bims-myxlip 2024-12-01 papers

Issue of 2024–12–01
four papers selected by
Laura Mannarino, Humanitas Research

J Exp Clin Cancer Res. 2024 Nov 26. 43(1): 309

Mechanism of efficacy of trabectedin against myxoid liposarcoma entails detachment of the FUS-DDIT3 transcription factor from its DNA binding sites.

Ilaria Craparotta, Laura Mannarino, Riccardo Zadro, Sara Ballabio, Sergio Marchini, Giulio Pavesi, Marta Russo, Salvatore Lorenzo Renne, Marina Meroni, Marianna Ponzo, Ezia Bello, Roberta Sanfilippo, Paolo G Casali, Maurizio D'Incalci, Roberta Frapolli.

BACKGROUND: The marine drug trabectedin has shown unusual effectiveness in the treatment of myxoid liposarcoma (MLPS), a liposarcoma characterized by the expression of the FUS-DDIT3 chimera. Trabectedin elicits a significant transcriptional response in MLPS resulting in cellular depletion and reactivation of adipogenesis. However, the role of the chimeric protein in the mechanism of action of the drug is not entirely understood.
METHODS: FUS-DDIT3-specific binding sites were assessed through Chromatin Immunoprecipitation Sequencing (ChIP-Seq). Trabectedin-induced effects were studied on pre-established patient-derived xenograft models of MLPS, one sensitive to (ML017) and one resistant against (ML017ET) trabectedin at different time points (24 and 72 h, 15 days). Data were integrated with RNA-Seq from the same models.
RESULTS: Through ChIP-Seq, here we demonstrate that trabectedin inhibits the binding of FUS-DDIT3 to its target genes, restoring adipocyte differentiation in a patient-derived xenograft model of MLPS sensitive to trabectedin. In addition, complementary RNA-Seq data on the same model demonstrates a two-phase effect of trabectedin, characterized by an initial FUS-DDIT3-independent cytotoxicity, followed by a transcriptionally active pro-differentiation phase due to the long-lasting detachment of the chimera from the DNA. Interestingly, in a trabectedin-resistant MLPS model, the effect of trabectedin on FUS-DDIT3 rapidly decreased over time, and prolonged treatment was no longer able to induce any transcription or post-transcriptional modifications.
CONCLUSIONS: These findings explain the unusual mechanism underlying trabectedin's effectiveness against MLPS by pinpointing the chimera's role in inducing the differentiation block responsible for MLPS pathogenesis. Additionally, the findings hint at a potential mechanism of resistance acquired in vivo.

Keywords: Adipogenesis; Chromatin immunoprecipitation sequencing; Heterografts; Liposarcoma; Myxoid; Recombinant fusion proteins; Trabectedin

DOI: https://doi.org/10.1186/s13046-024-03228-z

Cancers (Basel). 2024 Nov 18. pii: 3858. [Epub ahead of print]16(22):

Liposarcoma: A Journey into a Rare Tumor's Epidemiology, Diagnosis, Pathophysiology, and Limitations of Current Therapies.

Emily Jonczak, Julie Grossman, Francesco Alessandrino, Crystal Seldon Taswell, Jaylou M Velez-Torres, Jonathan Trent.

Sarcomas are a heterogeneous group of neoplasms that develop from bone and soft tissue. Approximately 80% of sarcomas affect soft tissue, with liposarcoma being one of the most common types, accounting for approximately 13-20% of all soft-tissue sarcomas. Per the World Health Organization, liposarcoma can be broadly classified into four different subtypes based on histologic examination: well-differentiated liposarcoma (WDLS)/atypical lipomatous tumors (ALT), dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS), and pleomorphic liposarcoma (PLS). WDLS/ALT is the most common liposarcoma subtype, accounting for approximately 31-33% of liposarcomas; DDLS accounts for 20%; MLS accounts for 19%; and PLS, the least common subtype, represents 7-8% of liposarcomas. Sarcoma diagnosis is challenging because of its rarity, intrinsic complexity, and diagnostic technological complexity. Sarcomas are misdiagnosed in approximately 30% of cases, leading to delays in diagnosis and access to appropriate therapy and clinical trials. Furthermore, treatment options are limited for those diagnosed with liposarcoma. This review discusses the epidemiology, pathology, and treatment options currently available for liposarcoma.

Keywords: diagnosis; epidemiology; liposarcoma; pathogenesis; pathophysiology

DOI: https://doi.org/10.3390/cancers16223858

Curr Oncol. 2024 Nov 01. 31(11): 6803-6813

Trabectedin for L-Type Sarcoma: A Retrospective Multicenter Study.

Sercan Ön, Barış Köksal, Zafer Arık, Burcu Caner, Duygu Ercan Uzundal, Ozan Yazıcı, Burcu Arslan Benli, Eda Eylemer Mocan, Can Güngör, Zeynep Gülsüm Güç, Seval Akay, Merve Keskinkılıç, Hande Dik Avcı, Burçak Karaca Yayla, Burcu Çakar, Ulus Ali Şanlı.

(1) Background: Metastatic L-type sarcomas (liposarcoma and leiomyosarcoma) are rare and have a poor prognosis. Trabectedin is an effective agent that can be used after anthracyclines. This study was designed to evaluate the real-life effectiveness and safety of trabectedin. (2) Methods: A retrospective multicenter study was conducted on patients who were treated with trabectedin for metastatic L-type sarcomas at ten tertiary oncology centers between 2015 and 2023. The objective response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and overall survival (OS) were evaluated in the cohort. Cox regression analysis was used to determine prognostic factors for survival. (3) Results: A total of 98 patients (52% liposarcoma and 48% leiomyosarcoma) were included in the study. The median treatment line was three (range: 1 to 6). Thirteen patients (13.3%) underwent local treatment due to oligoprogression, and dose reduction was required in seventeen patients (17.3%) due to toxicity. The ORR and DCR were 16% and 42%, respectively. The median TTF was 3 months, and the median OS was 10 months. In univariate analysis, a significantly longer median TTF was observed in patients who underwent local treatment (p = 0.008), obtained objective responses (p < 0.001), and underwent dose reduction (p = 0.002). No statistical differences were observed according to the histologic subtype and metastatic site. In the multivariate analysis for OS, it was found that obtaining an objective response was a good prognostic factor (p = 0.003), while the presence of liver metastases was associated with a poor prognosis (p = 0.016). (4) Conclusion: Trabectedin is a suitable option for L-type sarcoma after doxorubicin-based treatments. Survival was not worse in patients who underwent dose reduction. The use of local therapies simultaneously with trabectedin can be effective.

Keywords: drug toxicity; ecteinascidin 743; leiomyosarcomas; liposarcomas; targeted radiation therapy; trabectedin

DOI: https://doi.org/10.3390/curroncol31110502