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:
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.
2026-08-13 | 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.
2026-08-10 | 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.
2026-07-01 | 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.
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.
2026-08-13 | 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.
2026-08-10 | 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.
2026-07-01 | 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.
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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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