Synovial Sarcoma

IMCnyeso is well tolerated and, at doses ≥30 μg, induces pharmacodynamic changes consistent with T cell redirection. This study was registered at ClinicalTrials.gov (NCT03515551).

P1/2, N=27, Not yet recruiting, University of Florida | Initiation date: Feb 2025 --> Jun 2025

Adjuvant chemotherapy and radiotherapy are suggested. In advanced cases, comprehensive immunotherapy methods may be employed to enhance patient survival rates and quality of life.

P1, N=14, Active, not recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2025 --> Jan 2026

He passed away after one round of doxorubicin due to septic and obstructive shock (tamponade)...In some cases, they may present insidiously due to their sole presenting clinical manifestation being pericardial effusion. Particular care should be taken to rule out malignancy with MRI or PET-guided imaging in the AYA-aged population when idiopathic, recurrent pericardial effusion is found.

By integrating a refined analytical approach for SNVs and SVs, we achieved reliable ctDNA detection that corresponded with the clinical course of the patients' disease. This method enables non-invasive tumor detection in translocation-driven tumors with low mutational burden and can easily be adapted into routine clinical diagnostics.

Overall, manageable safety profiles and signals of efficacy have been observed, especially in patients with advanced synovial sarcoma, myxoid/round cell liposarcoma, ovarian, head and neck, and urothelial cancers, with one TCR T-cell therapy approved by the US Food and Drug Administration in August 2024. We also review the limitations, and strategies to enhance efficacy and improve safety, of these therapies, and summarize related immunotherapies targeting MAGE-A4.

Having its expression profile limited to germline cells has made MAGE A4 a sought-after immunotherapeutic target in certain malignancies. In this review, we focus on MAGE-A4's function and expression, current clinical trials involving targeted immunotherapy approaches, and challenges and opportunities facing MAGE-A4's targeted therapeutics.

Histopathology revealed cellular spindle cell tumour arranged into interlacing fascicle, Immunohistochemistry analysis revealed a positive TLE-1, CD99, B-cell lymphoma 2 (BLC2), Focal cytokeratin and focal epithelial membrane antigen (EMA). In our case, the patient was aggressively treated with two surgical resections and still progressed and metastasized and continued progressing even after different chemotherapy regimens.

P1/2, N=58, Active, not recruiting, Epizyme, Inc. | Enrolling by invitation --> Active, not recruiting | N=100 --> 58

The sensitivity and specificity of strong SOX11 expression in differentiating MPNST from its mimickers were 70 % and 73 %, respectively. In conclusion, the diagnostic utility of SOX11 expression for MPNST is limited, but the absence of significant SOX11 expression in benign/atypical nerve sheath tumors is interesting and deserves further investigation.

RSS, though rare, should be part of the differential diagnosis for spindle cell tumors in this location. Morphology, aided by thorough immunohistochemical and molecular analyses, is crucial to avoid diagnostic errors and improve patient outcomes.

Accurate diagnosis of SS is crucial for effective management. Clinicians should be aware of negative predictive factors, including tumor volume >30 cm³ and poor histologic differentiation, when making treatment decisions. The study highlights the importance of extended follow-up due to the risk of late recurrence.

P2, N=28, Recruiting, University Hospital Heidelberg | Not yet recruiting --> Recruiting | Initiation date: Sep 2024 --> Dec 2024

P2, N=52, Active, not recruiting, Adaptimmune | Recruiting --> Active, not recruiting | N=120 --> 52

Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma...The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale.

The research deepens our understanding of the tumor immune microenvironment and proposes a new immune mechanism for metastatic SS. Early intervention and reversal of immunosuppressive microenvironmental changes are expected to delay metastasis and improve survival.

P1, N=55, Not yet recruiting, Medigene AG

Together these data demonstrate that biphasic synovial sarcoma is immunologically different from monophasic synovial sarcoma and might be more susceptible to immunotherapies such as adoptive T-cell therapy. Finally, T-cell infiltration in primary synovial sarcoma was associated with prolonged overall survival of patients which suggests that intratumoral T cells may demonstrate anti-tumor activity.

Thus, the TYK2/STAT3/Bcl2 axis is a crucial mechanism through which SS18-SSX mediates apoptosis evasion in SS cells. In conclusion, our findings contribute to understanding how SS18-SSX-driven TYK2 expression mediates apoptosis evasion mechanisms and propose targeting TYK2 as a strategy to induce apoptosis in SS.

ORR and PFS were highly variable across sarcoma histologic subtype. In this large analysis, KS, ASPS, AS, MFS, and UPS demonstrated the highest ORR and longest PFS while osteosarcoma, SS, and LPS had the lowest ORR and shortest PFS. PD-L1 expression was also associated with increased ORR. Our findings provide further insight into understanding the sarcoma histologic and immunologic factors that correspond with response to ICIs.

P=N/A, N=167, Completed, Taproot Health | Recruiting --> Completed | N=100000 --> 167 | Trial completion date: Oct 2031 --> Oct 2024 | Trial primary completion date: Oct 2029 --> Oct 2024

P1, N=49, Terminated, C4 Therapeutics, Inc. | Phase classification: P1/2 --> P1

FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The MTDs were identified (40 mg BIW/80 mg QW) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.

Primary intracranial DICER1-mutant sarcoma is a rare tumor. Understanding its morphological characteristics, immunohistochemical and molecular markers and differential diagnosis is crucial to avoid misdiagnosis and to improve diagnostic accuracy of this tumor.

Furthermore, treatment with CBP/p300 dual inhibitor suppressed the growth of xenografts derived from SMARCA4/SMARCA2-deficient and SS18-SSX fusion cancer cells, resulting from repression of KREMEN2 and induction of apoptosis. Thus, CBP/p300 dual inhibitors could be promising for SMARCA4/SMARCA2-deficient lung cancer and SS18-SSX fusion synovial sarcoma, which are entirely deficient in the cBAF complex.

P2, N=87, Active, not recruiting, Adaptimmune

Exposure to GSK343 or ATRA results in inhibition of cell proliferation and induction of cellular senescence, where GSK343 shows a dominant effect. The Figure was created with Biorender.com.

While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility.

Treatment of synovial sarcoma typically comprises local surgery, radiotherapy and chemotherapy, while novel managements such as immunotherapy, targeted therapies and epigenetic modifiers are explored. This review focuses on the recent studies of SS18-SSX fusion gene, epigenetic landscape, signaling pathways, diagnostic techniques, and relevant therapeutic advances, aiming to inhibit the oncogenic processes and improve outcomes for patients with synovial sarcoma.

Furthermore, FANCI overexpression partially reversed the effects of SSX2IP knockdown on cell proliferation and metastasis. In summary, our findings revealed that SSX2IP contributes to the progression of breast cancer by regulating FANCI, hinting at its potential as a novel biomarker and therapeutic target for the treatment of breast cancer.

Our findings indicated that tyrosine kinase receptors are upregulated in NRSTS and exhibited a distinct expression pattern within various subgroups. High expression of VEGFR2 and PDGFRα significantly correlated with reduced survival and may guide targeted therapy approaches for this poor prognosis group of patients.

Taken together, the data shows that (1) lurbinectedin combined with ipilimumab and nivolumab is a safe regimen with a MTD of 3.2 mg/m2 for lurbinectedin and (2) there were no serious treatment related adverse events reported. The Phase 2 part of the study is currently open for previously untreated patient enrollment.

DDR pathway alterations are present in numerous histologic subtypes of sarcoma. In many subtypes, DDR pathway-altered tumors were found to have increased rates of PD-L1+, dMMR/MSI-high, and TMB-high biomarkers commonly used to identify patients who may benefit from immunotherapy. Further studies to validate these associations are needed associations and could lead to a novel clinical trial exploring the use of immune checkpoint inhibitors in DDR-mutated sarcoma.

The patient received two cycles of neoadjuvant doxorubicin and ifosfamide, radical surgery and one cycle of adjuvant doxorubicin and ifosfamide. Mutations and fusions may be detected in patients with sarcoma using the TSO500 HT assay and total RNA sequencing. Furthermore, it is feasible to detect patient-specific TP53 ctDNA with ddPCR, and the plasma levels detected corresponded to the clinical picture observed in each patient.

Consequently, this leads to the downregulation of tumor suppressor genes occupied by SS18 physiologically, like CAV1 and DAB2. These results reveal the underlying mechanism of genomic disorder and tumorigenesis caused by the remodeling of oncoprotein SS18-SSX1 condensates at the macroscopic level.

Novel approaches to treating synovial sarcoma include immune-based therapies (such as TCR-T cell therapy to NY-ESO-1, MAGE4, PRAME or using immune checkpoint inhibitors), epigenetic modifiers (HDAC inhibitors, EZH2 inhibitors, BRD disruptors), as well as novel or repurposed receptor tyrosine kinase inhibitors. In the presented review, we aimed to summarize the genetic and epigenetic landscape of SS as well as to find out the potential niches for the development of novel diagnostics and therapies.

SS18-SSX-positive staining may be used as a surrogate for FISH assay in a resource-limited setting where molecular assay is not available. Furthermore, IHC has a fairly shorter turn-around-time, is less complex, and of low cost.

P2, N=7, Active, not recruiting, Adaptimmune | Trial completion date: Jul 2024 --> Jul 2025

We identified three unique sarcoma cell cycle phenotypes that have prognostic significance. This performs similarly to the AJCC staging system.

In August 2024, afamitresgene autoleucel was approved in the USA under accelerated approval for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P or -A*02:06P positive and whose tumour expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This article summarizes the milestones in the development of afamitresgene autoleucel leading to this first approval for the treatment of advanced synovial sarcoma.

Our study identifies SUMO2 as a selective dependency in synovial sarcoma. We demonstrate that the SUMO2/3 inhibitor TAK-981 impairs sarcomagenesis and reverses the SS18-SSX fusion-driven oncotranscriptome. Our study indicates that SUMO2 inhibition may be an attractive therapeutic option in synovial sarcoma.