RARE DISEASE
Dedifferentiated liposarcoma
Dedifferentiated liposarcoma
Dedifferentiated liposarcoma
Synonyms: DDLS
Synonyms: DDLS
Synonyms: DDLS
Drug discovery
1
drug
With orphan designation
Overview
Dedifferentiated liposarcoma (DDLPS) is a high-grade sarcoma arising from well-differentiated liposarcoma or atypical lipomatous tumors, characterized by 12q13-15 amplification (MDM2/CDK4). It typically occurs in the retroperitoneum or extremities, with aggressive local recurrence (up to 70%) and metastatic potential (15-30%). Diagnosis relies on histopathology and molecular confirmation of MDM2 overexpression. Surgical resection remains cornerstone treatment, but systemic therapies (anthracycline-based regimens, targeted agents) show limited efficacy in advanced disease. Median overall survival for metastatic cases is 15-29 months. [1][3][6][10][16]
Burden
5-year survival: 44% overall, <30% for retroperitoneal tumors [6][10][16]
High symptom burden from mass effects (70% retroperitoneal cases) [4][7][16]
Requires median 2-3 systemic therapy lines in advanced stages, with 4.6-month median PFS for first-line chemotherapy [1][4][10]
Citations embedded per sentence relevance [sources 1-18]
Therapies
Localized disease: Wide surgical resection ± radiotherapy (extremity tumors) [1][7][12]
Advanced disease: Doxorubicin-based first-line therapy (12-20% response rate); clinical trials evaluating MDM2 inhibitors (selinexor, milademetan) and CDK4 inhibitors (abemaciclib) [3][7][13][16]
Emerging focus on biomarker-driven approaches (CTDSP1/2-DNM3OS fusion detection) [1][3]
Categories: rare neoplastic diseases
Research Papers
829 drug discovery papers about Dedifferentiated liposarcoma, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
829 drug discovery papers about Dedifferentiated liposarcoma, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Antitumor activity of novel transcriptional inhibitors ecubectedin and PM54 in soft tissue sarcoma patient-derived xenografts.
Trabectedin, prototype of the ecteinascidin class of drugs, is a known second or later line therapeutic option for advanced soft tissue sarcoma (STS). We evaluated the antitumor activity of two novel synthetic trabectedin derivatives, ecubectedin and PM54, in selected patient-derived xenograft (PDX) STS models. In total 364 NMRInu/nu mice were transplanted bilaterally with two leiomyosarcoma (LMS), two dedifferentiated liposarcoma (DDLPS), one synovial sarcoma (SynSa) and one CIC-rearranged sarcoma (CRS) PDX models. Mice were randomized to six groups and treated via tail vein injection with 1) vehicle, 2) doxorubicin, 3) trabectedin, 4) lurbinectedin, 5) ecubectedin, or 6) PM54. Treatment was given on days 1, 8 and 15, and mice were sacrificed on day 16. The SynSa experiment included extra mice to investigate post-treatment xenograft evolution. Antitumor activity was assessed by tumor volume measurement, histopathologic and immunohistochemical analysis. In all LMS and DDLPS models, ecubectedin and PM54 led to tumor growth delay compared to trabectedin. Histopathological evaluation of treated tumors showed moderately increased antitumor activity of novel ecteinascidins compared to trabectedin. The CRS showed tumor shrinkage in response to ecubectedin (63% regression from baseline) and PM54 (24% regression from baseline) while the SynSa showed tumor volume stabilization. Both translocation-related models showed significant antitumor effect on histopathological evaluation in response to the novel drugs, compared to trabectedin. Ecubectedin and PM54 have modest antitumor activity in STS PDX models, with the strongest effects seen in the translocation-related sarcoma models, showing the potential of this class of drugs in treatment of STS.
2026-08-10 | Extracellular vesicle-mediated suppression of macrophage STING signaling promotes immune dysfunction in dedifferentiated liposarcoma
Abstract Background Dedifferentiated liposarcoma (DDLPS) is characterized by abundant immune cell infiltration yet derives limited benefit from immune checkpoint blockade and stimulator of interferon genes (STING) agonist-based strategies, suggesting tumor-mediated suppression of antitumor immunity. Tumor-associated macrophages are the most abundant immune populations in DDLPS, but the factors regulating their function remain incompletely understood. Methods Extracellular vesicles (EVs) were isolated from two DDLPS cell lines and serum from 16 DDLPS patients and 13 healthy donors. EVs’ impact on cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) -induced macrophage activation was assessed by cytokine secretion, surface markers, functional assays and macrophage-T-cell coculture. Proteomics was performed in EV-treated and EV-untreated macrophages from three donors. Pathway and protein interaction analyses were integrated with The Cancer Genome Atlas (TCGA) DDLPS transcriptomic and survival data. Results We show that EVs released by DDLPS cells suppress macrophage responsiveness to classic STING agonist cGAMP. EVs derived from DDLPS attenuated cGAMP-induced expression of type I interferon-associated cytokines and chemokines, reduced IFN-β secretion, and impaired phosphorylation of STING, TBK1 and IRF3. Functionally, DDLPS EV exposure shifted macrophages toward an immunoregulatory phenotype, restrained phagocytic activity, and attenuated macrophage-dependent T-cell proliferation while promoting T-cell exhaustion. Proteomic profiling revealed extensive macrophage reprogramming characterized by suppression of STING-associated signaling, antigen processing and presentation associated pathways and proteins targeted by miR-16-5p. Consistent with these findings, STING expression was associated with prolonged overall survival in DDLPS, while reduced expression of miR-16-5p target proteins was associated with attenuated STING pathway activity and immunostimulatory macrophage signatures. Conclusions These findings identify EV-mediated suppression of macrophage STING signaling as a mechanism of immune dysfunction in DDLPS and provide a framework for understanding immune resistance in this disease.
2026-06-29 | A multi-platform genomic analysis of paired well- and dedifferentiated liposarcoma identifies recurrent genomic alterations associated with progression and recurrence
Processed multi-platform genomic data for Crago et al., "A multi-platform genomic analysis of paired well- and dedifferentiated liposarcoma identifies recurrent genomic alterations associated with progression and recurrence (manuscript in preparation). The cohort spans 349 tumor specimens from 162 patients (1994–2013): 152 well-differentiated and 162 dedifferentiated liposarcomas with 35 normal-fibroblast controls. Included are Affymetrix HG-U133A tumor and cell-line expression matrices, array CGH segmentation lesions and event calls, VEP/FACETS-annotated whole-exome somatic MAF, RNA-seq gene counts, miRNA target predictions, sample annotations.
2026-06-25 | Transcriptomic Signatures Associated with Doxorubicin Treatment in Liposarcoma Reveal Coordinated Regulatory Patterns.
Background/Objectives: Liposarcoma is a heterogeneous soft tissue sarcoma in which anthracycline-based chemotherapy, including doxorubicin, remains a cornerstone of treatment for advanced disease. However, variable and often limited therapeutic responses highlight the need for improved understanding of disease-associated transcriptional adaptation under chemotherapeutic stress. In this study, a bioinformatics-driven transcriptomic analysis was performed to characterize gene expression alterations associated with doxorubicin treatment in liposarcoma using publicly available data from the Gene Expression Omnibus (GSE12972). Results: Differential expression analysis identified 365 significantly altered genes, including 164 upregulated and 201 downregulated transcripts in treated samples compared with untreated controls. Functional interpretation using Ingenuity Pathway Analysis identified transforming growth factor beta 1 (TGFB1), tumor necrosis factor (TNF), and SMARCA4 as prominent predicted upstream regulators associated with transcriptional programs related to extracellular matrix remodeling, inflammatory and immune modulation, epithelial-to-mesenchymal transition-like states, and chromatin-mediated transcriptional plasticity. Enriched canonical pathways included Liposarcoma tumor microenvironment-associated signaling and fibrosis-related pathways, reflecting stromal activation and immune-related transcriptional changes. Notably, fibroblast growth factor 1 (FGF1) emerged as a supportive regulatory node linked to survival- and anti-apoptotic gene expression patterns. Conclusions: Collectively, these findings provide a disease-oriented, cross-subtype systems-level view of the transcriptional changes associated with doxorubicin treatment in liposarcoma. This work is intended as a hypothesis-generating framework that may inform future functional studies and integrative approaches aimed at understanding therapeutic response and disease progression.
2026-06-13 | Utidelone in patients with advanced soft tissue sarcoma refractory to anthracycline and antiangiogenic therapy (UTISARC): a single-arm phase II study.
Treatment options remain limited for patients with advanced or metastatic soft tissue sarcoma after failure of both anthracycline-based chemotherapy and antiangiogenic therapy. Utidelone, an epothilone analog, has demonstrated antitumor activity across a broad spectrum of preclinical models and clinical trials. This single-arm, phase II trial was designed to assess the efficacy and safety of utidelone in a heavily pretreated population. This study enrolled patients aged 18 years or older with locally advanced or metastatic soft tissue sarcoma who had previously been treated with anthracycline-based chemotherapy and antiangiogenic tyrosine kinase inhibitors. Participants received utidelone via a 90-minute intravenous infusion at a dose of 30 mg/m² on days 1-5 of each 21-day treatment cycle, continuing until disease progression or the occurrence of unacceptable toxicity. The primary endpoint was median progression-free survival. The secondary endpoints included the objective response rate, overall survival and safety. Between August 2022 and March 2025, a total of 27 patients were included in the study. The median age was 55 years (range, 30-68). There were 15 patients with leiomyosarcoma, 3 with dedifferentiated liposarcoma, 3 with epithelioid sarcoma, 2 with angiosarcoma, and 4 with other types of sarcoma. The median number of prior systemic therapy regimens was 2 (range, 1-4). The median treatment exposure was 5 cycles (range, 1-10). Two patients achieved a partial response, resulting in an objective response rate of 7%. The median progression-free survival was 4.6 months (95% confidence interval, 3.6-5.6). Overall survival data were immature, with only 9 death events (33%) observed. The estimated 12-month overall survival rate was 80%. Most adverse events were grade 1 or 2 in severity. The most frequently observed grade ≥ 3 adverse event was peripheral neuropathy (11%). In this exploratory trial, utidelone demonstrated preliminary antitumor activity and a manageable safety profile in patients with refractory soft tissue sarcoma. Further exploration of novel combination therapies involving utidelone is warranted to enhance its clinical utility. ChiCTR2200062161, registered on July 26, 2022.
cell therapies
2026-05-28 | A pilot study of autologous tumor-infiltrating lymphocytes (LN-145) in adult patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.
e23566 Background: Advanced undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLS) are difficult to treat soft tissue sarcomas with response rates to first line systemic therapy between 10-30%. However, both UPS and DDLPS have been shown to have measurable tumor infiltrating lymphocyte (TIL) populations. LN-144 (lifileucel), an autologous TIL product derived from unresectable or metastatic melanoma, was shown to have an overall response rate (ORR) of 36% in heavily pretreated melanoma patients with a median DOR of 19.7 months. We hypothesized that generation and infusion of LN-145, an autologous TIL product from non-melanoma solid tumors, in this case UPS and DDLPS, would be both safe and feasible. Methods: NCT05607095 is a single center multi-cohort pilot trial with Cohort 2 enrolling patients with metastatic or unresectable UPS or DDLS to undergo autologous TIL therapy with LN-145. Eligible patients had to receive at least 1 prior line of systemic therapy, a lesion at least 1.5 cm in size available for TIL harvest, and adequate organ function and performance status (ECOG 0-1). After surgical excision of suitable tumor for TIL expansion, successful LN-145 product generation was determined by characteristics that meet pre-specified criteria in the LN-145 IND. Patients then underwent nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m 2 x 5 doses). LN-145 was then infused and expanded with intravenous interleukin 2 (600,000 IU/kg up to 6 doses). Primary endpoints of the trial were feasibility, defined as ³6 of 10 harvested pts undergoing LN-145 therapy, and safety, defined by the incidence of Grade ³3 adverse events (AE) as measured by CTCAE v5.0. Key secondary endpoints included estimated LN-145 manufacture rates and efficacy (ORR) utilizing RECIST 1.1. Exploratory endpoints include persistence of LN-145 cells and immune correlates in tissue and peripheral blood and their potential association with objective response and toxicity. Safety and efficacy measures will be summarized using point estimates and a Clopper Pearson exact confidence interval will be used. The final results of the primary feasibility and safety endpoints and secondary feasibility endpoint for the first 10 enrolled patients as well as and preliminary secondary efficacy and exploratory correlative studies through week 12 for 7 treated patients will be reported as late-breaking abstract after data lock on March 1, 2026. Clinical trial information: NCT05607095 .
2026-01-16 | A Huge Recurrent Atypical Lipomatous Tumor (Well-Differentiated Liposarcoma) going in to Dedifferentiation 12 years after its First Detection.
Soft-tissue sarcoma (STS) being a rare malignancy, many times it undergoes inadequate surgery at first instance, leading to higher chances of recurrence. Atypical lipomatous tumor (ALT)/well-differentiated liposarcoma frequently undergoes first inadequate surgery leading to higher recurrence rate and sometimes getting converted to higher grade malignancy like dedifferentiated liposarcoma. We had a 63-year-old female who presented with recurrent huge (dimension on final histopathology report: 29 × 24 × 11 cm) ALT of thigh after three prior surgeries over the span of 8 years. We resected it with wide margins and did a prophylactic nailing at second stage. Final histopathology report came out to be liposarcoma with foci of low-grade dedifferentiation (FNCLCC Grade 3). Patient received post-operative radiotherapy. At final follow-up of 35 months, our patient is recurrence free, doing all her daily routine activity independently. Ten percentages of the ALT dedifferentiate into dedifferentiated liposarcoma, which has 15-20% metastatic potential compared to almost nil in ALT which happened in our case. Due to this, we recommend treatment of ALT and all STS at a tertiary cancer care center by a multidisciplinary team as it requires adjuvant treatment also apart from surgery with adequate margins.
2025-12-26 | Primary dedifferentiated liposarcoma of the ovary: expanding the surgical management spectrum with a different resection extent than existing reports - a case report and literature review.
Dedifferentiated liposarcoma (DDLPS) is a relatively common type of liposarcoma, typically occurring in the retroperitoneum and limbs. It is rarely found in the female reproductive system, leading to the absence of a standard treatment protocol for primary ovarian dedifferentiated liposarcoma. This case presents a personal experience-based approach, as there is a lack of standard treatment guidelines, relying on treatment consensus for more common locations and decades of clinical experience. This case report describes a 55-year-old woman who was admitted due to a gradually enlarging mass in the right lower abdomen, accompanied by bloating and abdominal pain. Physical examination revealed a palpable abdominal mass. Gynecological ultrasound showed a hyperechoic mass measuring 135*128*91mm in the pelvic-abdominal cavity. CT imaging suggested a large cystic and solid mixed liposarcoma originating from the ovary, with unclear delineation of the uterine fundus and slight compression of surrounding organs. Pelvic MRI revealed an irregular mass approximately 10.7cm×12.6cm×12.2cm, with slightly prolonged T1 and heterogeneous T2 signals, showing fat signal in the right fatty tissue, suggesting invasion of the uterine wall by liposarcoma. The patient then underwent open surgery, and postoperative pathology with immunohistochemistry confirmed dedifferentiated liposarcoma. FISH testing was positive for MDM2, confirming the diagnosis of ovarian-origin dedifferentiated liposarcoma. Although the patient refused chemotherapy, she has been followed up every three months, and the current follow-up shows no signs of tumor recurrence. Ovarian dedifferentiated liposarcoma is an extremely rare condition, with surgery being the preferred treatment method. This report presents a rare case of ovarian dedifferentiated liposarcoma, providing a reference for clinical diagnosis and treatment. Through collaboration between gynecology, pathology, and imaging departments, the accuracy of the diagnosis and comprehensiveness of treatment were ensured. Long-term follow-up of the patient provided valuable insights into the recurrence and prognosis of the disease.
2025-11-20 | Extracellular Vesicles in Sarcoma: Implications for Tumor Progression and Therapy.
Sarcoma, a heterogeneous group of malignancies arising from mesenchymal tissues, poses significant clinical challenges due to its aggressive behavior, early metastasis, and resistance to conventional therapies. Recent advancements highlight the pivotal role of extracellular vesicles (EVs)-nanoscale particles secreted by tumor and stromal cells-in modulating sarcoma progression through intercellular communication within the tumor microenvironment. This review comprehensively examines the multifaceted functions of EVs in sarcoma pathogenesis, focusing on their subtype-specific mechanisms (eg, osteosarcoma, liposarcoma) in promoting epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion. Additionally, we discuss the emerging potential of EVs as non-invasive biomarkers for early diagnosis and prognosis, as well as their engineered applications in targeted drug delivery and immunotherapy. By integrating cutting-edge research, this article underscores the translational value of EVs in overcoming current therapeutic limitations and provides a roadmap for future investigations into EV-based precision strategies for sarcoma management.
2025-09-10 | Immunocompetent Murine Models Recapitulate the Heterogeneous Tumor-Immune Microenvironment of Human Liposarcoma.
Liposarcoma is the most common soft tissue sarcoma. Well-differentiated liposarcoma can progress to dedifferentiated liposarcoma (DDLPS), a more aggressive form with higher metastatic potential and poor response to existing therapies. Progress in understanding and treating liposarcoma has been limited. To address this, we sought to develop an immunocompetent genetically engineered mouse model of liposarcoma. We developed an autochthonous, immunocompetent liposarcoma mouse model [AAV8-Ap2.2-eGFP/Cre Ptenf/f;Trp53f/f C57BL/6 (ACPP)] by using targeted Cre-mediated deletion of Trp53 and Pten in adipocytes to mimic the signaling alterations observed in human liposarcoma. We characterized the histology, transcriptional features, and tumor microenvironment of this model. Additionally, we established syngeneic cell lines derived from ACPP DDLPS tumors and evaluated them for tumor formation, growth dynamics, and immune composition after implantation. ACPP mice develop well-differentiated liposarcoma, DDLPS, and mixed tumors, mirroring human disease. Both murine and human DDLPS tumors share key transcriptional features and exhibit heterogeneous T-cell infiltration. Syngeneic DDLPS cell lines reliably form tumors in vivo, with each line demonstrating distinct growth kinetics, aggressiveness, and immune profiles. The ACPP model provides a novel and clinically relevant platform to study liposarcoma in an immunocompetent setting. Along with the ACPP-derived cell lines, these models not only provide essential tools to understand the complex immunobiology of liposarcoma but also can be used to elucidate the underlying molecular mechanisms driving liposarcoma generation and progression and significantly accelerate the pace of preclinical studies aimed at uncovering more effective new therapies for patients with this aggressive malignancy.
antibodies
2026-08-13 | Single-cell analysis reveals the potential immunoregulatory role of C3 + malignant cell subpopulations in dedifferentiated liposarcoma
Dedifferentiated liposarcoma (DDLPS), a rare disease with limited research, exhibits resistance to radiotherapy and chemotherapy. Few reports have analyzed the tumor microenvironment of retroperitoneal undifferentiated liposarcoma using single-cell sequencing. Single-cell analysis of three retroperitoneal DDLPS cases characterized the cellular and immune microenvironment. Our findings reveal significant heterogeneity among malignant cells in DDLPS, with chromosome 6 deletions being prevalent across malignant cell subpopulations and potentially linked to reduced immunogenicity based on pathway analyses. Notably, the coexistence of CD8 + T cell exhaustion and cytotoxicity reflects a continuum of exhaustion transition. Moreover, we identify a C3 + malignant cell subpopulation with ECM remodeling, angiogenesis, and activated complement pathway. Further exploration suggested that C3 + malignant cells may recruit IL2RA+ regulatory T cells and SPP1 + macrophages through the C3-C3aR1 axis. Our findings provide new insights into the application of immunotherapy in sarcoma.
2026-08-13 | Immunotherapy in the Treatment of Soft Tissue Sarcoma Since SARC028: An NCDB Analysis.
The publication of SARC028 in late 2017 revolutionized soft tissue sarcoma (STS) treatment by demonstrating promising response to anti-PD1 immunotherapy in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). Data on immunotherapy efficacy and outcomes in larger cohorts and with longer follow-up remain limited. 31 672 cases of UPS, DDLPS, alveolar soft part sarcoma, and myxofibrosarcoma were extracted from the NCDB. Factors associated with the use of immunotherapy were evaluated using logistic regression, and survival analysis was performed with Kaplan-Meier curves and Cox proportional hazards models. Patients diagnosed with STS after 2017 were 3.67 times more likely to receive immunotherapy. Immunotherapy was associated with an approximately 20% reduction in mortality in stage IV STS, which was driven by cases of UPS. This survival benefit was observed in male, but not female, patients. There was no survival benefit in stage III STS. These data are consistent with a survival benefit with immunotherapy in stage IV STS, predominantly in UPS, supporting the findings of SARC028. Benefit in stage III STS was not observed, limiting concordance with later trials like SARC032. Further prospective data on long-term outcomes and immunotherapy efficacy according to histology and sex are needed.
2026-06-18 | Tumor-infiltrating CD8+Ki-67+ and CD8+LAG-3+ T cells are associated with improved patient survival in retroperitoneal dedifferentiated liposarcomas and leiomyosarcomas.
Tumor-infiltrating immune cells play a fundamental role in shaping patient prognosis across many cancers. Retroperitoneal dedifferentiated liposarcomas (DDLPS) and leiomyosarcomas (LMS) are associated with poor prognosis, therefore, a deeper understanding of the immune landscape in these tumors is warranted to identify novel prognostic biomarkers and immunotherapeutic targets. In this exploratory study, we analyzed spatial organization, frequency, and proportions of CD8+ T cell (including activated, proliferating, and exhausted phenotypes), T helper, and macrophage subsets, and B cells in primary treatment-naive retroperitoneal DDLPS (n = 22) and LMS tissues (n = 10) using classical and multiplex immunohistochemistry. CD8+LAG-3+ T cells comprised the highest proportion of all analyzed CD8+ subsets. Their elevated density was associated with improved overall survival (OS). Moreover, higher density of CD8+Ki-67+ T cells was linked to better OS and tended to independently predict OS. Interestingly, enhanced density of regulatory T cells was associated with favorable OS. Densities and proportions of T cell subsets did not significantly differ between DDLPS and LMS. A lower density of M2-like macrophages (CD68+CD163+) was linked to better progression-free survival (PFS) and tended to serve as an independent prognostic factor. Invasive margin revealed distinct prognostic patterns compared to tumor core, where high levels of CD8+Ki-67+TCF1+ were linked to better PFS and elevated proportions of CD8+GrzB+ and CD3+T-Bet+ T cells were associated with inferior PFS. These findings highlight the clinical relevance of immune infiltration in retroperitoneal DDLPS and LMS. Moreover, they support the rationale for further exploration of the immune architecture for prognostic biomarkers and development of targeted immunotherapeutic strategies to improve the clinical outcomes of the patients.
2026-05-21 | Tocilizumab as a novel bridging therapy for surgery in dedifferentiated liposarcoma complicated by paraneoplastic leukemoid reaction, severe anemia, and thrombocytopenia: a case report.
Dedifferentiated liposarcoma (DDLPS) is a malignant mesenchymal tumor. While paraneoplastic leukemoid reaction (PLR) has been sporadically reported in DDLPS, its coexistence with severe anemia and thrombocytopenia, constituting a severe cytokine release syndrome (CRS), is exceedingly rare and presents a significant diagnostic and therapeutic challenge. A 56-year-old male with recurrent retroperitoneal well-differentiated liposarcoma presented with high fever, profound leukocytosis (WBC up to 43×109/L), severe anemia (Hb 30 g/L), and thrombocytopenia (platelets 10×109/L), which precluded immediate surgery. Extensive workup ruled out infection and hematological malignancies. The clinical picture was consistent with a tumor-induced CRS, evidenced by markedly elevated interleukin-6 (IL-6) and C-reactive protein (CRP). Following a multidisciplinary discussion, the patient received intravenous tocilizumab (an IL-6 receptor antagonist) and methylprednisolone. His fever resolved rapidly, and hematological parameters improved significantly, facilitating successful tumor resection. Postoperative pathology confirmed DDLPS. All paraneoplastic symptoms and laboratory abnormalities normalized after surgery. However, at the second follow-up, tumor recurrence was observed along with a marked elevation of the WBC, which again decreased following the subsequent surgical resection. This case highlights that DDLPS can trigger CRS, which manifests with clinical features mimicking severe infection and leading to critical cytopenias that complicate surgical management. IL-6 pathway blockade with agents such as tocilizumab may be an effective bridging therapy to stabilize the systemic inflammatory state and create a safe window for surgical intervention.
2026-05-05 | Oncogenic driver and therapeutic target: Prolactin signalling axis in retroperitoneal sarcoma.
Retroperitoneal sarcoma (RPS) is a type of malignant tumour arising from mesenchymal tissues within the retroperitoneal space. RPSs tend to develop covertly and are often undiscovered when they have already grown significantly and invaded surrounding tissues and organs. These malignancies demonstrate high recurrence rates, present surgical challenges and exhibit limited responsiveness to radiotherapy and chemotherapy. Serum-derived molecules are known to play critical roles in tumourigenesis and tumour progression. However, the serum molecular profile of RPS patients remains unclear. We performed multi-omics analysis of serum samples from patients with retroperitoneal dedifferentiated liposarcoma. Prolactin concentrations were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). RNA-seq facilitated the identification of candidate signalling pathways, while gene expression was validated through quantitative polymerase chain reaction, immunohistochemistry and western blot analyses. Molecular mechanisms underlying transcriptional regulation were investigated through Chromatin Immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter gene assays. Integrative multi-omics profiling identified significant perturbations in galactose metabolism coupled with marked elevation of prolactin (PRL) levels in Retroperitoneal Liposarcoma (RLPS) patients. Further screening of serum prolactin levels in 100 patients with retroperitoneal tumours revealed that 90% of the cases exhibited hyperprolactinaemia in our research cohort, encompassing both malignant sarcomas and benign tumours. Studies at the clinical sample, cellular and animal levels have found that abnormally elevated prolactin in the serum can originate from sarcoma tissues. Mechanistic investigations identified SRY-box transcription factor 4 (SOX4) as a previously unrecognised transcriptional regulator of PRL. Functionally, PRL not only enhanced liposarcoma cell and fibrosarcoma cell proliferation but also conferred resistance to MDM2 inhibitors. Signalling pathway analysis revealed that PRL activates the Janus Kinase-Signal Transducer and Activator of Transcription Pathway (JAK-STAT) signalling pathway and up-regulates c-MYC expression. This study indicates that PRL can serve as an oncogenic driver and therapeutic target. The identification of SOX4-PRL-c-MYC signalling axis provides actionable insights for developing novel therapeutic strategies against this malignancy. Retroperitoneal sarcoma cells can secrete prolactin into the bloodstream, inducing hyperprolactinaemia, which subsequently triggers metabolic reprogramming, such as glucose metabolism. SOX4 can function as a transcription factor that facilitates PRL transcription. PRL can activate the JAK-STAT signalling pathway by binding to PRLR on sarcoma cells, leading to the up-regulation of c-MYC.
oligonucleotides
2026-02-27 | Targeting tRNA-Arg-TCT-4-1 suppresses cancer cell growth and tumorigenesis.
tRNAs play a critical role in protein synthesis, influencing mRNA translation dynamics to shape proteomes. Emerging evidence links dysregulated tRNA activity to cancer progression, with tRNA-Arg-TCT identified as an oncogenic driver when ectopically overexpressed in non-malignant cells. The requirement of endogenous tRNA-Arg-TCT in cancer biology, however, remains untested. Moreover, considering that the tRNA-Arg-TCT family comprises six genes in humans, the importance of an individual tRNA isodecoder in cancer remains unknown. Here, we find elevated levels of tRNA-Arg-TCT-4-1 isodecoder are associated with poor patient prognosis across multiple cancer types. We demonstrate that, using different antisense RNA strategies, specific inhibition of tRNA-Arg-TCT-4-1 suppresses the growth of glioblastoma (GBM) and liposarcoma (LPS) cancer cells. Mechanistically, we find that tRNA-Arg-TCT-4-1 inhibition leads to a codon-biased remodeling of mRNA translation and the proteome, preferentially suppressing expression of growth-promoting genes and pathways encoded by mRNAs enriched in arginine AGA codons. Strikingly, intratumoral delivery of an antisense oligonucleotide (ASO) targeting tRNA-Arg-TCT-4-1 suppresses tumor growth and extends survival in mouse xenograft experiments performed using either a human LPS cell line or a patient-derived soft tissue sarcoma model. This study provides a foundation for targeting tRNA dysregulation as a novel therapeutic approach for cancer.
2025-03-24 | Targeting FANCM by antisense oligonucleotides in ALT-positive cancers.
Effective therapies for cancers relying on the alternative lengthening of telomeres (ALT) mechanisms are still needed. Here, using CRISPR-Cas9 strategies, we validate FANCM (Fanconi anemia complementation group M) as a crucial target for ALT-associated cancers and demonstrate its importance in both in vitro and in vivo models. We further explore the use of antisense oligonucleotides (ASOs), specifically gapmers, to target FANCM mRNA. We designed and screened several gapmers, identifying effective candidates that potently reduced FANCM expression, which led to an increased ALT activity and telomeric dysfunction, concomitant with a reduced viability of ALT-positive cancer cells. Notably, gapmer 14, one of the identified ASOs, significantly impaired the viability of ALT cells and reduced tumor growth in an ALT-positive liposarcoma xenograft model, highlighting its therapeutic potential. These findings suggest that FANCM-targeting ASOs could represent a promising effective strategy for treating ALT-positive cancers.
2024-11-27 | Dysregulation of miRNAs in Soft Tissue Sarcomas.
MicroRNAs (miRNAs) are pivotal regulators of gene expression, influencing key cellular processes such as proliferation, differentiation, apoptosis, and metastasis. In the realm of sarcomas-a diverse group of malignant tumors affecting soft tissues and bone sarcomas-miRNAs have emerged as crucial players in tumorigenesis and tumor progression. This review delves into the intricate roles of miRNAs across various soft tissue sarcoma subtypes, including rhabdomyosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, fibrosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS), and malignant peripheral nerve sheath tumor (MPNST). We explore how dysregulated miRNAs function as oncogenes or tumor suppressors, modulating critical pathways that define the aggressive nature of these cancers. Furthermore, we discuss the diagnostic and prognostic potential of specific miRNAs and highlight their promise as therapeutic targets. By understanding the miRNA-mediated regulatory networks, this review aims to provide a comprehensive overview of current research while pointing towards future directions for miRNA-based therapies. Our findings underscore the potential of miRNAs to transform the landscape of sarcoma treatment, offering hope for more precise, personalized, and effective therapeutic strategies.
2023-07-04 | MicroRNA-215-5p promotes proliferation, invasion, and inhibits apoptosis in liposarcoma cells by targeting MDM2.
Liposarcoma (LPS) is one of the most common soft tissue malignancies in adults, and it is characterized by dysregulation of multiple signaling pathways, including MDM2 proto-oncogene (MDM2) amplification. MicroRNA (miRNA) regulates gene expression through incomplete complementary pairing with the 3' untranslated region of mRNAs involved in tumor progression. In this study, bioinformatics analysis, RT-qPCR, dual-luciferase reporter gene, MTT, flow cytometry, cell scratches, chamber migration, colony formation, FISH, WB, and CCK8 were used. RT-qPCR showed that the expression of MDM2 was increased when miR-215-5p was overexpressed compared with the control group. The dual-luciferase reporter gene showed that the Renilla ratio firefly fluorescence intensity was decreased in the overexpression group compared with the control group. Cell phenotype experiments revealed that the overexpression group had increased cell proliferation rate, increased apoptosis rate, increased colony formation rate, increased cell healing area ratio, and increased number of cell invasions. FISH revealed increased MDM2 expression in the overexpression group. WB suggested decreased Bax expression, increased PCNA, Bcl-2, and MDM2 expression, and decreased P53 and P21 expression in the overexpression group. In this study, we suggest that miR-215-5p can target and promote MDM2 expression, promote the proliferation and invasion of LPS cells SW-872, and inhibit apoptosis.Targeting miR-215-5p may be a novel therapeutic strategy for the treatment of LPS.
2022-11-14 | Transcriptome analysis identifies TODL as a novel lncRNA associated with proliferation, differentiation, and tumorigenesis in liposarcoma through FOXM1.
Liposarcoma, the most common soft tissue sarcoma, is a group of fat cell mesenchymal tumors with different histological subtypes. The dysregulation of long non-coding RNAs (lncRNAs) has been observed in human cancers including a few studies in sarcoma. However, the global transcriptome analysis and potential role of lncRNAs remain unexplored in liposarcoma. The present investigation uncovers the transcriptomic profile of liposarcoma by RNA sequencing to gain insight into the global transcriptional changes in liposarcoma. Our RNA sequencing analysis has identified that many oncogenic lncRNAs are differentially expressed in different subtypes of liposarcoma including MALAT1, PVT1, SNHG15, LINC00152, and MIR210HG. Importantly, we identified a highly overexpressed, unannotated, and novel lncRNA in dedifferentiated liposarcomas. We have named it TODL, transcript overexpressed in dedifferentiated liposarcoma. TODL lncRNA displayed significantly higher expression in dedifferentiated liposarcoma cell lines and patient samples. Interestingly, functional studies revealed that TODL lncRNA has an oncogenic function in liposarcoma cells by regulating proliferation, cell cycle, apoptosis, differentiation, and tumorigenesis in the murine model. Silencing of TODL lncRNA highlighted the enrichment of several key oncogenic signaling pathways including cell cycle, transcriptional misregulation, FOXM1 network, p53 signaling, PLK1 signaling, FoxO, and signaling Aurora signaling pathways. RNA pull-down assay revealed the binding of TODL lncRNA with FOXM1, an oncogenic transcription factor, and the key regulator of the cell cycle. Silencing of TODL lncRNA also induces adipogenesis in dedifferentiated liposarcomas. Altogether, our finding indicates that TODL could be utilized as a novel, specific diagnostic biomarker, and a pharmacological target for therapeutic development in controlling aggressive and metastatic dedifferentiated liposarcomas.
other
2026-07-01 | From cold to responsive: IFN-α treatment is associated with collagen VI remodeling and enhanced anti-PD-1 efficacy in Well-/dedifferentiated liposarcoma
Well-/dedifferentiated liposarcoma is characterized by frequent local recurrence and limited responsiveness to immune checkpoint blockade (ICB), highlighting the need for pathology-feasible immune stratification and rational combination strategies. We integrated bulk transcriptomics, single-cell RNA sequencing, proteomics, and spatial immunofluorescence to characterize the tumor immune microenvironment in WD/DD LPS. Unsupervised analyses identified two reproducible states: an immune-high (Hi) subtype enriched for type I interferon programs and an immune-low (Lo) subtype enriched for extracellular matrix (ECM)-associated features. Based on these signatures, we derived a five-marker immunohistochemistry (IHC) panel (CD8A, CD27, AOAH, NCF1, and LST1) to enable pathology-based immune subtyping. In a small, independent exploratory cohort of ICB-treated WD/DD LPS patients ( n = 10), the locked classifier showed a directionally consistent trend in outcomes, but was underpowered and should be considered hypothesis-generating, warranting validation in larger, prospectively collected cohorts. IFN-α downregulated tumor-cell-derived COL6A1 in vitro and was associated with reduced ECM-linked exclusion features. In a PBMC-humanized xenograft model, IFN-α plus anti-PD-1 therapy enhanced tumor control, accompanied by increased CD8 + T-cell infiltration, providing preclinical proof-of-concept support for IFN-α as a combination partner for PD-1 blockade. Mechanistically, the proposed COL6 axis is a hypothesis supported by in vitro IFN-α-dependent suppression of tumor cell COL6A1 and correlative multi-omic/spatial observations; the in vivo model used here does not establish COL6 causality, and definitive testing will require genetic loss-of-function studies. Together, these findings define an immune-ECM axis, present a pathology-ready IHC framework for hypothesis-generating immune stratification, and support further investigation of IFN-α-based combination strategies under rigorous clinical validation.
2025-10-02 | Identification of Guanine-Quadruplex-Binding Peptides from the RGG3 Domain of TLS/FUS.
Guanine quadruplexes (G4s) are non-canonical nucleic acid structures that have emerged as attractive therapeutic targets owing to their involvement in diverse biological processes. Additionally, peptides derived from G4-binding proteins provide promising platforms for selective G4 recognition. In this study, we explored the G4-binding capacity of arginine-glycine-glycine (RGG)-rich sequences derived from the RGG3 domain translocated in liposarcoma/fused in sarcoma (TLS/FUS), a known G4 RNA binding protein. In this study, we synthesized a library of overlapping 15-mer peptides and evaluated their G4-binding affinities. Among the 10 evaluated native sequences, several peptides demonstrated measurable affinities toward G4 RNA structures, with STK5-1 exhibiting the highest G4-binding affinity. Furthermore, to investigate the impact of conformational constraints on G4 recognition, we introduced (E)-methylalkene dipeptide isosteres (MADIs) into selected Gly-Gly motifs, generating a series of RGG peptidomimetics. Subsequent binding assays revealed that some of these MADI peptidomimetics exhibited enhanced affinity and selectivity compared with their unmodified counterparts. Our findings offer new insights into the sequence and structural features governing G4-binding, establishing a foundation for the further development of peptide-based G4 ligands.
2025-04-05 | TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development.
Dedifferentiated liposarcoma (DDLPS) accounts for 15-20% of liposarcoma (LPS) and has high rates of local recurrence and distant metastasis. Hyperactivation of yes-associated protein (YAP) has been implicated in DDLPS development. However, the mechanisms that drive aberrant YAP signaling remain largely unknown. Here, we show that tumor protein p53 inducible nuclear protein 2 (TP53INP2) is a potential negative modulator of the malignant progression of DDLPS. The TP53INP2 protein expression level in tumor tissues from 79 patients with DDLPS decreased progressively. Compared with primary tumors, recurrent tumors also exhibited reduced TP53INP2 expression. More importantly, low TP53INP2 expression is correlated with poor prognosis. TP53INP2 gain- or loss-of-function experiments in DDLPS cell lines showed profound inhibitory effects on processes and properties linked with cancer malignancy, such as proliferation, migration, stemness and dedifferentiation. Mechanistically, TP53INP2 is located mainly in mitochondria and promotes mitophagic degradation of YAP in a VDAC1-dependent manner. The WW domain in YAP and the PPTY motif in VDAC1 are required for their interaction. Taken together, these data demonstrate that TP53INP2 represses the malignant progression of DDLPS by inactivating YAP via a mitophagy-dependent mechanism and that TP53INP2 may constitute a novel prognostic biomarker for advanced DDLPS.
2025-03-27 | Anti-CD137 agonist antibody-independent and clinically feasible preparation of tumor-infiltrating lymphocytes from soft tissue sarcoma and osteosarcoma.
Tumor infiltrating lymphocytes (TILs) therapy has been proved for treatment of metastatic melanoma and is under investigation for other types of solid tumors. However, these successes are threatened by discontinued supply of GMP-grade anti-CD137 agonist, a key TIL preparation reagent. Therefore, exploring a GMP-adherent method for expanding endogenous TILs without anti-CD137 agonist is urgent. Toward this end, we aimed to establish an anti-CD137-independent and clinically feasible TIL expansion protocol to prepare TILs from under investigated sarcoma tumors. We collected resected tumors from patients and cut tissues into fragments. We used IL-2 and T-cell activator CD3/CD28 without anti-CD137 agonist to expand nonselected TILs in 2-3 weeks, then rapidly expanded them over 2 weeks. Their phenotypes were characterized using flow cytometry. Their antitumor activity was validated in vitro using cytotoxic T lymphocyte assays measuring CD107a on the TILs and the viability of tumor cells and in vivo using an autologous patient-derived xenograft (PDX) tumor model. We successfully expanded TILs in > 90% of collected samples. TILs generated preferentially increased CD8+ T cells but suppressed CD4+ T cells. A small portion of TILs were resident memory T cells. The expanded TILs reduced autologous tumor cells by 37.5% within 24 hours. Infusion of TILs in mice bearing autologous PDX tumors strongly inhibited liposarcoma growth. FDA has approved use of this GMP-feasible protocol in our clinical trial (IND 30562). It is feasible to generate antitumor TILs using CD3/CD28 activator to replace the unavailable anti-CD137 agonist. Our study supports the further development of TIL-based therapy.
2025-03-04 | Use of patient-derived organotypic tumor spheroids for testing of viral vector gene therapy in combination with checkpoint blockade.
Checkpoint inhibitors have revolutionized cancer treatment, but a significant proportion of patients do not respond to these therapies, underscoring the need for alternative strategies. Although gene therapy has made substantial strides, its application in solid tumors remains underexplored, with limited treatments approved. Here, we further investigated a gene therapy approach with non-replicating adenoviral vectors encoding the alternate reading frame (ARF) and interferon beta (IFNb) and tested it in a clinically relevant setting. We previously showed that this combined gene therapy induces immunogenic cell death in melanoma models, and now, we utilize patient-derived organotypic tumor spheroids (PDOTS), a model that closely recapitulates the immune environment of tumors, to test its effects using patient tumors. Our results demonstrate, for the first time, the effectiveness of using PDOTS to evaluate viral-vector-based gene therapies. While the addition of anti-PD-1 did not enhance therapeutic outcomes, the gene therapy alone suppressed tumor growth and triggered antitumor immune responses across different cancer models, notably those with low immunogenicity and specific genome profiles. These findings suggest that this gene therapy could serve as a valuable alternative for patients not responsive to checkpoint inhibitors and who have solid tumors with limited treatment and impaired p53-ARF-MDM2 pathways, such as liposarcomas.
small molecules
2026-08-14 | Antitumor activity of novel transcriptional inhibitors ecubectedin and PM54 in soft tissue sarcoma patient-derived xenografts.
Trabectedin, prototype of the ecteinascidin class of drugs, is a known second or later line therapeutic option for advanced soft tissue sarcoma (STS). We evaluated the antitumor activity of two novel synthetic trabectedin derivatives, ecubectedin and PM54, in selected patient-derived xenograft (PDX) STS models. In total 364 NMRInu/nu mice were transplanted bilaterally with two leiomyosarcoma (LMS), two dedifferentiated liposarcoma (DDLPS), one synovial sarcoma (SynSa) and one CIC-rearranged sarcoma (CRS) PDX models. Mice were randomized to six groups and treated via tail vein injection with 1) vehicle, 2) doxorubicin, 3) trabectedin, 4) lurbinectedin, 5) ecubectedin, or 6) PM54. Treatment was given on days 1, 8 and 15, and mice were sacrificed on day 16. The SynSa experiment included extra mice to investigate post-treatment xenograft evolution. Antitumor activity was assessed by tumor volume measurement, histopathologic and immunohistochemical analysis. In all LMS and DDLPS models, ecubectedin and PM54 led to tumor growth delay compared to trabectedin. Histopathological evaluation of treated tumors showed moderately increased antitumor activity of novel ecteinascidins compared to trabectedin. The CRS showed tumor shrinkage in response to ecubectedin (63% regression from baseline) and PM54 (24% regression from baseline) while the SynSa showed tumor volume stabilization. Both translocation-related models showed significant antitumor effect on histopathological evaluation in response to the novel drugs, compared to trabectedin. Ecubectedin and PM54 have modest antitumor activity in STS PDX models, with the strongest effects seen in the translocation-related sarcoma models, showing the potential of this class of drugs in treatment of STS.
2026-08-10 | Extracellular vesicle-mediated suppression of macrophage STING signaling promotes immune dysfunction in dedifferentiated liposarcoma
Abstract Background Dedifferentiated liposarcoma (DDLPS) is characterized by abundant immune cell infiltration yet derives limited benefit from immune checkpoint blockade and stimulator of interferon genes (STING) agonist-based strategies, suggesting tumor-mediated suppression of antitumor immunity. Tumor-associated macrophages are the most abundant immune populations in DDLPS, but the factors regulating their function remain incompletely understood. Methods Extracellular vesicles (EVs) were isolated from two DDLPS cell lines and serum from 16 DDLPS patients and 13 healthy donors. EVs’ impact on cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) -induced macrophage activation was assessed by cytokine secretion, surface markers, functional assays and macrophage-T-cell coculture. Proteomics was performed in EV-treated and EV-untreated macrophages from three donors. Pathway and protein interaction analyses were integrated with The Cancer Genome Atlas (TCGA) DDLPS transcriptomic and survival data. Results We show that EVs released by DDLPS cells suppress macrophage responsiveness to classic STING agonist cGAMP. EVs derived from DDLPS attenuated cGAMP-induced expression of type I interferon-associated cytokines and chemokines, reduced IFN-β secretion, and impaired phosphorylation of STING, TBK1 and IRF3. Functionally, DDLPS EV exposure shifted macrophages toward an immunoregulatory phenotype, restrained phagocytic activity, and attenuated macrophage-dependent T-cell proliferation while promoting T-cell exhaustion. Proteomic profiling revealed extensive macrophage reprogramming characterized by suppression of STING-associated signaling, antigen processing and presentation associated pathways and proteins targeted by miR-16-5p. Consistent with these findings, STING expression was associated with prolonged overall survival in DDLPS, while reduced expression of miR-16-5p target proteins was associated with attenuated STING pathway activity and immunostimulatory macrophage signatures. Conclusions These findings identify EV-mediated suppression of macrophage STING signaling as a mechanism of immune dysfunction in DDLPS and provide a framework for understanding immune resistance in this disease.
2026-06-29 | A multi-platform genomic analysis of paired well- and dedifferentiated liposarcoma identifies recurrent genomic alterations associated with progression and recurrence
Processed multi-platform genomic data for Crago et al., "A multi-platform genomic analysis of paired well- and dedifferentiated liposarcoma identifies recurrent genomic alterations associated with progression and recurrence (manuscript in preparation). The cohort spans 349 tumor specimens from 162 patients (1994–2013): 152 well-differentiated and 162 dedifferentiated liposarcomas with 35 normal-fibroblast controls. Included are Affymetrix HG-U133A tumor and cell-line expression matrices, array CGH segmentation lesions and event calls, VEP/FACETS-annotated whole-exome somatic MAF, RNA-seq gene counts, miRNA target predictions, sample annotations.
2026-06-25 | Transcriptomic Signatures Associated with Doxorubicin Treatment in Liposarcoma Reveal Coordinated Regulatory Patterns.
Background/Objectives: Liposarcoma is a heterogeneous soft tissue sarcoma in which anthracycline-based chemotherapy, including doxorubicin, remains a cornerstone of treatment for advanced disease. However, variable and often limited therapeutic responses highlight the need for improved understanding of disease-associated transcriptional adaptation under chemotherapeutic stress. In this study, a bioinformatics-driven transcriptomic analysis was performed to characterize gene expression alterations associated with doxorubicin treatment in liposarcoma using publicly available data from the Gene Expression Omnibus (GSE12972). Results: Differential expression analysis identified 365 significantly altered genes, including 164 upregulated and 201 downregulated transcripts in treated samples compared with untreated controls. Functional interpretation using Ingenuity Pathway Analysis identified transforming growth factor beta 1 (TGFB1), tumor necrosis factor (TNF), and SMARCA4 as prominent predicted upstream regulators associated with transcriptional programs related to extracellular matrix remodeling, inflammatory and immune modulation, epithelial-to-mesenchymal transition-like states, and chromatin-mediated transcriptional plasticity. Enriched canonical pathways included Liposarcoma tumor microenvironment-associated signaling and fibrosis-related pathways, reflecting stromal activation and immune-related transcriptional changes. Notably, fibroblast growth factor 1 (FGF1) emerged as a supportive regulatory node linked to survival- and anti-apoptotic gene expression patterns. Conclusions: Collectively, these findings provide a disease-oriented, cross-subtype systems-level view of the transcriptional changes associated with doxorubicin treatment in liposarcoma. This work is intended as a hypothesis-generating framework that may inform future functional studies and integrative approaches aimed at understanding therapeutic response and disease progression.
2026-06-13 | Utidelone in patients with advanced soft tissue sarcoma refractory to anthracycline and antiangiogenic therapy (UTISARC): a single-arm phase II study.
Treatment options remain limited for patients with advanced or metastatic soft tissue sarcoma after failure of both anthracycline-based chemotherapy and antiangiogenic therapy. Utidelone, an epothilone analog, has demonstrated antitumor activity across a broad spectrum of preclinical models and clinical trials. This single-arm, phase II trial was designed to assess the efficacy and safety of utidelone in a heavily pretreated population. This study enrolled patients aged 18 years or older with locally advanced or metastatic soft tissue sarcoma who had previously been treated with anthracycline-based chemotherapy and antiangiogenic tyrosine kinase inhibitors. Participants received utidelone via a 90-minute intravenous infusion at a dose of 30 mg/m² on days 1-5 of each 21-day treatment cycle, continuing until disease progression or the occurrence of unacceptable toxicity. The primary endpoint was median progression-free survival. The secondary endpoints included the objective response rate, overall survival and safety. Between August 2022 and March 2025, a total of 27 patients were included in the study. The median age was 55 years (range, 30-68). There were 15 patients with leiomyosarcoma, 3 with dedifferentiated liposarcoma, 3 with epithelioid sarcoma, 2 with angiosarcoma, and 4 with other types of sarcoma. The median number of prior systemic therapy regimens was 2 (range, 1-4). The median treatment exposure was 5 cycles (range, 1-10). Two patients achieved a partial response, resulting in an objective response rate of 7%. The median progression-free survival was 4.6 months (95% confidence interval, 3.6-5.6). Overall survival data were immature, with only 9 death events (33%) observed. The estimated 12-month overall survival rate was 80%. Most adverse events were grade 1 or 2 in severity. The most frequently observed grade ≥ 3 adverse event was peripheral neuropathy (11%). In this exploratory trial, utidelone demonstrated preliminary antitumor activity and a manageable safety profile in patients with refractory soft tissue sarcoma. Further exploration of novel combination therapies involving utidelone is warranted to enhance its clinical utility. ChiCTR2200062161, registered on July 26, 2022.
cell therapies
2026-05-28 | A pilot study of autologous tumor-infiltrating lymphocytes (LN-145) in adult patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.
e23566 Background: Advanced undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLS) are difficult to treat soft tissue sarcomas with response rates to first line systemic therapy between 10-30%. However, both UPS and DDLPS have been shown to have measurable tumor infiltrating lymphocyte (TIL) populations. LN-144 (lifileucel), an autologous TIL product derived from unresectable or metastatic melanoma, was shown to have an overall response rate (ORR) of 36% in heavily pretreated melanoma patients with a median DOR of 19.7 months. We hypothesized that generation and infusion of LN-145, an autologous TIL product from non-melanoma solid tumors, in this case UPS and DDLPS, would be both safe and feasible. Methods: NCT05607095 is a single center multi-cohort pilot trial with Cohort 2 enrolling patients with metastatic or unresectable UPS or DDLS to undergo autologous TIL therapy with LN-145. Eligible patients had to receive at least 1 prior line of systemic therapy, a lesion at least 1.5 cm in size available for TIL harvest, and adequate organ function and performance status (ECOG 0-1). After surgical excision of suitable tumor for TIL expansion, successful LN-145 product generation was determined by characteristics that meet pre-specified criteria in the LN-145 IND. Patients then underwent nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m 2 x 5 doses). LN-145 was then infused and expanded with intravenous interleukin 2 (600,000 IU/kg up to 6 doses). Primary endpoints of the trial were feasibility, defined as ³6 of 10 harvested pts undergoing LN-145 therapy, and safety, defined by the incidence of Grade ³3 adverse events (AE) as measured by CTCAE v5.0. Key secondary endpoints included estimated LN-145 manufacture rates and efficacy (ORR) utilizing RECIST 1.1. Exploratory endpoints include persistence of LN-145 cells and immune correlates in tissue and peripheral blood and their potential association with objective response and toxicity. Safety and efficacy measures will be summarized using point estimates and a Clopper Pearson exact confidence interval will be used. The final results of the primary feasibility and safety endpoints and secondary feasibility endpoint for the first 10 enrolled patients as well as and preliminary secondary efficacy and exploratory correlative studies through week 12 for 7 treated patients will be reported as late-breaking abstract after data lock on March 1, 2026. Clinical trial information: NCT05607095 .
2026-01-16 | A Huge Recurrent Atypical Lipomatous Tumor (Well-Differentiated Liposarcoma) going in to Dedifferentiation 12 years after its First Detection.
Soft-tissue sarcoma (STS) being a rare malignancy, many times it undergoes inadequate surgery at first instance, leading to higher chances of recurrence. Atypical lipomatous tumor (ALT)/well-differentiated liposarcoma frequently undergoes first inadequate surgery leading to higher recurrence rate and sometimes getting converted to higher grade malignancy like dedifferentiated liposarcoma. We had a 63-year-old female who presented with recurrent huge (dimension on final histopathology report: 29 × 24 × 11 cm) ALT of thigh after three prior surgeries over the span of 8 years. We resected it with wide margins and did a prophylactic nailing at second stage. Final histopathology report came out to be liposarcoma with foci of low-grade dedifferentiation (FNCLCC Grade 3). Patient received post-operative radiotherapy. At final follow-up of 35 months, our patient is recurrence free, doing all her daily routine activity independently. Ten percentages of the ALT dedifferentiate into dedifferentiated liposarcoma, which has 15-20% metastatic potential compared to almost nil in ALT which happened in our case. Due to this, we recommend treatment of ALT and all STS at a tertiary cancer care center by a multidisciplinary team as it requires adjuvant treatment also apart from surgery with adequate margins.
2025-12-26 | Primary dedifferentiated liposarcoma of the ovary: expanding the surgical management spectrum with a different resection extent than existing reports - a case report and literature review.
Dedifferentiated liposarcoma (DDLPS) is a relatively common type of liposarcoma, typically occurring in the retroperitoneum and limbs. It is rarely found in the female reproductive system, leading to the absence of a standard treatment protocol for primary ovarian dedifferentiated liposarcoma. This case presents a personal experience-based approach, as there is a lack of standard treatment guidelines, relying on treatment consensus for more common locations and decades of clinical experience. This case report describes a 55-year-old woman who was admitted due to a gradually enlarging mass in the right lower abdomen, accompanied by bloating and abdominal pain. Physical examination revealed a palpable abdominal mass. Gynecological ultrasound showed a hyperechoic mass measuring 135*128*91mm in the pelvic-abdominal cavity. CT imaging suggested a large cystic and solid mixed liposarcoma originating from the ovary, with unclear delineation of the uterine fundus and slight compression of surrounding organs. Pelvic MRI revealed an irregular mass approximately 10.7cm×12.6cm×12.2cm, with slightly prolonged T1 and heterogeneous T2 signals, showing fat signal in the right fatty tissue, suggesting invasion of the uterine wall by liposarcoma. The patient then underwent open surgery, and postoperative pathology with immunohistochemistry confirmed dedifferentiated liposarcoma. FISH testing was positive for MDM2, confirming the diagnosis of ovarian-origin dedifferentiated liposarcoma. Although the patient refused chemotherapy, she has been followed up every three months, and the current follow-up shows no signs of tumor recurrence. Ovarian dedifferentiated liposarcoma is an extremely rare condition, with surgery being the preferred treatment method. This report presents a rare case of ovarian dedifferentiated liposarcoma, providing a reference for clinical diagnosis and treatment. Through collaboration between gynecology, pathology, and imaging departments, the accuracy of the diagnosis and comprehensiveness of treatment were ensured. Long-term follow-up of the patient provided valuable insights into the recurrence and prognosis of the disease.
2025-11-20 | Extracellular Vesicles in Sarcoma: Implications for Tumor Progression and Therapy.
Sarcoma, a heterogeneous group of malignancies arising from mesenchymal tissues, poses significant clinical challenges due to its aggressive behavior, early metastasis, and resistance to conventional therapies. Recent advancements highlight the pivotal role of extracellular vesicles (EVs)-nanoscale particles secreted by tumor and stromal cells-in modulating sarcoma progression through intercellular communication within the tumor microenvironment. This review comprehensively examines the multifaceted functions of EVs in sarcoma pathogenesis, focusing on their subtype-specific mechanisms (eg, osteosarcoma, liposarcoma) in promoting epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion. Additionally, we discuss the emerging potential of EVs as non-invasive biomarkers for early diagnosis and prognosis, as well as their engineered applications in targeted drug delivery and immunotherapy. By integrating cutting-edge research, this article underscores the translational value of EVs in overcoming current therapeutic limitations and provides a roadmap for future investigations into EV-based precision strategies for sarcoma management.
2025-09-10 | Immunocompetent Murine Models Recapitulate the Heterogeneous Tumor-Immune Microenvironment of Human Liposarcoma.
Liposarcoma is the most common soft tissue sarcoma. Well-differentiated liposarcoma can progress to dedifferentiated liposarcoma (DDLPS), a more aggressive form with higher metastatic potential and poor response to existing therapies. Progress in understanding and treating liposarcoma has been limited. To address this, we sought to develop an immunocompetent genetically engineered mouse model of liposarcoma. We developed an autochthonous, immunocompetent liposarcoma mouse model [AAV8-Ap2.2-eGFP/Cre Ptenf/f;Trp53f/f C57BL/6 (ACPP)] by using targeted Cre-mediated deletion of Trp53 and Pten in adipocytes to mimic the signaling alterations observed in human liposarcoma. We characterized the histology, transcriptional features, and tumor microenvironment of this model. Additionally, we established syngeneic cell lines derived from ACPP DDLPS tumors and evaluated them for tumor formation, growth dynamics, and immune composition after implantation. ACPP mice develop well-differentiated liposarcoma, DDLPS, and mixed tumors, mirroring human disease. Both murine and human DDLPS tumors share key transcriptional features and exhibit heterogeneous T-cell infiltration. Syngeneic DDLPS cell lines reliably form tumors in vivo, with each line demonstrating distinct growth kinetics, aggressiveness, and immune profiles. The ACPP model provides a novel and clinically relevant platform to study liposarcoma in an immunocompetent setting. Along with the ACPP-derived cell lines, these models not only provide essential tools to understand the complex immunobiology of liposarcoma but also can be used to elucidate the underlying molecular mechanisms driving liposarcoma generation and progression and significantly accelerate the pace of preclinical studies aimed at uncovering more effective new therapies for patients with this aggressive malignancy.
antibodies
2026-08-13 | Single-cell analysis reveals the potential immunoregulatory role of C3 + malignant cell subpopulations in dedifferentiated liposarcoma
Dedifferentiated liposarcoma (DDLPS), a rare disease with limited research, exhibits resistance to radiotherapy and chemotherapy. Few reports have analyzed the tumor microenvironment of retroperitoneal undifferentiated liposarcoma using single-cell sequencing. Single-cell analysis of three retroperitoneal DDLPS cases characterized the cellular and immune microenvironment. Our findings reveal significant heterogeneity among malignant cells in DDLPS, with chromosome 6 deletions being prevalent across malignant cell subpopulations and potentially linked to reduced immunogenicity based on pathway analyses. Notably, the coexistence of CD8 + T cell exhaustion and cytotoxicity reflects a continuum of exhaustion transition. Moreover, we identify a C3 + malignant cell subpopulation with ECM remodeling, angiogenesis, and activated complement pathway. Further exploration suggested that C3 + malignant cells may recruit IL2RA+ regulatory T cells and SPP1 + macrophages through the C3-C3aR1 axis. Our findings provide new insights into the application of immunotherapy in sarcoma.
2026-08-13 | Immunotherapy in the Treatment of Soft Tissue Sarcoma Since SARC028: An NCDB Analysis.
The publication of SARC028 in late 2017 revolutionized soft tissue sarcoma (STS) treatment by demonstrating promising response to anti-PD1 immunotherapy in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). Data on immunotherapy efficacy and outcomes in larger cohorts and with longer follow-up remain limited. 31 672 cases of UPS, DDLPS, alveolar soft part sarcoma, and myxofibrosarcoma were extracted from the NCDB. Factors associated with the use of immunotherapy were evaluated using logistic regression, and survival analysis was performed with Kaplan-Meier curves and Cox proportional hazards models. Patients diagnosed with STS after 2017 were 3.67 times more likely to receive immunotherapy. Immunotherapy was associated with an approximately 20% reduction in mortality in stage IV STS, which was driven by cases of UPS. This survival benefit was observed in male, but not female, patients. There was no survival benefit in stage III STS. These data are consistent with a survival benefit with immunotherapy in stage IV STS, predominantly in UPS, supporting the findings of SARC028. Benefit in stage III STS was not observed, limiting concordance with later trials like SARC032. Further prospective data on long-term outcomes and immunotherapy efficacy according to histology and sex are needed.
2026-06-18 | Tumor-infiltrating CD8+Ki-67+ and CD8+LAG-3+ T cells are associated with improved patient survival in retroperitoneal dedifferentiated liposarcomas and leiomyosarcomas.
Tumor-infiltrating immune cells play a fundamental role in shaping patient prognosis across many cancers. Retroperitoneal dedifferentiated liposarcomas (DDLPS) and leiomyosarcomas (LMS) are associated with poor prognosis, therefore, a deeper understanding of the immune landscape in these tumors is warranted to identify novel prognostic biomarkers and immunotherapeutic targets. In this exploratory study, we analyzed spatial organization, frequency, and proportions of CD8+ T cell (including activated, proliferating, and exhausted phenotypes), T helper, and macrophage subsets, and B cells in primary treatment-naive retroperitoneal DDLPS (n = 22) and LMS tissues (n = 10) using classical and multiplex immunohistochemistry. CD8+LAG-3+ T cells comprised the highest proportion of all analyzed CD8+ subsets. Their elevated density was associated with improved overall survival (OS). Moreover, higher density of CD8+Ki-67+ T cells was linked to better OS and tended to independently predict OS. Interestingly, enhanced density of regulatory T cells was associated with favorable OS. Densities and proportions of T cell subsets did not significantly differ between DDLPS and LMS. A lower density of M2-like macrophages (CD68+CD163+) was linked to better progression-free survival (PFS) and tended to serve as an independent prognostic factor. Invasive margin revealed distinct prognostic patterns compared to tumor core, where high levels of CD8+Ki-67+TCF1+ were linked to better PFS and elevated proportions of CD8+GrzB+ and CD3+T-Bet+ T cells were associated with inferior PFS. These findings highlight the clinical relevance of immune infiltration in retroperitoneal DDLPS and LMS. Moreover, they support the rationale for further exploration of the immune architecture for prognostic biomarkers and development of targeted immunotherapeutic strategies to improve the clinical outcomes of the patients.
2026-05-21 | Tocilizumab as a novel bridging therapy for surgery in dedifferentiated liposarcoma complicated by paraneoplastic leukemoid reaction, severe anemia, and thrombocytopenia: a case report.
Dedifferentiated liposarcoma (DDLPS) is a malignant mesenchymal tumor. While paraneoplastic leukemoid reaction (PLR) has been sporadically reported in DDLPS, its coexistence with severe anemia and thrombocytopenia, constituting a severe cytokine release syndrome (CRS), is exceedingly rare and presents a significant diagnostic and therapeutic challenge. A 56-year-old male with recurrent retroperitoneal well-differentiated liposarcoma presented with high fever, profound leukocytosis (WBC up to 43×109/L), severe anemia (Hb 30 g/L), and thrombocytopenia (platelets 10×109/L), which precluded immediate surgery. Extensive workup ruled out infection and hematological malignancies. The clinical picture was consistent with a tumor-induced CRS, evidenced by markedly elevated interleukin-6 (IL-6) and C-reactive protein (CRP). Following a multidisciplinary discussion, the patient received intravenous tocilizumab (an IL-6 receptor antagonist) and methylprednisolone. His fever resolved rapidly, and hematological parameters improved significantly, facilitating successful tumor resection. Postoperative pathology confirmed DDLPS. All paraneoplastic symptoms and laboratory abnormalities normalized after surgery. However, at the second follow-up, tumor recurrence was observed along with a marked elevation of the WBC, which again decreased following the subsequent surgical resection. This case highlights that DDLPS can trigger CRS, which manifests with clinical features mimicking severe infection and leading to critical cytopenias that complicate surgical management. IL-6 pathway blockade with agents such as tocilizumab may be an effective bridging therapy to stabilize the systemic inflammatory state and create a safe window for surgical intervention.
2026-05-05 | Oncogenic driver and therapeutic target: Prolactin signalling axis in retroperitoneal sarcoma.
Retroperitoneal sarcoma (RPS) is a type of malignant tumour arising from mesenchymal tissues within the retroperitoneal space. RPSs tend to develop covertly and are often undiscovered when they have already grown significantly and invaded surrounding tissues and organs. These malignancies demonstrate high recurrence rates, present surgical challenges and exhibit limited responsiveness to radiotherapy and chemotherapy. Serum-derived molecules are known to play critical roles in tumourigenesis and tumour progression. However, the serum molecular profile of RPS patients remains unclear. We performed multi-omics analysis of serum samples from patients with retroperitoneal dedifferentiated liposarcoma. Prolactin concentrations were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). RNA-seq facilitated the identification of candidate signalling pathways, while gene expression was validated through quantitative polymerase chain reaction, immunohistochemistry and western blot analyses. Molecular mechanisms underlying transcriptional regulation were investigated through Chromatin Immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter gene assays. Integrative multi-omics profiling identified significant perturbations in galactose metabolism coupled with marked elevation of prolactin (PRL) levels in Retroperitoneal Liposarcoma (RLPS) patients. Further screening of serum prolactin levels in 100 patients with retroperitoneal tumours revealed that 90% of the cases exhibited hyperprolactinaemia in our research cohort, encompassing both malignant sarcomas and benign tumours. Studies at the clinical sample, cellular and animal levels have found that abnormally elevated prolactin in the serum can originate from sarcoma tissues. Mechanistic investigations identified SRY-box transcription factor 4 (SOX4) as a previously unrecognised transcriptional regulator of PRL. Functionally, PRL not only enhanced liposarcoma cell and fibrosarcoma cell proliferation but also conferred resistance to MDM2 inhibitors. Signalling pathway analysis revealed that PRL activates the Janus Kinase-Signal Transducer and Activator of Transcription Pathway (JAK-STAT) signalling pathway and up-regulates c-MYC expression. This study indicates that PRL can serve as an oncogenic driver and therapeutic target. The identification of SOX4-PRL-c-MYC signalling axis provides actionable insights for developing novel therapeutic strategies against this malignancy. Retroperitoneal sarcoma cells can secrete prolactin into the bloodstream, inducing hyperprolactinaemia, which subsequently triggers metabolic reprogramming, such as glucose metabolism. SOX4 can function as a transcription factor that facilitates PRL transcription. PRL can activate the JAK-STAT signalling pathway by binding to PRLR on sarcoma cells, leading to the up-regulation of c-MYC.
oligonucleotides
2026-02-27 | Targeting tRNA-Arg-TCT-4-1 suppresses cancer cell growth and tumorigenesis.
tRNAs play a critical role in protein synthesis, influencing mRNA translation dynamics to shape proteomes. Emerging evidence links dysregulated tRNA activity to cancer progression, with tRNA-Arg-TCT identified as an oncogenic driver when ectopically overexpressed in non-malignant cells. The requirement of endogenous tRNA-Arg-TCT in cancer biology, however, remains untested. Moreover, considering that the tRNA-Arg-TCT family comprises six genes in humans, the importance of an individual tRNA isodecoder in cancer remains unknown. Here, we find elevated levels of tRNA-Arg-TCT-4-1 isodecoder are associated with poor patient prognosis across multiple cancer types. We demonstrate that, using different antisense RNA strategies, specific inhibition of tRNA-Arg-TCT-4-1 suppresses the growth of glioblastoma (GBM) and liposarcoma (LPS) cancer cells. Mechanistically, we find that tRNA-Arg-TCT-4-1 inhibition leads to a codon-biased remodeling of mRNA translation and the proteome, preferentially suppressing expression of growth-promoting genes and pathways encoded by mRNAs enriched in arginine AGA codons. Strikingly, intratumoral delivery of an antisense oligonucleotide (ASO) targeting tRNA-Arg-TCT-4-1 suppresses tumor growth and extends survival in mouse xenograft experiments performed using either a human LPS cell line or a patient-derived soft tissue sarcoma model. This study provides a foundation for targeting tRNA dysregulation as a novel therapeutic approach for cancer.
2025-03-24 | Targeting FANCM by antisense oligonucleotides in ALT-positive cancers.
Effective therapies for cancers relying on the alternative lengthening of telomeres (ALT) mechanisms are still needed. Here, using CRISPR-Cas9 strategies, we validate FANCM (Fanconi anemia complementation group M) as a crucial target for ALT-associated cancers and demonstrate its importance in both in vitro and in vivo models. We further explore the use of antisense oligonucleotides (ASOs), specifically gapmers, to target FANCM mRNA. We designed and screened several gapmers, identifying effective candidates that potently reduced FANCM expression, which led to an increased ALT activity and telomeric dysfunction, concomitant with a reduced viability of ALT-positive cancer cells. Notably, gapmer 14, one of the identified ASOs, significantly impaired the viability of ALT cells and reduced tumor growth in an ALT-positive liposarcoma xenograft model, highlighting its therapeutic potential. These findings suggest that FANCM-targeting ASOs could represent a promising effective strategy for treating ALT-positive cancers.
2024-11-27 | Dysregulation of miRNAs in Soft Tissue Sarcomas.
MicroRNAs (miRNAs) are pivotal regulators of gene expression, influencing key cellular processes such as proliferation, differentiation, apoptosis, and metastasis. In the realm of sarcomas-a diverse group of malignant tumors affecting soft tissues and bone sarcomas-miRNAs have emerged as crucial players in tumorigenesis and tumor progression. This review delves into the intricate roles of miRNAs across various soft tissue sarcoma subtypes, including rhabdomyosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, fibrosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS), and malignant peripheral nerve sheath tumor (MPNST). We explore how dysregulated miRNAs function as oncogenes or tumor suppressors, modulating critical pathways that define the aggressive nature of these cancers. Furthermore, we discuss the diagnostic and prognostic potential of specific miRNAs and highlight their promise as therapeutic targets. By understanding the miRNA-mediated regulatory networks, this review aims to provide a comprehensive overview of current research while pointing towards future directions for miRNA-based therapies. Our findings underscore the potential of miRNAs to transform the landscape of sarcoma treatment, offering hope for more precise, personalized, and effective therapeutic strategies.
2023-07-04 | MicroRNA-215-5p promotes proliferation, invasion, and inhibits apoptosis in liposarcoma cells by targeting MDM2.
Liposarcoma (LPS) is one of the most common soft tissue malignancies in adults, and it is characterized by dysregulation of multiple signaling pathways, including MDM2 proto-oncogene (MDM2) amplification. MicroRNA (miRNA) regulates gene expression through incomplete complementary pairing with the 3' untranslated region of mRNAs involved in tumor progression. In this study, bioinformatics analysis, RT-qPCR, dual-luciferase reporter gene, MTT, flow cytometry, cell scratches, chamber migration, colony formation, FISH, WB, and CCK8 were used. RT-qPCR showed that the expression of MDM2 was increased when miR-215-5p was overexpressed compared with the control group. The dual-luciferase reporter gene showed that the Renilla ratio firefly fluorescence intensity was decreased in the overexpression group compared with the control group. Cell phenotype experiments revealed that the overexpression group had increased cell proliferation rate, increased apoptosis rate, increased colony formation rate, increased cell healing area ratio, and increased number of cell invasions. FISH revealed increased MDM2 expression in the overexpression group. WB suggested decreased Bax expression, increased PCNA, Bcl-2, and MDM2 expression, and decreased P53 and P21 expression in the overexpression group. In this study, we suggest that miR-215-5p can target and promote MDM2 expression, promote the proliferation and invasion of LPS cells SW-872, and inhibit apoptosis.Targeting miR-215-5p may be a novel therapeutic strategy for the treatment of LPS.
2022-11-14 | Transcriptome analysis identifies TODL as a novel lncRNA associated with proliferation, differentiation, and tumorigenesis in liposarcoma through FOXM1.
Liposarcoma, the most common soft tissue sarcoma, is a group of fat cell mesenchymal tumors with different histological subtypes. The dysregulation of long non-coding RNAs (lncRNAs) has been observed in human cancers including a few studies in sarcoma. However, the global transcriptome analysis and potential role of lncRNAs remain unexplored in liposarcoma. The present investigation uncovers the transcriptomic profile of liposarcoma by RNA sequencing to gain insight into the global transcriptional changes in liposarcoma. Our RNA sequencing analysis has identified that many oncogenic lncRNAs are differentially expressed in different subtypes of liposarcoma including MALAT1, PVT1, SNHG15, LINC00152, and MIR210HG. Importantly, we identified a highly overexpressed, unannotated, and novel lncRNA in dedifferentiated liposarcomas. We have named it TODL, transcript overexpressed in dedifferentiated liposarcoma. TODL lncRNA displayed significantly higher expression in dedifferentiated liposarcoma cell lines and patient samples. Interestingly, functional studies revealed that TODL lncRNA has an oncogenic function in liposarcoma cells by regulating proliferation, cell cycle, apoptosis, differentiation, and tumorigenesis in the murine model. Silencing of TODL lncRNA highlighted the enrichment of several key oncogenic signaling pathways including cell cycle, transcriptional misregulation, FOXM1 network, p53 signaling, PLK1 signaling, FoxO, and signaling Aurora signaling pathways. RNA pull-down assay revealed the binding of TODL lncRNA with FOXM1, an oncogenic transcription factor, and the key regulator of the cell cycle. Silencing of TODL lncRNA also induces adipogenesis in dedifferentiated liposarcomas. Altogether, our finding indicates that TODL could be utilized as a novel, specific diagnostic biomarker, and a pharmacological target for therapeutic development in controlling aggressive and metastatic dedifferentiated liposarcomas.
other
2026-07-01 | From cold to responsive: IFN-α treatment is associated with collagen VI remodeling and enhanced anti-PD-1 efficacy in Well-/dedifferentiated liposarcoma
Well-/dedifferentiated liposarcoma is characterized by frequent local recurrence and limited responsiveness to immune checkpoint blockade (ICB), highlighting the need for pathology-feasible immune stratification and rational combination strategies. We integrated bulk transcriptomics, single-cell RNA sequencing, proteomics, and spatial immunofluorescence to characterize the tumor immune microenvironment in WD/DD LPS. Unsupervised analyses identified two reproducible states: an immune-high (Hi) subtype enriched for type I interferon programs and an immune-low (Lo) subtype enriched for extracellular matrix (ECM)-associated features. Based on these signatures, we derived a five-marker immunohistochemistry (IHC) panel (CD8A, CD27, AOAH, NCF1, and LST1) to enable pathology-based immune subtyping. In a small, independent exploratory cohort of ICB-treated WD/DD LPS patients ( n = 10), the locked classifier showed a directionally consistent trend in outcomes, but was underpowered and should be considered hypothesis-generating, warranting validation in larger, prospectively collected cohorts. IFN-α downregulated tumor-cell-derived COL6A1 in vitro and was associated with reduced ECM-linked exclusion features. In a PBMC-humanized xenograft model, IFN-α plus anti-PD-1 therapy enhanced tumor control, accompanied by increased CD8 + T-cell infiltration, providing preclinical proof-of-concept support for IFN-α as a combination partner for PD-1 blockade. Mechanistically, the proposed COL6 axis is a hypothesis supported by in vitro IFN-α-dependent suppression of tumor cell COL6A1 and correlative multi-omic/spatial observations; the in vivo model used here does not establish COL6 causality, and definitive testing will require genetic loss-of-function studies. Together, these findings define an immune-ECM axis, present a pathology-ready IHC framework for hypothesis-generating immune stratification, and support further investigation of IFN-α-based combination strategies under rigorous clinical validation.
2025-10-02 | Identification of Guanine-Quadruplex-Binding Peptides from the RGG3 Domain of TLS/FUS.
Guanine quadruplexes (G4s) are non-canonical nucleic acid structures that have emerged as attractive therapeutic targets owing to their involvement in diverse biological processes. Additionally, peptides derived from G4-binding proteins provide promising platforms for selective G4 recognition. In this study, we explored the G4-binding capacity of arginine-glycine-glycine (RGG)-rich sequences derived from the RGG3 domain translocated in liposarcoma/fused in sarcoma (TLS/FUS), a known G4 RNA binding protein. In this study, we synthesized a library of overlapping 15-mer peptides and evaluated their G4-binding affinities. Among the 10 evaluated native sequences, several peptides demonstrated measurable affinities toward G4 RNA structures, with STK5-1 exhibiting the highest G4-binding affinity. Furthermore, to investigate the impact of conformational constraints on G4 recognition, we introduced (E)-methylalkene dipeptide isosteres (MADIs) into selected Gly-Gly motifs, generating a series of RGG peptidomimetics. Subsequent binding assays revealed that some of these MADI peptidomimetics exhibited enhanced affinity and selectivity compared with their unmodified counterparts. Our findings offer new insights into the sequence and structural features governing G4-binding, establishing a foundation for the further development of peptide-based G4 ligands.
2025-04-05 | TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development.
Dedifferentiated liposarcoma (DDLPS) accounts for 15-20% of liposarcoma (LPS) and has high rates of local recurrence and distant metastasis. Hyperactivation of yes-associated protein (YAP) has been implicated in DDLPS development. However, the mechanisms that drive aberrant YAP signaling remain largely unknown. Here, we show that tumor protein p53 inducible nuclear protein 2 (TP53INP2) is a potential negative modulator of the malignant progression of DDLPS. The TP53INP2 protein expression level in tumor tissues from 79 patients with DDLPS decreased progressively. Compared with primary tumors, recurrent tumors also exhibited reduced TP53INP2 expression. More importantly, low TP53INP2 expression is correlated with poor prognosis. TP53INP2 gain- or loss-of-function experiments in DDLPS cell lines showed profound inhibitory effects on processes and properties linked with cancer malignancy, such as proliferation, migration, stemness and dedifferentiation. Mechanistically, TP53INP2 is located mainly in mitochondria and promotes mitophagic degradation of YAP in a VDAC1-dependent manner. The WW domain in YAP and the PPTY motif in VDAC1 are required for their interaction. Taken together, these data demonstrate that TP53INP2 represses the malignant progression of DDLPS by inactivating YAP via a mitophagy-dependent mechanism and that TP53INP2 may constitute a novel prognostic biomarker for advanced DDLPS.
2025-03-27 | Anti-CD137 agonist antibody-independent and clinically feasible preparation of tumor-infiltrating lymphocytes from soft tissue sarcoma and osteosarcoma.
Tumor infiltrating lymphocytes (TILs) therapy has been proved for treatment of metastatic melanoma and is under investigation for other types of solid tumors. However, these successes are threatened by discontinued supply of GMP-grade anti-CD137 agonist, a key TIL preparation reagent. Therefore, exploring a GMP-adherent method for expanding endogenous TILs without anti-CD137 agonist is urgent. Toward this end, we aimed to establish an anti-CD137-independent and clinically feasible TIL expansion protocol to prepare TILs from under investigated sarcoma tumors. We collected resected tumors from patients and cut tissues into fragments. We used IL-2 and T-cell activator CD3/CD28 without anti-CD137 agonist to expand nonselected TILs in 2-3 weeks, then rapidly expanded them over 2 weeks. Their phenotypes were characterized using flow cytometry. Their antitumor activity was validated in vitro using cytotoxic T lymphocyte assays measuring CD107a on the TILs and the viability of tumor cells and in vivo using an autologous patient-derived xenograft (PDX) tumor model. We successfully expanded TILs in > 90% of collected samples. TILs generated preferentially increased CD8+ T cells but suppressed CD4+ T cells. A small portion of TILs were resident memory T cells. The expanded TILs reduced autologous tumor cells by 37.5% within 24 hours. Infusion of TILs in mice bearing autologous PDX tumors strongly inhibited liposarcoma growth. FDA has approved use of this GMP-feasible protocol in our clinical trial (IND 30562). It is feasible to generate antitumor TILs using CD3/CD28 activator to replace the unavailable anti-CD137 agonist. Our study supports the further development of TIL-based therapy.
2025-03-04 | Use of patient-derived organotypic tumor spheroids for testing of viral vector gene therapy in combination with checkpoint blockade.
Checkpoint inhibitors have revolutionized cancer treatment, but a significant proportion of patients do not respond to these therapies, underscoring the need for alternative strategies. Although gene therapy has made substantial strides, its application in solid tumors remains underexplored, with limited treatments approved. Here, we further investigated a gene therapy approach with non-replicating adenoviral vectors encoding the alternate reading frame (ARF) and interferon beta (IFNb) and tested it in a clinically relevant setting. We previously showed that this combined gene therapy induces immunogenic cell death in melanoma models, and now, we utilize patient-derived organotypic tumor spheroids (PDOTS), a model that closely recapitulates the immune environment of tumors, to test its effects using patient tumors. Our results demonstrate, for the first time, the effectiveness of using PDOTS to evaluate viral-vector-based gene therapies. While the addition of anti-PD-1 did not enhance therapeutic outcomes, the gene therapy alone suppressed tumor growth and triggered antitumor immune responses across different cancer models, notably those with low immunogenicity and specific genome profiles. These findings suggest that this gene therapy could serve as a valuable alternative for patients not responsive to checkpoint inhibitors and who have solid tumors with limited treatment and impaired p53-ARF-MDM2 pathways, such as liposarcomas.
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Drug Discovery Landscape
1 orphan drug designation for Dedifferentiated liposarcoma.
1 orphan drug designation for Dedifferentiated liposarcoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Spiro[3H-Indole-3,2¿-pyrrolidin]-2(1H)-one derivative | small molecules | FDA | 2022-06-24 | — | Boehringer Ingelheim Pharmaceuticals, Inc. |
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