malignancies.
Sarcomas are highly heterogenous and rare malignant tumors derived from mesenchymal cells. The current standard treatments for advanced disease have low response rates and are typically associated with considerable toxicity. The aim of this study was to investigate the expression of a potential novel therapeutic target and its clinical correlation in sarcomas, namely urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180/CD280). We evaluated uPARAP expression in various sarcoma subtypes and in normal tissues using 12 tissue microarrays. Expression was assessed on immunohistochemically stained slides and scored according to staining intensity and the percentage of positive tumor cells. Clinical correlations between uPARAP expression and selected parameters (gender and sample origin) were analyzed using generalized estimating equations, and survival outcomes were evaluated with Kaplan-Meier and log-rank tests. Our results demonstrated limited uPARAP expression in normal tissues, while high expression was observed in the majority of analyzed sarcoma subtypes, particularly high (>80% of highly positive cases) in fibrosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumor, and various bone sarcomas. Based on the correlation analyses between uPARAP expression and selected clinical parameters or survival outcomes, most subtypes did not show a statistically significant association. In conclusion, this study highlights the potential of uPARAP as an innovative target for targeted treatments, such as novel antibody-drug conjugates in sarcoma.
2025-05-28 | Multicenter phase II study of anlotinib and toripalimab in patients with advanced soft tissue sarcoma (STS) and bone sarcoma (BS).
11556 Background: This multicenter phase II study aims to evaluate the efficacy and safety of anlotinib combined with toripalimab in the treatment of patients (pts) with advanced STS or BS. Methods: Pts with advanced STS or BS, 14-70 years, at least one measurable tumor lesion per RECIST 1.1 and failure or intolerance of standard systemic therapy, or no standard treatment existed, are eligible. Pts with alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) can be included as the first-line therapy. Anlotinib (12 mg/d, po, d1-14) and toripalimab (240mg, IV, d1) would be administered every 3 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety using NCI-CTCAE v4.03. Results: Between March, 2020 and November, 2024, 70 pts were enrolled, of whom 68 were evaluable for the efficacy analyses. The STS subtypes mainly included synovial sarcoma (SS, 15.7%), rhabdomyosarcoma (RMS, 8.6%), extraskeletal Ewing's sarcoma (EES, 7.1%), epithelioid sarcoma (EpS, 7.1%), leiomyosarcoma (LMS, 7.1%), ASPS (5.7%), liposarcoma (5.7%), undifferentiated sarcoma (5.7%) and others (31.4%). The BS subtypes included 2 (2.9%) osteosarcoma and 2 (2.9%) chondrosarcoma. With a median follow up of 29.1 months, partial response occurred in 19 pts: 4 with SS, 3 with ASPS, 2 with LMS, 2 with EpS, 2 with inflammatory myofibroblastic tumor, and one patient each with RMS, EES, undifferentiated sarcoma, CCS, malignant peripheral nerve sheath tumor, or desmoplastic small round cell tumor. The ORR and DCR for the entire cohort were 27.9% and 86.8%, respectively. The median PFS was 7.0 months (95% CI: 4.2-9.8). The median OS was 23.5 months (95% CI: 9.2-37.8). For the 64 efficacy-evaluable STS cohort, the ORR was 29.7% and the median PFS was 8.1 months (95% CI: 4.7-11.5). Most of the treatment-related adverse events were mild (grade 1-2). The most common grade 3/4 adverse events (AE) were hypertension (15.7%), hand-foot syndrome reaction (12.9%), and hypertriglyceridemia (7.1%). Conclusions: The combination of anlotinib and toripalimab showed good anti-tumor activity and durable efficacy in advanced STS patients, with acceptable toxicity. Clinical trial information: NCT04172805 .
2025-02-25 | TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis
Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood. Here, we studied the effects of TOMM20 overexpression and downregulation on the redox state, mitochondrial oxidative phosphorylation (OXPHOS), and tumor growth using fibrosarcoma and chondrosarcoma models. TOMM20 overexpression increased OXPHOS, NADH, and NADPH with reduced cellular reactive oxygen species (ROS). TOMM20 induced resistance to apoptosis, including with BCL-2 and OXPHOS complex IV inhibitors, but with increased sensitivity to an OXPHOS complex I inhibitor. Also, TOMM20 induced cell growth and migration in vitro and promoted tumor growth in vivo. Conversely, knocking down TOMM20 using CRISPR-Cas9 reduced cancer aggressiveness in vivo in both chondrosarcoma and fibrosarcoma mouse models. In conclusion, TOMM20 is a driver of cancer aggressiveness by OXPHOS, apoptosis resistance, and the maintenance of a reduced state.
small molecules
2026-09-26 | High-Grade Undifferentiated Pleomorphic Sarcoma of the Distal Tibia Presenting as a Radiographically Benign-Appearing Lesion: A Case Report and Review of the Literature.
Background: Undifferentiated pleomorphic sarcoma (UPS) of the bone is a rare, high-grade malignancy of uncertain origin, most commonly affecting the extremities of adults. Its diagnosis may be challenging, particularly when clinical and radiological findings are confounded by trauma-related conditions. Case presentation: In this paper, the case of a 51-year-old man who sustained a high-energy trauma resulting in a diaphyseal fracture of the left tibia and fibula, initially treated with intramedullary nailing. Preoperative radiographs raised suspicion of an osteolytic lesion in the distal tibia; however, second-level imaging was performed postoperatively, suggesting a benign process. At initial evaluation at a primary Musculoskeletal Oncology Centre, strict clinical and radiological follow-up was recommended, but the patient failed to adhere. Over the following years, persistent symptoms were attributed to post-traumatic and inflammatory conditions, including suspected complex regional pain syndrome. Progressive clinical deterioration led to repeat imaging, revealing an aggressive lesion. A biopsy (March 2025) ultimately confirmed a primary bone high-grade UPS with no metastasis. Following multidisciplinary discussion, below-knee amputation was performed, achieving clear surgical margins. At one-year CT imaging follow-up, the patient remained disease-free and was able to ambulate with a prosthesis. Conclusions: High-energy trauma and later attribution of symptoms to post-traumatic conditions may complicate the diagnostic process, contributing to diagnostic delay. Early referral to specialised Musculoskeletal Oncology Centres, strict adherence to follow-up, and timely histological confirmation are essential to optimise outcomes. Suspicious bone lesions should always be fully characterised prior to surgical intervention.
2026-09-18 | Epidemiology and treatment outcomes of bone and soft tissue sarcoma in pediatric and adolescent and young adult patients in Japan: data from population-based National Cancer Registry 2016-2019.
This Japanese population-based retrospective study using National Cancer Registry data (2016-2019) revealed age-specific disparities in treatment and outcomes of bone and soft tissue sarcomas in patients under 40 years. A total of 1,209 bone sarcoma (BS) and 3,096 soft tissue sarcoma (STS) cases were analyzed for demographics, treatment modalities, survival rates, and prognostic factors. Osteosarcoma (53%) and Ewing sarcoma (15%) were the most common BS subtypes. Pediatric patients presented more frequently with metastases and received more chemotherapy, while surgery was performed in 80% of BS cases. For STS, fibrosarcoma (19%) and rhabdomyosarcoma (13%) predominated. AYA (adolescent and young adult) patients underwent more surgeries, whereas pediatric patients received more chemotherapy/radiotherapy. Three-year overall survival rates were 67% for BS and 79% for STS. Prognosis was significantly influenced by disease extent and surgical intervention. Age was an adverse prognostic factor for STS but not for BS. This first comprehensive Japanese population-based study demonstrates treatment disparities across age groups in sarcoma care. We revealed that pediatric and AYA sarcoma care in Japan shows clear age-related disparities.
2026-09-01 | Real-World Efficacy and Safety of Tyrosine Kinase Inhibitors in Patients With Advanced Bone Sarcomas: The TOGBONE Study of the Turkish Oncology Group
PURPOSE: Primary bone sarcomas, including osteosarcoma, chondrosarcoma, and Ewing sarcoma, have poor prognoses, with 5-year overall survival (OS) rates of < 20%-30% in metastatic or recurrent disease. Although tyrosine kinase inhibitors (TKIs) targeting angiogenic and oncogenic pathways have shown efficacy in phase II trials, there is a lack of supporting real-world data. This study aimed to evaluate the efficacy and safety of TKI use in patients with advanced bone sarcomas in a real-world setting. MATERIALS AND METHODS: This multicenter, retrospective study included 72 patients with advanced or metastatic osteosarcoma, chondrosarcoma, or Ewing sarcoma who received at least one TKI (regorafenib, pazopanib, sorafenib, or cabozantinib) at multiple centers in Türkiye. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Adverse events were recorded and graded according to standard criteria. RESULTS: The median age was 28.5 years (range, 17-72 years), and 62.5% (n = 45) of the patients were male. The most frequently used TKIs were regorafenib (n = 31, 43.1%) and pazopanib (n = 22, 30.6%); in the majority of patients (n = 68, 94.4%), TKIs were used as second-line or subsequent treatment. The median PFS for the entire cohort was 4.8 months (95% CI, 3.05 to 6.48), and the median OS was 9.9 months (95% CI, 6.48 to 13.25). In histologic subgroup analyses, the median PFS was 4.4 months for osteosarcoma, 4.8 months for chondrosarcoma, and 5.4 months for Ewing sarcoma. Adverse events were observed in 50% (n = 36) of patients, and 89.2% (n = 58) of these were grade 1-2. Dose reduction was required in 27.8% (n = 20) of patients, and permanent treatment discontinuation due to toxicity was necessary in 6.9% (n = 5) of patients. CONCLUSION: In this real-world cohort, although TKIs were associated with limited survival outcomes, they had an acceptable safety profile in patients with advanced bone sarcomas. These findings are consistent with the results of phase II studies and suggest that TKIs may be a treatment option for patients who have disease progression after standard therapies.
2026-08-27 | Emerging Treatments in Bone Tumors: Lessons Learned from the ESMO Annual Meeting.
Primary bone sarcomas are rare, heterogeneous malignancies with limited therapeutic options, particularly in metastatic disease where outcomes remain poor. This study synthesizes current literature to evaluate emerging therapeutic strategies and biological determinants of response across osteosarcoma, Ewing sarcoma, and chondrosarcoma, as presented at the ESMO Annual Meeting, 2025. Key approaches reviewed include VEGFR-targeted tyrosine kinase inhibitors (TKIs), DNA damage response (DDR) inhibition, MYC targeting, immune checkpoint inhibitors (ICIs), and surfaceome-directed therapies such as antibody-drug conjugates (ADCs) and chimeric antigen receptor T cell therapy. Across studies, TKIs demonstrated short lasting activity as monotherapy but improved outcomes in some of the studies when combined with ICIs or chemotherapy, reflecting their role in remodeling the tumor microenvironment (TME); importantly, controlled studies with TKI and chemotherapy upfront are ongoing. DDR- and MYC-targeted therapies have shown strong preclinical rationale but limited clinical efficacy, highlighting challenges in translation. Immune-based therapies exhibited variable responses, with dedifferentiated chondrosarcoma (DDCS) emerging as a responsive histotype. Surfaceome-targeting strategies, particularly ADCs, demonstrated promising early clinical activity. Overall, bone sarcoma rarity, tumor heterogeneity, immunosuppressive TME, and lack of predictive factors challenge drug discovery for bone sarcoma patients. These findings underscore the importance of combination strategies and biomarker-driven patient selection and suggest that continued integration of targeted and immunotherapeutic approaches will be critical to improving outcomes in bone sarcoma.
2026-07-17 | Systemic therapy of bone sarcomas: current evidence and emerging strategies
Summary Bone sarcomas are rare, biologically heterogeneous malignancies in which progress in systemic therapy has historically been slow. In Ewing sarcoma, dose-dense VDC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide) has become the global induction standard, with EURO-EWING 2012 and AEWS0031 demonstrating survival benefits through interval compression. Contemporary international platforms, including INTER-EWING and iEuroEwing, now provide harmonized, biomarker-integrated frameworks to evaluate novel agents, radiotherapy optimization, and maintenance strategies. In relapsed disease, the rEECur trial has redefined standards by identifying high-dose ifosfamide as the most active salvage regimen, while deprioritizing less effective combinations; additional rational combinations such as ifosfamide plus lenvatinib and trabectedin plus irinotecan are under active investigation. In osteosarcoma, MAP (high-dose methotrexate, doxorubicin, cisplatin) chemotherapy remains the first-line standard, and postoperative intensification with MAPIE (MAP, ifosfamide, etoposide) has not improved outcomes. Targeted multikinase inhibitors (TKIs), including cabozantinib and regorafenib, provide meaningful but time-limited activity in refractory disease. A large ongoing National Cancer Institute (NCI) phase II/III trial is currently evaluating the addition of cabozantinib to frontline MAP in newly diagnosed patients. Antibody–drug conjugates (ADCs) targeting LRRC15 and B7-H3 represent further promising strategies. Chondrosarcoma remains largely chemoresistant, but targeted approaches are beginning to alter the therapeutic landscape. Isocitrate dehydrogenase (IDH) 1 inhibition with ivosidenib has shown durable disease control, and death receptor (DR) 5 agonism with INBRX-109 has delivered the first positive randomized systemic therapy signal in conventional chondrosarcoma. Continued international collaboration and biomarker-driven trial design are essential to translate these advances into clinical practice.
cell therapies
2026-09-24 | Beyond Implant Design: Surgical Principles and Early Outcomes of Patient-Specific Scapular Reconstruction After Total Scapulectomy.
Background/Objectives: Total scapulectomy for malignant scapular tumors remains a major reconstructive challenge because resection removes the osseous framework, muscular insertions, and biomechanical support required for shoulder function. Patient-specific three-dimensional (3D)-printed implants may improve anatomical reconstruction, but the indications and surgical principles underlying successful total scapular replacement remain poorly defined. Methods: This retrospective single-center case series included the first three consecutive patients who underwent total scapulectomy followed by immediate reconstruction using a patient-specific 3D-printed scapular prosthesis between January 2024 and December 2025. Clinical, radiographic, oncological, and functional outcomes were reviewed. Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) score and active shoulder range of motion. Results: The cohort included two women and one man with a median age of 53 years (range, 43-58 years). Diagnoses were chondrosarcoma in two patients and osteosarcoma in one. All tumors were Enneking stage IIB. Negative margins were achieved in all patients, and the axillary nerve and principal shoulder-girdle stabilizers were preserved in every case. Median follow-up was 13 months (range, 12-27 months). At latest follow-up, two patients had no evidence of disease and one was alive with disease after developing pulmonary metastases. The median MSTS score was 25/30 (range, 21-26). Median active elbow flexion, abduction, and forward flexion measured 88°, 80°, and 80°, respectively. Two patients experienced complications: one clavicular fracture and one aseptic wound dehiscence; neither resulted in implant failure or required revision of the reconstruction. Conclusions: Patient-specific total scapular reconstruction may provide satisfactory early radiographic and functional outcomes in carefully selected patients, although outcomes remain variable depending on individual patient and tumor characteristics. Implant design, patient selection, preservation of the axillary nerve and viable innervated shoulder-girdle musculature, and soft-tissue reconstruction should be considered complementary components of this reconstructive strategy.
2026-08-25 | Navigating CAR-T translation in Australia: lessons from an academic program.
Adoptive cell therapies utilizing both gene-modified and unmodified immune cells have revolutionized treatments for cancer and infection. Seven Chimeric antigen receptor (CAR) T cell products have been approved as therapies, providing the momentum to expand their clinical benefit to several cancer types. Many novel receptor-expressing cell therapies remain in preclinical development and require robust clinical testing Translating these into early-phase clinical trials requires navigating manufacturing, quality, and regulatory systems that are often not documented explicitly for academic investigators. This manuscript provides a stage-by-stage roadmap for translating academic CAR T-cell research into an investigator-led Phase I clinical trial in the Australian public sector. It draws on the E2CAR program, the first clinical translation of an EphA2-directed CAR T-cell product into pediatric bone sarcoma, conducted at the Children's Hospital at Westmead. We present our experience across six stages: construct finalization and vector strategy, manufacturing process development, quality infrastructure, assay development and validation, multi-entity operational coordination, and CTA regulatory engagement and provide recommendations for researchers at each stage. We also present a consolidated program timeline, minimum personnel requirements, and indicative costs to support grant applications and institutional planning. While the operational framework described here was developed specifically for our Health Precinct some of the recommendations we provide are likely to benefit academic groups navigating constraints in comparable settings.
2026-08-24 | Biological reconstruction in the growing child after tumour resection: long-term outcomes of vascularized fibular epiphyseal transfer.
Paediatric limb-salvage surgery after tumour resection is challenging because reconstruction must account for small skeletal dimensions, immature bone, and residual growth. This study aimed to evaluate the long-term clinical, radiological, functional, and oncological outcomes of vascularized fibular epiphyseal transfer (VFET) after paediatric oncological resection. We retrospectively reviewed nine children who underwent VFET between 1995 and 2025 at two institutions. Surgical techniques, bone union, graft hypertrophy, neo-joint remodelling, growth-related changes, complications, functional outcomes, and oncological status were analysed. The mean age at surgery was 6.8 years (range, 2-14), and the mean follow-up was 105 months (range, 7-330). Reconstruction sites included the proximal humerus, proximal radius, proximal femur, and distal tibia. Mean resection length was 12.25 cm. Bone union was achieved in seven patients after a mean of 22 months. Graft hypertrophy was observed in all patients at one year, with a mean increase of 34%. Neo-joint remodelling occurred in three patients. Two patients developed proximal humeral graft overgrowth with instability and dislocation. Mechanical complications occurred in eight patients, mainly non-union and graft fracture. One-year complication-free survival was 33 ± 16%. Functional outcomes were better in the upper limb than in the lower limb. Three-year overall survival was 71 ± 18%. VFET is a demanding biological reconstruction option in growing children after tumour resection. Although graft hypertrophy and selected joint remodelling may occur, growth behaviour is unpredictable and mechanical complications are frequent.
2026-07-28 | Bridging the Gap: Biological Reconstruction with Vascularised Fibula, Massive Allograft, or Capanna Technique After Intercalary Resection in Children and Young Adults with Lower Limb Bone Sarcoma.
Background. When free margins can be achieved and adjacent joints can be preserved, limb salvage surgery is the preferred treatment for intercalary paediatric bone tumours in the lower extremity. Biological reconstruction techniques include allograft, free vascularised fibular graft (FVFG), and allograft combined with FVGF (Capanna technique). This review summarises current evidence on outcomes and complications, and proposes directions for future research to refine patient selection. Methods. A systematic review was conducted using PubMed, Scopus, Embase, and Cochrane Library. Eligible studies reported outcomes of allograft, FVFG, or combined techniques for intercalary lower limb reconstruction in children or adolescents. Results. Twenty-five articles met the inclusion criteria (8 allograft, 7 FVFG, 14 Capanna); four studies reported two techniques. In total, 391 patients were included (allograft 147, FVFG 51, Capanna 193). Mean defect lengths were 14.9 cm (allograft), 14.5 cm (FVFG), and 14.7 cm (Capanna). Time to union was 8.5 months for allografts, 11.4 for Capanna, and 12.5 for FVFG. Non-union occurred in 14.7%, 13.2%, and 10.3%, and delayed union in 13.6%, 4.8%, and 7.9% for FVFG, allograft, and Capanna, respectively. Fractures were 40.5% for FVFG, 18.4% for allograft, and 23.5% for Capanna. Infections were least common with FVFG (2.7%). Conclusions. The reconstruction strategy should be tailored to anatomical location, defect size, and patient-specific factors. Although infections rates were lowest with FVFG, time to union was longer and the postoperative fracture rate was higher compared to the allograft or Capanna technique. Allografts demonstrated the shortest time to union and lowest fracture risk. The Capanna technique may be beneficial when factors including chemotherapy, poor host bone quality, or high mechanical load are present, but comes at a cost of morbidity and complexity.
2026-07-22 | Biological Reconstruction of Proximal Humerus Primary Malignant Tumors with Free Vascularized Fibular Epiphyseal Autograft.
Primary malignant bone tumors of the proximal humerus in skeletally immature patients pose complex challenges due to the need for resection with safe margins while preserving joint function and growth potential. This study aims to evaluate the functional, radiological, and oncological outcomes, along with the complications, of biological reconstruction using free vascularized epiphyseal fibular autograft (FVEFG) following resection of proximal humerus primary malignant tumors in pediatric patients. Ten patients (mean age: 10 years; range: 5-14) who underwent proximal humeral reconstruction with FVEFG between 2001 and 2022 were retrospectively analyzed. All patients had a minimum of 24 months of follow-up (mean: 39 months). Radiological outcomes were evaluated using the ISOLS scoring system, Boer and Wood index, and the annual graft growth rate. Functional results were assessed with the MSTS and TESS scoring systems. Oncological status and complications were also recorded. The mean ISOLS radiographic score was 85%, Boer and Wood hypertrophy index was 68%, and the mean annual longitudinal growth was 4.7 mm/year. The average MSTS and TESS scores were 76.9% and 83%, respectively. One patient developed local recurrence, and one died of distant metastasis. No infections or non-unions were observed. Graft fracture occurred in 3 patients (30%), with successful healing in all. Peroneal nerve palsy (transient) occurred in two cases. No patient required conversion to non-biological reconstruction or amputation. FVEFG is a reliable biological reconstruction technique for proximal humerus osteoarticular defects following resection of primary malignant tumors in skeletally immature patients, yielding favorable functional and radiological outcomes with a relatively low complication rate. The technique preserves longitudinal growth potential and articular surface function. Meticulous graft harvesting and fixation techniques are essential for minimizing complications.
antibodies
2026-09-11 | Exploring New Frontiers in Osteosarcoma Treatment: Clinical Trial Insights.
Osteosarcoma (OS) is a common bone malignancy in adolescents and older adults and typically develops in the long bones. Outcomes in advanced cases remain poor despite the use of chemotherapeutic drugs like doxorubicin, methotrexate, and cisplatin, underscoring the urgent need for safer, more focused treatments. A comprehensive review of clinical trials and literature identified emerging OS therapies targeting DNA repair, immune pathways, and tumor-specific markers. The EMA's approval of Mepact for nonmetastatic OS underscores the shift toward precision treatments and the evolving landscape of OS management. Patent protection can influence the pricing and accessibility of innovative medicines for OS by affecting market exclusivity and competition. According to recent research, bone morphogenetic protein (BMP), RB, and TP53 gene alterations both contribute to the development of OS. These results highlight the importance of conducting further proteomic and genomic research in order to develop focused and efficient treatment plans. Furthermore, patent protection stimulates innovative drug development by encouraging research investment and faster launches, but restricts affordability due to exclusivity, posing a policy dilemma. Treatment for OS is still challenging, particularly in high-grade and metastatic cases when conventional chemotherapy is frequently harmful and unsuccessful. While new targeted medicines and advances in understanding bone cell dynamics and genetic abnormalities such as TP53, RB, and BMPs offer hope for more accurate, less invasive treatments, the approval of Mapact represents progress. The necessity for integrated therapies combining immunotherapy, targeted delivery, and molecular insights to enhance OS treatment results is highlighted by developments in genomics and bone remodeling.
2026-08-04 | GD2-targeted immunotherapy in pediatric bone sarcomas: a systematic review of emerging strategies and combination approaches
Introduction Primary bone sarcomas, including Osteosarcoma (OS) and Ewing sarcoma (ES), are rare pediatric malignancies with limited therapeutic advances over recent decades and poor outcomes, especially for patients with metastatic and refractory/relapsed disease. Disialoganglioside 2 (GD2) has emerged as a promising immunotherapeutic target due to its high expression in pediatric bone sarcomas and its role in tumor progression and treatment resistance. This systematic review summarizes current evidence on GD2-targeted therapies and combination strategies in pediatric bone sarcomas. Methods A systematic review was conducted according to PRISMA 2020 guidelines using PubMed, Embase, Web of Science, and ClinicalTrials.gov. Preclinical and clinical studies investigating GD2-targeted therapies in pediatric bone sarcomas were included, together with registered clinical trials. Results Twenty-six studies met inclusion criteria, including 17 preclinical and 9 clinical studies, alongside 15 ongoing clinical trials. Preclinical evidence consistently demonstrated antitumor activity of GD2-directed approaches, including monoclonal antibodies (mAbs), CAR-T cells, bispecific antibodies, and radio-immunotherapy. Combination strategies, particularly anti-GD2 mAbs with chemotherapy, enhanced antitumor efficacy through induction of apoptosis, activation of endoplasmic reticulum stress pathways, and inhibition of tumor invasiveness. Clinical evidence, although limited and heterogeneous, suggested encouraging activity of Dinutuximab beta-based chemo-immunotherapy, especially in ES. Several clinical trials are ongoing, mainly early-phase and focusing on relapsed or refractory diseases. Discussion GD2 represents a biologically relevant and clinically promising target in pediatric bone sarcomas. However, major translational challenges remain, including limited clinical data, heterogeneous study designs, and the lack of standardized assays for GD2 expression assessment. Further collaborative international studies are needed to optimize patient selection and accelerate the development of GD2-targeted combination immunotherapy strategies.
2026-06-26 | Exploring the Role of CD44 in the Progression and Invasion of Chondrosarcoma.
Objectives: Chondrosarcoma is the most common type of primary bone sarcoma in adults with a high risk of local recurrence and metastasis. Chondrosarcomas are largely resistant to chemotherapy and radiotherapy, meaning that surgery is the mainstay of treatment for most patients. Therefore, new therapeutic targets are required. Cluster of differentiation 44 (CD44) is a transmembrane protein that has roles in cell proliferation, adhesion and migration and is shown to be overexpressed in several cancer types. Consequently, this work was undertaken to understand whether CD44 could be a potential therapeutic target in chondrosarcoma. Methods: In this study, tissue sections from chondrosarcoma patients were evaluated for CD44 expression using immunohistochemical analysis. The relationship between CD44 expression in the patient tissue and overall and event-free survival was investigated. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing was used to generate a CD44 knockout chondrosarcoma cell line which was used for a spheroid invasion assay to understand the role of CD44 in chondrosarcoma cell invasion. Results: Cox multivariate analysis of CD44 expression in chondrosarcoma patient tissue revealed that high CD44 expression was linked to decreased overall (p < 0.01) and event-free survival (p < 0.01). The observed invasion of CD44 knockout cells in the spheroid assay was less than that of the wild type cells (p < 0.001). Conclusions: The increased expression of CD44 in intermediate and high grade chondrosarcomas, as well as reduced invasion of CD44 knockout cells suggests that CD44 plays an important role in chondrosarcoma progression and metastasis. These findings support further investigation of CD44 as an imaging and/or therapeutic target for the management of chondrosarcoma.
2026-06-07 | B7-H3 membranous expression correlates with histological grading in a two-center cohort of 133 pre-treatment bone and soft tissue sarcoma samples.
B7-H3 targeted therapies are an upcoming promising treatment option for a variety of solid tumors. High levels of B7-H3 expression have only been reported for a few sarcoma subtypes in previous studies, but a systematic analysis in an untreated sarcoma cohort and across many different sarcoma subtypes has not yet been conducted. One hundred thirty-three sarcoma samples of previously untreated patients from different sarcoma entities including soft tissue sarcoma (STS, n = 103) and bone sarcoma (BS, n = 30) were collected from two sarcoma centers in South-West Germany. Samples were centrally immunohistochemically stained and assessed for membranous B7-H3 expression. For further analysis of B7-H3 expression, H-Scores were calculated. Baseline characteristics such as sex, age, histology, grading, staging as well as outcome data like treatments, event-free and overall survival were collected. B7-H3 was found to be broadly expressed (97%) across all tested sarcoma subtypes, with only four samples (3%) without B7-H3 expression. 45% of all samples had low (H-Score 1-100), 33% intermediate (H-Score 101-200) and 19% high (H-Score 201-300) membranous B7-H3 expression. Highest expression was found in pleomorphic liposarcoma (median 202.5), osteosarcoma (median 175) and angiosarcoma (median 167.5), whereas expression was lowest in myxoid and well differentiated liposarcoma (medians 44.5 & 62.5) and chondrosarcoma (median 60). H-Scores were found to significantly correlate positive with histological grading irrespective of histological sarcoma subtype. Pre-treatment B7-H3 H-Scores did predict event-free but not overall survival. B7-H3 is a promising treatment target in sarcomas as it is highly expressed particular in high grade bone and soft tissue sarcomas, such as pleomorphic liposarcomas and osteosarcomas.
2026-05-27 | Overall survival analysis of a heavily pretreated population of patients with bone sarcomas treated with mecbotamab vedotin, a conditionally binding ADC targeting AXL.
11511 Background: Patients with metastatic bone sarcomas continue to lack effective therapies. AXL, a cell-surface receptor tyrosine kinase, is highly expressed in bone sarcoma subtypes and has been shown to drive increased metastasis, resistance to chemotherapy, and poor outcomes. Mecbotamab vedotin (Mec-V, BA3011, Conditionally Active Biologic CAB-AXL-ADC) is designed to reduce off-tumor toxicity and improve pharmacokinetics by conditionally binding to AXL under low-pH conditions (pH<6.7) of the tumor microenvironment. Methods: A phase 1/2 open-label study evaluated Mec-V among adult and adolescent patients with AXL-expressing locally advanced, unresectable, or metastatic osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma with measurable disease by RECIST v1.1. Patients received Mec-V monotherapy intravenously 1.8 mg/kg every 2 weeks (Q2W). Results: This report focuses upon the long term follow up among 33 patients treated with Mec-V with osteosarcoma (n=13), Ewing (n=9), chondrosarcoma (n=8) or chordoma (n=3). Patients received a median of 2 prior lines of treatment. Most related treatment-related adverse events (TEAE) in patients with bone sarcomas were low grade (64%) and reversible; the most common related grade 3/4 TEAE of special interest was neutropenia (18%). No grade 5 TEAE were observed. As of March 25, 2025, disease control rate (DCR) was 100% among patients with chondrosarcoma and chordoma. In patients with osteosarcoma and Ewing sarcoma, DCR was 50% with 3 confirmed responses (14%; osteosarcoma n=2, Ewing n=1). The median OS with Mec-V for all bone sarcoma patients was 17.6 months. Observed median OS by tumor type in months: osteosarcoma (11.9 [95% CI: 3.2-Not Estimable (NE)]), Ewing sarcoma (19.4 [95% CI: 5.2–NE]), chondrosarcoma (NE [95% CI: 16.3-NE]), and chordoma (15.1 [95% CI: 7.2-NE]). Conclusions: Patients with treatment refractory bone sarcomas treated with Mec-V monotherapy achieved a median OS of 17.6 months which compares favorably to reported outcomes with other therapies including combination therapies. Mec-V monotherapy holds considerable promise for these high unmet need indications with potential increased benefit when used in combination. Clinical trial information: NCT03425279 .
oligonucleotides
2024-07-03 | miR-488-3p Represses Malignant Behaviors and Facilitates Autophagy of Osteosarcoma Cells by Targeting Neurensin-2.
Osteosarcoma (OS) is a primary bone sarcoma that primarily affects children and adolescents and poses significant challenges in terms of treatment. microRNAs (miRNAs) have been implicated in OS cell growth and regulation. This study sought to investigate the role of hsa-miR-488-3p in autophagy and apoptosis of OS cells. The expression of miR-488-3p was examined in normal human osteoblasts and OS cell lines (U2OS, Saos2, and OS 99-1) using RT-qPCR. U2OS cells were transfected with miR-488- 3p-mimic, and cell viability, apoptosis, migration, and invasion were assessed using CCK-8, flow cytometry, and Transwell assays, respectively. Western blotting and immunofluorescence were employed to measure apoptosis- and autophagy-related protein levels, as well as the autophagosome marker LC3. The binding sites between miR-488-3p and neurensin-2 (NRSN2) were predicted using online bioinformatics tools and confirmed by a dual-luciferase assay. Functional rescue experiments were conducted by co-transfecting miR-488-3p-mimic and pcDNA3.1-NRSN2 into U2OS cells to validate the effects of the miR-488-3p/NRSN2 axis on OS cell behaviors. Additionally, 3-MA, an autophagy inhibitor, was used to investigate the relationship between miR- 488-3p/NRSN2 and cell apoptosis and autophagy. miR-488-3p was found to be downregulated in OS cell lines, and its over-expression inhibited the viability, migration, and invasion while promoting apoptosis of U2OS cells. NRSN2 was identified as a direct target of miR-488-3p. Over-expression of NRSN2 partially counteracted the inhibitory effects of miR-488-3p on malignant behaviors of U2OS cells. Furthermore, miR- 488-3p induced autophagy in U2OS cells through NRSN2-mediated mechanisms. The autophagy inhibitor 3-MA partially reversed the effects of the miR-488-3p/NRSN2 axis in U2OS cells. Our findings demonstrate that miR-488-3p suppresses malignant behaviors and promotes autophagy in OS cells by targeting NRSN2. This study provides insights into the role of miR-488-3p in OS pathogenesis and suggests its potential as a therapeutic target for OS treatment.
2024-03-29 | MicroRNAs as Prognostic Biomarkers and Therapeutic Targets in Chondrosarcoma.
Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes.
2023-08-31 | MiR-4270 acts as a tumor suppressor by directly targeting Bcl-xL in human osteosarcoma cells
Chondrosarcomas and osteosarcomas are malignant bone tumors with a poor prognosis when unresectable or metastasized. Moreover, radiotherapy and chemotherapy could be ineffective. MiRNAs represent an alternative therapeutic approach. Based on high-throughput functional screening, we identified four miRNAs with a potential antiproliferative effect on SW1353 chondrosarcoma cells. Individual functional validations were then performed in SW1353 cells, as well as in three osteosarcoma cell lines. The antiproliferative and cytotoxic effects of miRNAs were evaluated in comparison with a positive control, miR-342-5p. The cytotoxic effect of four selected miRNAs was not confirmed on SW1353 cells, but we unambiguously revealed that miR-4270 had a potent cytotoxic effect on HOS and MG-63 osteosarcoma cell lines, but not on SaOS-2 cell line. Furthermore, like miR-342-5p, miR-4270 induced apoptosis in these two cell lines. In addition, we provided the first report of Bcl-xL as a direct target of miR-4270. MiR-4270 also decreased the expression of the anti-apoptotic protein Mcl-1, and increased the expression of the pro-apoptotic protein Bak. Our findings demonstrated that miR-4270 has tumor suppressive activity in osteosarcoma cells, particularly through Bcl-xL downregulation.
2023-06-30 | Functional Role of RBP in Osteosarcoma: Regulatory Mechanism and Clinical Therapy
Malignant bone neoplasms can be represented by osteosarcoma (OS), which accounts for 36% of all sarcomas. To reduce tumor malignancy, extensive efforts have been devoted to find an ideal target from numerous candidates, among which RNA-binding proteins (RBPs) have shown their unparalleled competitiveness. With the special structure of RNA-binding domains, RBPs have the potential to establish relationships with RNAs or small molecules and are considered regulators of different sections of RNA processes, including splicing, transport, translation, and degradation of RNAs. RBPs have considerable significant roles in various cancers, and experiments revealed that there was a strong association of RBPs with tumorigenesis and tumor cell progression. Regarding OS, RBPs are a new orientation, but achievements in hand are noteworthy. Higher or lower expression of RBPs was first found in tumor cells compared to normal tissue. By binding to different molecules, RBPs are capable of influencing tumor cell phenotypes through different signaling pathways or other axes, and researches on medical treatment have been largely inspired. Exploring the prognostic and therapeutic values of RBPs in OS is a hotspot where diverse avenues on regulating RBPs have achieved dramatical effects. In this review, we briefly summarize the contribution of RBPs and their binding molecules to OS oncogenicity and generally introduce distinctive RBPs as samples. Moreover, we focus on the attempts to differentiate RBP’s opposite functions in predicting prognosis and collect possible strategies for treatment. Our review provides forwards insight into improving the understanding of OS and suggests RBPs as potential biomarkers for therapies.
2023-05-29 | The promising roles of exosomal microRNAs in osteosarcoma: A new insight into the clinical therapy.
Osteosarcoma is the most common malignant bone sarcoma in children. Chemotherapy drugs resistance significantly hinders the overall survival of patients. Due to high biocompatibility and immunocompatibility, exosomes have been explored extensively. Multiple parent cells can actively secrete numerous exosomes, and the membrane structure of exosomes can protect miRNAs from degradation. Based on these characteristics, exosomal miRNAs play an important role in the occurrence, development, drug resistance. Therefore, in-depth exploration of exosome biogenesis and role of exosomal miRNAs will provide new strategies and targets for understanding the pathogenesis of osteosarcoma and overcoming chemotherapy drug resistance. Moreover, advancing evidences have showed that engineering modification could attribute stronger targeting to exosomes to deliver cargos to recipient cells more effectively. In this review, we focus on the mechanisms of exosomal miRNAs on the occurrence and development of osteosarcoma and the potential to function as tumor biomarkers for diagnosis and prognosis prediction. In addition, we also summarize recent advances in the clinical application values of engineering exosomes to provide novel ideas and directions for overcoming the chemotherapy resistance in osteosarcoma.
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2026-05-27 | First-in-human dose escalation trial of an engineered salmonella delivering L-methioninase in advanced bone and soft tissue sarcomas.
11530 Background: Advanced bone and soft-tissue sarcomas have limited treatment options. Tumor-selective methionine dependency is a known metabolic vulnerability. SGN1 is designed to deplete methionine locally within tumors via intratumoral colonization of an attenuated Salmonella vector expressing L-methioninase. Preclinical studies have demonstrated safety and targeted antitumor activity. Here, we report the results from the escalation and expansion phases of the Phase I study in patients (pts) with advanced bone and soft-tissue sarcomas. Methods: The Phase I study includes a dose-escalation phase where pts received intravenous (IV) (2.0×10⁸ to 4.0×10⁸ CFU) or intra-arterial (IA) infusion (2.0×10⁸ to 6.0×10⁸ CFU) once a week (QW) in 28-day cycles, followed by an expansion phase with the putative recommended Phase 2 dose (RP2D) (2.0×10⁸ CFU for IV or 6.0×10⁸ CFU for IA QW) in 6 cohorts, including pts with recurrent either bone or soft tissue sarcoma after at least 2 lines of chemo therapies. SGN1 was administered in combination with physician's choice systemic therapy. Administration of SGN1 was via one of three routes: IV, IA, or a combined IV/IA regimen. Efficacy was assessed by RECIST version 1.1. Results: At the cut-off of Aug 19, 2024, 25 pts with advanced bone and soft-tissue sarcomas were enrolled in the escalation and expansion phases (median follow-up of 5.6 months; range, 0.5-18.2), including pts with bone sarcoma (n=10) and soft tissue sarcoma (n=15). Treatment was administered via IV (n=13), IA (n=8), or a combined IV/IA (n=4) route. The disease control rate (DCR) was 76.0% (95% CI: 56.5, 93.0) in all, 70.0% (95% CI: 34.8, 93.3) in bone sarcoma, 80.0% (95% CI: 52.0, 95.6) in soft tissue sarcoma pts, and 69.2% (95% CI: 38.5, 90.9) in IV, 75.0% (95% CI: 34.8, 93.3) in IA, 100% in combined IV/IA route. Quantitative PCR analysis confirmed significant intra-tumoral colonization by SGN1 post-treatment. The median progression-free survival (mPFS) was 11.5 months (95% CI: 11.1, NE) in all, 11.1 months (95% CI: 1.1, NE) in bone sarcoma, not reached (NR) (95% CI: 3.2, NE) in soft tissue sarcoma pts, and NR (95% CI: 2.7, NE) in IV, 11.5 months (95% CI: 1.3, NE) in IA, NR (95% CI: 11.1, NE) in combined IV/IA route. Complete tumor necrosis was observed in at least two soft tissue sarcoma patients. In all pts, the most frequent treatment-related adverse events (TRAEs) were pyrexia (32.0%) and elevation of blood LDH increased (20.0%). No TRAEs leading to temporary drug discontinuation, no serious TRAEs resulting in withdrawal from the study, and no treatment-related deaths occurred. Conclusions: SGN1 exhibits a manageable safety profile, and showed encouraging clinical benefit in advanced bone and soft-tissue sarcoma, as evidenced by mPFS and DCR. The promising data from this phase I study supports further testing of SGN1 in Phase II studies. Clinical trial information: ChiCTR2400085361.
2026-03-14 | Vasculogenic Mimicry: A Potential Therapeutic Target for Chondrosarcoma Therapy.
Chondrosarcomas (ChSs) are mesenchymal chemo- and radiation-resistant tumors, representing the second most frequently diagnosed bone sarcoma after osteosarcoma and 20% of all bone sarcomas. Most of ChS patients have a good prognosis after complete surgical resection. Conversely, patients with inoperable disease, due to the tumor location or metastatic dissemination, represent a great clinical challenge due to the lack of effective therapeutic options. In this study, to the best of our knowledge, we document, for the first time in human ChS tissues, the existence of CD-31- and Podoplanin-negative vascular-like channels containing red blood cells, allowing us to hypothesize the occurrence of vasculogenic mimicry (VM) in ChSs. By using patient-derived ChS cells and a stabilized ChS cell line, we demonstrate that ChS cells are able to form in vitro tubules apparently similar to those formed by endothelial cells. Further characterization of these vessels revealed the pivotal role of the Urokinase Plasminogen Activator Receptor (uPAR) in mediating the capability of ChS cells to form VM. Finally, we provide evidence that, unlike bevacizumab, which did not exert any effect, the uPAR-derived antiangiogenic peptide RI-3 behaves as a potent inhibitor of VM.
2026-02-25 | Molecular epidemiology of the expression of urokinase plasminogen activator receptor-associated protein (uPARAP) in mesenchymal malignancies.
Sarcomas are highly heterogenous and rare malignant tumors derived from mesenchymal cells. The current standard treatments for advanced disease have low response rates and are typically associated with considerable toxicity. The aim of this study was to investigate the expression of a potential novel therapeutic target and its clinical correlation in sarcomas, namely urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180/CD280). We evaluated uPARAP expression in various sarcoma subtypes and in normal tissues using 12 tissue microarrays. Expression was assessed on immunohistochemically stained slides and scored according to staining intensity and the percentage of positive tumor cells. Clinical correlations between uPARAP expression and selected parameters (gender and sample origin) were analyzed using generalized estimating equations, and survival outcomes were evaluated with Kaplan-Meier and log-rank tests. Our results demonstrated limited uPARAP expression in normal tissues, while high expression was observed in the majority of analyzed sarcoma subtypes, particularly high (>80% of highly positive cases) in fibrosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumor, and various bone sarcomas. Based on the correlation analyses between uPARAP expression and selected clinical parameters or survival outcomes, most subtypes did not show a statistically significant association. In conclusion, this study highlights the potential of uPARAP as an innovative target for targeted treatments, such as novel antibody-drug conjugates in sarcoma.
2025-05-28 | Multicenter phase II study of anlotinib and toripalimab in patients with advanced soft tissue sarcoma (STS) and bone sarcoma (BS).
11556 Background: This multicenter phase II study aims to evaluate the efficacy and safety of anlotinib combined with toripalimab in the treatment of patients (pts) with advanced STS or BS. Methods: Pts with advanced STS or BS, 14-70 years, at least one measurable tumor lesion per RECIST 1.1 and failure or intolerance of standard systemic therapy, or no standard treatment existed, are eligible. Pts with alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) can be included as the first-line therapy. Anlotinib (12 mg/d, po, d1-14) and toripalimab (240mg, IV, d1) would be administered every 3 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety using NCI-CTCAE v4.03. Results: Between March, 2020 and November, 2024, 70 pts were enrolled, of whom 68 were evaluable for the efficacy analyses. The STS subtypes mainly included synovial sarcoma (SS, 15.7%), rhabdomyosarcoma (RMS, 8.6%), extraskeletal Ewing's sarcoma (EES, 7.1%), epithelioid sarcoma (EpS, 7.1%), leiomyosarcoma (LMS, 7.1%), ASPS (5.7%), liposarcoma (5.7%), undifferentiated sarcoma (5.7%) and others (31.4%). The BS subtypes included 2 (2.9%) osteosarcoma and 2 (2.9%) chondrosarcoma. With a median follow up of 29.1 months, partial response occurred in 19 pts: 4 with SS, 3 with ASPS, 2 with LMS, 2 with EpS, 2 with inflammatory myofibroblastic tumor, and one patient each with RMS, EES, undifferentiated sarcoma, CCS, malignant peripheral nerve sheath tumor, or desmoplastic small round cell tumor. The ORR and DCR for the entire cohort were 27.9% and 86.8%, respectively. The median PFS was 7.0 months (95% CI: 4.2-9.8). The median OS was 23.5 months (95% CI: 9.2-37.8). For the 64 efficacy-evaluable STS cohort, the ORR was 29.7% and the median PFS was 8.1 months (95% CI: 4.7-11.5). Most of the treatment-related adverse events were mild (grade 1-2). The most common grade 3/4 adverse events (AE) were hypertension (15.7%), hand-foot syndrome reaction (12.9%), and hypertriglyceridemia (7.1%). Conclusions: The combination of anlotinib and toripalimab showed good anti-tumor activity and durable efficacy in advanced STS patients, with acceptable toxicity. Clinical trial information: NCT04172805 .
2025-02-25 | TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis
Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood. Here, we studied the effects of TOMM20 overexpression and downregulation on the redox state, mitochondrial oxidative phosphorylation (OXPHOS), and tumor growth using fibrosarcoma and chondrosarcoma models. TOMM20 overexpression increased OXPHOS, NADH, and NADPH with reduced cellular reactive oxygen species (ROS). TOMM20 induced resistance to apoptosis, including with BCL-2 and OXPHOS complex IV inhibitors, but with increased sensitivity to an OXPHOS complex I inhibitor. Also, TOMM20 induced cell growth and migration in vitro and promoted tumor growth in vivo. Conversely, knocking down TOMM20 using CRISPR-Cas9 reduced cancer aggressiveness in vivo in both chondrosarcoma and fibrosarcoma mouse models. In conclusion, TOMM20 is a driver of cancer aggressiveness by OXPHOS, apoptosis resistance, and the maintenance of a reduced state.
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Drug Discovery Landscape
2 orphan drug designations for Bone sarcoma.
2 orphan drug designations for Bone sarcoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Rapamycin (mTOR) inhibitor | small molecules | FDA | Merck Sharp & Dohme Corp. | |
ifosfamide | small molecules | FDA | Bristol-Myers Squibb Company |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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