BackgroundIntimal sarcoma (IS) and angiosarcoma (AS), two rare yet highly aggressive vascular mesenchymal malignancies, present significant therapeutic challenges due to their scarcity, which underscoring the urgent need to investigate genetic alterations and tumor microenvironment (TME) features for novel therapeutic development.MethodsWe performed integrated analysis of whole-exome sequencing (WES)/1021-gene panel sequencing, RNA sequencing, and immunohistochemistry (IHC) data from 31 IS and 35 AS patients to identify potential precision therapy.ResultsGenomic profiling revealed 522 and 518 single nucleotide variants (SNVs) in the IS and AS cohorts, respectively. TP53 mutations predominated in AS versus IS (15/35 vs 2/31, p < 0.001). Conversely, IS exhibited significantly more copy number variants (CNVs), particularly involving the KDR/KIT/PDGFRA locus (chromosome 4) and the CDK4/MDM2 locus (chromosome 12) (p < 0.001). Strikingly, 25/31 (81%) IS patients harbored CDK4 copy number gains or CDKN2A/B losses, compared to only 2/35 (6%) AS patients (p < 0.001). TME analysis revealed no significant inter-group differences overall; however, pulmonary artery IS specimens demonstrated substantial immune infiltration. Notably, reduced CD3+ T-cell density correlated with shorter survival (p =0.029). PD-L1 expression analysis (≥1% cutoff) showed positivity in 6/8 evaluable patients, including 3 with >50% tumor cell staining. Two IS patients receiving postoperative Sintilimab (PD-1 inhibitor) experienced prolonged survival (overall survival: 14+ and 56+ months, respectively).ConclusionsThis study characterizes the distinct mutation landscape yet similar immune microenvironment of rare IS and AS. Given the frequent cell cycle dysregulation and the observed PD-L1 expression in a subset of patients, CDK4/6 inhibitors and PD-1/PD-L1 inhibitors warrant further clinical investigation for these patients.

Outcome of systemic therapy in patients with advanced rare skin cancers: A retrospective multicenter DeCOG study of 209 patients.

De-Novo Hepatic Angiosarcoma in a Liver Transplant Recipient.

Background: Angiosarcomas (ASs) represent a heterogeneous and highly aggressive subset of tumors that respond poorly to systemic treatments and are associated with short progression-free survival (PFS) and overall survival (OS). The aim of this study was to develop and validate an immune-related prognostic model-termed the AS score-using data from two independent sarcoma cohorts. Methods: A prognostic model was developed using a previously characterized cohort of 25 angiosarcoma samples. Candidate genes were identified via the Maxstat algorithm (Maxstat v0.7-25 for R), combined with log-rank testing. The AS score was then computed by weighing normalized gene expression levels according to Cox regression coefficients. For external validation, transcriptomic data from TCGA Sarcoma cohort (n = 253) were analyzed. The Immunoscore-which reflects the tumor immune microenvironment-was inferred using the ESTIMATE package (v1.0.13) in R. All statistical analyses were performed in RStudio (v 4.0.3). Results: Four genes-IGF1R, MAP2K1, SERPINE1, and TCF12-were ultimately selected to construct the prognostic model. The resulting AS score enabled the classification of angiosarcoma cases into two prognostically distinct groups (p = 0.00012). Cases with high AS score values, which included both cutaneous and non-cutaneous forms, exhibited significantly poorer outcomes, whereas cases with low AS scores were predominantly cutaneous. A significant association was observed between the AS score and the Immunoscore (p = 0.025), with higher Immunoscore values found in high-AS score tumors. Validation using TCGA sarcoma cohort confirmed the prognostic value of both the AS score (p = 0.0066) and the Immunoscore (p = 0.0029), with a strong correlation between their continuous values (p = 2.9 × 10-8). Further survival analysis, integrating categorized scores into four groups, demonstrated robust prognostic significance (p = 0.00021). Notably, in tumors with a low Immunoscore, AS score stratification was not prognostic. In contrast, among cases with a high Immunoscore, the AS score effectively distinguished outcomes (p < 0.0001), identifying a subgroup with poor prognosis but potential sensitivity to immunotherapy. Conclusions: This combined classification using the AS score and Immunoscore has prognostic relevance in sarcoma, suggesting that angiosarcomas with an immunologically active microenvironment (high Immunoscore) and poor prognosis (high AS score) may be prime candidates for immunotherapy and this approach warrants prospective validation.

Abstract Background: Angiosarcoma (AS), a clinically aggressive cancer of endothelial origin, is a rare subtype of soft-tissue sarcoma characterised by resistance to chemotherapy and poor prognosis. This study aims to identify transcriptomic biomarkers of chemoresistance in angiosarcoma. Methods: Transcriptomic profiles of 72 Asian AS formalin-fixed paraffin embedded (FFPE) tissue samples were analysed using the NanoString PanCancer IO 360™ Panel and correlated with clinicopathological data. Whole transcriptome data of a subset of samples were available for tumour (n=12) and matched normal tissue (n=6). Differential gene expression of a subset of 35 patients treated with palliative chemotherapy was correlated with treatment response to determine candidate biomarkers of chemoresistance (defined as stable disease or progression). Protein expression of the top candidate biomarker, SPP1, was verified using immunohistochemistry (IHC) on the tissue samples. Correlation of SPP1 protein expression with chemoresistance was examined on two patient-derived AS cell lines. Results: NanoString profiling revealed significant overexpression of genes including SPP1 (log2foldchange -3.49, adj. p=0.0112), CXCL13, CD48 and CLEC5A, accompanied by significant enrichment of myeloid compartment and cytokine and chemokine signalling pathways, as well as neutrophils and macrophages, in chemoresistant tumours. RNA-seq data revealed higher SPP1 expression (p=0.0008) in tumour tissues over adjacent normal compartments. IHC showed a significant moderate positive correlation with SPP1 mRNA expression (r=0.7016; p&amp;lt;0.00110). Higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in AS cell lines. Further analysis on SPP1-overepressed tumours revealed significant overexpression (adjusted p&amp;lt;0.001) of myeloid compartment pathway genes (SLC11A1, CXCL3, CXCL2, TREM1, IL1β) and cytokine and chemokine signalling pathway genes (CXCL3, IL6, CXCL2, IL1β). Conclusions: Our findings suggest that SPP1 overexpression is a biomarker of chemoresistance and poor prognosis in angiosarcoma and is thus a potential therapeutic target. Future research includes validating our results in a larger independent study as well as elucidating the molecular mechanisms of SPP1-mediated chemoresistance. Citation Format: Glenys Mai Shia Khor, Tiffany Rui En Tan, Elizabeth Chun Yong Lee, Bavani Kannan, Boon Yee Lim, Tun Kiat Ko, Jason Yongsheng Chan. High-throughput Transcriptomics Identifies Chemoresistance-associated Gene Expression Signatures in Human Angiosarcoma [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P33.

Angiosarcoma (AS) is a rare and aggressive tumor arising within the endothelium, characterized by a high metastatic rate and poor prognosis. Our prior work established that endothelial loss of Dicer1, a key enzyme in microRNA (miRNA) processing, drives AS formation in mice, indicating a tumor suppressive role for miRNAs in tumorigenesis. Here, we corroborated this hypothesis by generating a novel conditional knockout model targeting Dgcr8, a core component of the microprocessor complex required for pri-miRNA processing. Conditional deletion of Dgcr8 phenocopies Dicer1 loss, resulting in spontaneous AS formation and global loss of mature miRNAs. We further demonstrate that treatment with enoxacin (ENX), a repurposed antibiotic known to enhance miRNA processing, reduces viability, migration, and clonogenicity of AS cells. ENX increases the abundance of tumor-suppressive miRNAs and downregulates oncogenic pathways, including pathways related to cell cycle progression, angiogenesis, and cell migration. These results establish the essential role of miRNA biogenesis in suppressing AS and reveal a pharmacologically targetable vulnerability via ENX-mediated enhancement of miRNA expression in tumors.

Purpose:Angiosarcomas (AS) are rare vascular sarcomas. Secondary AS (sAS) arise from DNA-damaging factors such as radiotherapy and UV radiation (UV-AS) or due to chronic lymphedema. The prognosis for advanced AS is poor, with limited treatment options. Immune checkpoint inhibition is not approved for AS, but high intratumoral T-cell density and frequent mutations in sAS may support efficacy.Patients and Methods:This prospective, single-arm, multicenter phase II trial assessed the efficacy and safety of cemiplimab (350 mg, intravenously every 3 weeks) in patients with locally advanced or metastatic sAS using a Simon’s two-stage design. The primary outcome was the best overall response rate within 24 weeks of treatment. Secondary outcomes included time to response, duration of response, progression-free survival, overall survival, and predictive biomarkers for treatment response.Results:Eighteen patients (12 with AS from radiotherapy, 3 with UV-AS, and 3 with AS due to chronic lymphedema) were treated with cemiplimab. The best overall response rate was 27.8% (4 partial responses, 1 complete response), with a time to response of 2.6 months and a duration of response of 6.9 months. The median progression-free survival was 3.7 months, and the median overall survival was 13.1 months. Grade ≥3 immune-related adverse events occurred in 33.3% of patients. High tumor mutational burden was observed in three patients with UV-AS, two of whom showed a response. High intratumoral CD3+ (P = 0.019), CD4 (P = 0.046), CD8+ (P = 0.026), and FoxP3+ (P = 0.026) T-cell densities; low platelet-to-lymphocyte ratio (P = 0.026); and Colidextribacter abundance were associated with response.Conclusions:Cemiplimab shows promising effectivity in sAS and warrants further investigation. Promising predictive blood and tissue biomarkers were identified, indicating potential for improved patient selection.

Spinal angiosarcoma (AS) is rare, with limited understanding of its therapeutic outcomes and prognostic factors. This study aimed to evaluate the impact of surgery and adjuvant treatments on the prognosis of patients with primary and metastatic spinal AS, as well as potential prognostic factors affecting spinal AS patients. A retrospective review was conducted on 29 consecutive patients with spinal AS at our center from 2014 to 2023. We divided spinal AS patients into primary and metastatic groups, and analyzed the effects of surgical methods, along with adjuvant chemotherapy and radiotherapy, in the prognosis of the two groups. Additionally, the prognostic factors for progression-free survival (PFS) and overall survival (OS) were analyzed by using the univariate and multivariate analyses in spinal AS patients. In isolated primary spinal AS patients, the 5-year OS and PFS rates were 47.9% and 44.9%, respectively. While the 5-year OS and PFS rates were both 0% in metastatic patients. Total tumor resection improved the OS of primary group (P = 0.023), but had limited impact on the prognosis of the metastatic group. Chemotherapy improved the OS of spinal AS patients (P = 0.047), and showed possible trend on improving prognosis in both groups though without statistical significance. Multivariate analysis confirmed that involved segments, surgical protocol, and preoperative C-reactive protein-to-albumin ratio (CAR) were independent prognostic factors for PFS, while preoperative metastasis, tumor size, and preoperative neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for OS in spinal AS patients. Total tumor resection is recommended for primary spinal AS patients without metastasis. Chemotherapy may improve the OS of all spinal AS patients. Besides tumor size and range, metastasis, and surgical methods, inflammatory indicators including NLR and CAR may also function in the prognostic prediction of spinal AS patients.

Splenic hemangiosarcoma (HSA) is a common canine tumor with histology and genetics analogous to human angiosarcoma (AS), a rare and aggressive malignancy arising from vascular cells. To assess biomarkers and inform therapeutics options, spontaneously arising HSAs were systematically profiled for genetic mutations prior to long-term assessment of patient response to chemotherapy and/or targeted therapy. We leveraged the real-world clinical-genomic data of dogs from the FidoCure® platform, a next-generation sequencing (NGS) screen of cancer loci. For all dogs, regardless of therapeutic approach, PTEN and P53 mutations were overall predictors of poor outcome, while NRAS mutation predicted better outcome. However, P53, PIK3CA, ATRX and NRAS predicted a better response to therapies that specifically included a targeted drug. Analyzing gene-drug interactions, we found tumors with P53 mutation were highly responsive to HDAC or MTOR inhibition, while tumors with PIK3CA mutation only predicted response to MTOR inhibition. For veterinarians, this real-world evidence bridges an important translational gap for targeted therapies, demonstrating a comparable or better outcome compared to standard adjuvant chemotherapy alone and an even further enhancement of survival with combined targeted therapy and chemotherapy. The investigation also uncovered a relationship between specific therapeutic interventions and outcomes when particular gene mutations were present, suggesting they could serve as biomarkers. Since canine HSA is a likely correlate for human AS, the study highlights the benefit of canine HSA as a model to inform precision medicine for AS, a rare human malignancy.

Background/Objectives: Anastomosing hemangioma (AH) is a rare, benign vascular tumor predominantly found in the genitourinary tract and often associated with impaired renal function. Due to its nonspecific radiological features, AH is frequently misinterpreted as a malignant vascular neoplasm, particularly angiosarcoma (AS), leading to potentially unnecessary surgical interventions. This study presents a systematic review of AH cases and describes a rare instance of retroperitoneal AH arising from the left gonadal vein, which was resected due to diagnostic uncertainty. Methods: A 68-year-old man underwent imaging for benign prostatic hyperplasia, incidentally revealing a 15-mm hypervascular retroperitoneal nodule adjacent to the left psoas muscle. Imaging findings, including moderate metabolic uptake on 18FDG-PET/CT, raised suspicion for AS. Given the diagnostic uncertainty and high-risk location, the multidisciplinary team (MDT) recommended surgical resection. Laparoscopic excision was performed, and histopathological analysis confirmed AH. The patient remained asymptomatic at a 22 month follow-up. In addition, a systematic review of 159 cases from 64 studies (2009-2024) was conducted to analyze radiological features, treatment approaches, and outcomes. Results: Among the reviewed cases, 68% were incidentally diagnosed, with AH occurring predominantly in the genitourinary system (70%), especially in the kidney, adrenal gland, and ovary. Chronic kidney disease (CKD) was present in 23.3% of cases, while 19.5% had a history of malignancy. Imaging was inconclusive in differentiating AH from malignancies: CT (71.9%) and MRI (6.1%) were the most used modalities, but none could reliably exclude AS. Management strategies included upfront surgical resection in 85%, while a growing proportion (9%) of cases underwent biopsy-based observation rather than immediate surgery. No cases were followed with imaging alone. Conclusions: AH remains a diagnostic challenge due to its overlap with malignant vascular tumors. While surgical excision is often performed, our review highlights an increasing trend toward conservative management with biopsy-based diagnosis. Improved awareness and the integration of histopathology, molecular markers, and MDT-based decision-making are crucial to prevent overtreatment in cases of suspected AH.

Abstract Angiosarcoma (AS) is a rare and highly aggressive vascular sarcoma characterized by a poor prognosis with a 5-year survival rate of only 20-30%. The underlying oncogenic drivers and potential therapeutic targets remain unidentified in most AS cases. Standard treatments, including chemotherapy, surgery, and radiotherapy, demonstrate limited efficacy and are frequently associated with relapse and metastatic progression. These challenges highlight an urgent need to identify novel therapeutic targets and develop effective strategies to improve outcomes for patients with angiosarcoma. We identified Polo-like kinase 1 (PLK1), an overexpressed mitotic kinase, as a potential therapeutic target in angiosarcoma (AS). PLK1, a key mitotic regulator, is a promising candidate for clinical intervention in AS. Through differential gene expression analysis in mouse and human AS models, combined with druggability assessments utilizing publicly available databases and AI-based tools, we have validated PLK1 as a promising therapeutic target for AS. Furthermore, our studies demonstrate the potential combinational synergy of PLK1 and mTOR inhibition using small molecule inhibitors. We have shown that genetic Plk1 depletion by doxycycline-inducible shRNAs and pharmacological PLK1 inhibition using small molecule inhibitor BI 6727 in AS cells reduces cell proliferation colony forming ability in vitro and demonstrates significantly reduced tumor growth in vivo. Moreover, our data reveal that genetic depletion of Plk1 delays tumor onset and significantly improves survival in genetically engineered angiosarcoma mouse models (GEMMs). Previously, we observed activation of the mTOR signaling pathway in AS GEMMs and demonstrated that AS cells are susceptible to mTOR inhibition. In the current study, we observed a synergistic combination of PLK1 inhibition by Volasertib and mTOR inhibition by Rapamycin in AS in vitro and in vivo. Our objective is to determine the mechanisms and pathways governing the development and progression of AS to generate novel precision-targeted therapies. Our findings conclude that PLK1 is a viable therapeutic target in AS, and the combined inhibition of PLK1 and mTOR represents a promising novel therapeutic strategy for this aggressive cancer. Citation Format: Nimod D. Janson, Alejandra R. Alzate, Annaleigh Powell-Benton, Bozhi Liu, Ant Murphy, Jason A. Hanna. Novel combinational therapeutic strategy in angiosarcoma through PLK1 and mTOR co-inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5974.

Abstract Angiosarcoma (AS) is an aggressive tumor resulting in a very poor prognosis for patients. MicroRNAs (miRNAs) regulate gene expression and play important roles in a variety of diseases including cancer. Our previous studies demonstrate miRNA loss leads to AS in mice. To further understand the role of miRNAs that function as critical tumor suppressors in AS, we performed a miRNA-focused CRIPSR-Cas9 screen. The gRNA library was transduced into a human AS cell line expressing doxycycline (dox)-inducible Cas9. After passaging the cells for 28 days, sgRNA amplicon sequencing was performed to determine the change in the frequency of gRNAs. We anticipated that the loss of function of tumor suppressing miRNAs would lead to gRNA enrichment in the cells. Indeed, three miRNAs were identified as hits with significant enrichment of multiple gRNAs, including miR-200b, miR-181b, and miR-410. We hypothesize these miRNAs act as tumor suppressors and reduce proliferation and cell viability in AS. Based on our RNA-seq data, all three miRNAs are expressed in normal endothelial cells. Additionally, miR-410, miR-181b and a miR-200 family member are significantly downregulated in a human AS cell line and miR-410 is frequently deleted in AS patient samples. We are currently conducting functional validation studies by overexpressing these miRNAs in a panel of AS cell lines by lentiviral based expressing the pre-miRNAs. In preliminary results, the overexpression of miR-410 consistently inhibits cell proliferation and colony formation ability in both human and mouse AS cell lines. Additionally, to gain mechanistic insights for these miRNAs, a novel technique called AgoTRIBE was used to identify important mRNA targets regulated by miRNAs. In AgoTRIBE, the miRNA effector Ago2 is fused to ADAR's RNA editing domain, directing ADAR activity to miRNA natural targets. The ADAR editing events on miRNA targets can be detected by RNA seq. We used a dox-inducible lentiviral vector expressing human ADAR (hADAR) or hADAR-Ago in a mouse AS cell line. In preliminary data, we validated the protein expression of ADAR and ADAR-Ago upon dox treatment and the cellular localization of these complexes in cytoplasm. We are working on validating the function of AgoTRIBE by RNA seq and utilize this tool to identify targets regulated by our screen hits. This project represents the first global screen on miRNAs in AS. Functional validation of the hits from the screen in combination with the mechanistic insights from AgoTRIBE can provide fundamental evidence for the role of tumor suppressive miRNAs in AS. Citation Format: Bozhi Liu, Jillian Stachon, Annaleigh Powell-Benton, Sagar Utturkar, Nimod Janson, Anthony Murphy, Nadia Lanman, Jason Hanna. Investigation on the role of tumor suppressive microRNAs in angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2786.

Abstract Human angiosarcoma (AS) is a rare and aggressive subtype of soft tissue sarcoma of endothelial cell origin with a propensity for local recurrence and metastasis. The optimal treatment of metastatic AS is unclear and is associated with a generally poor prognosis unless diagnosed early. The lack of insight into the pathogenesis always causes treatment failure in the clinic. To discover new treatment strategies for AS, it is necessary to develop new and relevant preclinical models for AS. Dogs commonly suffer from a similar neoplasm, called hemangiosarcoma (HA), with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. Angiosarcomas and HA were reported to share pathology, immunohistochemical characteristics, and molecular signatures. Therefore, HA is considered a closer preclinical model for advancing AS research than rodent models. In veterinary clinic, malignant HA always occurs with nodular hyperplasia (NH), a kind of benign tumor. However, the AS orthotopic xenograft mouse still needs standard guidelines for validation. In this study, we successfully generated 5 canine HA cell lines from fresh patient tumor tissues. We compared the RNA sequencing data between HA and NH patient-derived cell strains (5:5). Data revealed that pathways related to autophagy and lysosomal membrane were found upregulated in HA compared to NH. Additionally, PIK3IP1, HIP1, PLAAT3, and MARVELD3 can be considered potential pharmacological targets and biomarkers for HA. Furthermore, we established an orthotopic xenograft model on mouse spleen using canine patient-derived HA cell lines by splenic injection. The results of xenograft spleen mass and drug screening test of toceranib, carboplatin, doxorubicin and cyclophosphamide using xenograft mouse HA cells showed corresponded sensitivity, supported that our model could maintain the original features of the patient tumor. In conclusion, the transcriptional difference between HA and NH might provide a better understanding of the progress of blood vessel sarcoma, and new pharmacological targets and biomarkers for diagnosis. Also, the xenograft model study may provide a reference for both AS and HA therapeutic predictions in basic medical science. Citation Format: Yishan Liu, Haru Yamamoto, Mohamed Elbadawy, Amira Abugomaa, Tatsuya Usui, Kazuaki Sasaki. Transcriptional heterogeneity between hemangiosarcoma and nodular hyperplasia using patient-derived cell lines and orthotopic xenograft model revealed new therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3912.

Abstract OMX-0407 is an orally available spectrum-selective kinase inhibitor targeting key oncology-relevant tyrosine kinases and the salt-inducible kinase family. OMX-0407 offers a dual mode of action (MoA) in cancer by inducing cell cycle arrest in tumor cells and sensitizing the tumor environment to immune cell-mediated tumor cell killing. It is being developed as first-in-class treatment for solid tumor indications with high unmet medical need. Key oncogenic signaling pathways of tyrosine kinases drive cancer progression by regulating cell cycle and growth signaling cascades. Dysregulation of these kinases, such as platelet-derived growth factor receptors, Eph receptors, and Src family kinases, contributes to cancer progression and therapy resistance. OMX-0407 effectively disrupts these processes through potent inhibition of these kinases and their downstream signaling cascades. A comprehensive viability screen of over 380 human cancer cell lines revealed a selective anti-tumor activity across a subset of cancers, including in renal cell carcinomas (RCC) and sarcomas. Pharmacodynamics studies via phospho-proteomics, Simple-Western or functional kinase activity assays revealed that OMX-0407 induces a G1 cell cycle arrest, accompanied by dose-dependent downregulation of cell cycle-associated proteins and kinase signaling pathways. These effects have been confirmed across in vitro cell line studies, in vivo cell line-derived models or even patient-derived xenograft models. Besides its direct effect on tumor cells, OMX-0407 is repolarizing the tumor microenvironment by reducing immunosuppressive regulatory T cells in the tumor bed and shifting toward a pro-inflammatory state. This dual MoA contributes to the potent anti-tumor effects in various syngeneic animal studies. In a human patient-derived xenograft of epithelioid angiosarcoma (AS), derived from a 9-year-old patient, OMX-0407 demonstrated remarkable dose-dependent anti-tumor efficacy as a single agent. The strong anti-tumor efficacy, with tumor reduction in individual animals, was associated with dose-dependent downregulation of phosphoproteins and significant inactivation of key OMX-0407 regulated signaling pathways on kinase level. Clinical data from a patient, diagnosed with secondary radiation-induced AS, resistant to prior lines of chemotherapy, demonstrated that OMX-0407 was well tolerated and achieved a complete response at doses of up to 60 mg twice daily, which remains ongoing at 14 month. These findings support OMX-0407 as a promising first-in-class therapeutic candidate for the treatment of AS and RCC, with a dual mechanism combining direct anti-tumor effects with repolarization of an immunosuppressive tumor microenvironment. As of September 2024, Ph1b expansion cohorts of the first-in-human trial (NCT05826600) were initiated for patients with unresectable or metastatic AS or clear cell RCC. Citation Format: Ilona Petra Maser, Carolin Strobl, Bettina Bauer, Andreas Schirmer, Moritz Zulley, Carmen Amerhauser, Marisa Stebegg-Wagner, Tiantom Jarutat, Hannes Loferer, Stefan Bissinger. OMX-0407 - A spectrum selective kinase inhibitor shows preclinical efficacy in RCC as well as sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 374.

Objective: Soft tissue sarcoma (STS) is a heterogeneous group of rare, malignant mesenchymal tumors, comprising over 70 subtypes. Doxorubicin-based chemotherapy, the standard treatment for the majority of advanced or metastatic STS, has limited efficacy, with low response rates and poor disease control. Identifying new molecular targets is crucial for developing more effective treatments and overcoming resistance, considering the high unmet medical need in this indication. Tissue factor (TF) is a transmembrane protein essential for hemostasis and thrombosis. High levels of TF have been observed in cancers, particularly adenocarcinomas, where it promotes tumor growth, invasion, metastasis and angiogenesis. TF expression in tumors and in tumor-associated endothelial cells is currently considered a putative therapeutic target. Consequently, a TF-targeted antibody-drug conjugate (tisotumab vedotin) has been approved by the Food and Drug Administration for the treatment of cervical cancer.As its expression in STS remains unexplored, we aimed to assess the expression of TF in tissue microarrays (TMA) constructed from archival tumor material from patients and patient-derived xenograft (PDX) models. Methods: Immunohistochemical staining was performed on TMA. Over 550 patient samples with 2-3 cores per tumor were analyzed, covering the 11 most common STS subtypes, such as leiomyosarcoma (LMS), liposarcoma (LPS), angiosarcoma (AS) and myxofibrosarcoma (MFS).In addition, TMA from 31 PDX models from our XenoSarc platform, covering 14 STS subtypes, were included with at least 2 cores per model, with multiple passages of the xenografts to account for potential intra-tumor variability of TF expression during passaging.TMA were evaluated using the scoring: 0 (no expression), 1 (&amp;lt;25% positive cells), 2 (25-50%), and 3 (&amp;gt;50%); scores of 2 or 3 were considered as high expression. Results: Analysis of a multi-sarcoma clinical TMA revealed a limited number of cases with high expression of the target in only a few samples from AS, LPS, LMS and MFS, subtypes that were selected for further analysis using subtype-specific TMAs from these entities. High expression was found in 22.5% of MFS (27 out of 120 donors), 8.0% of AS (6 out of 79 cases), 4.7% of LMS (6 out of 128 patients), 3.2% of LPS (2 out of 62 patients). Detailed correlations with relevant clinical data are currently ongoing and results will be disclosed at the meeting.In the PDX, high TF expression was observed in 9 out of 31 models in at least one passage. Three out of 4 MFS models showed TF high expression in at least one passage and two high-grade sarcoma models maintained high expression across multiple passages (≥3). Conclusion: TF expression in STS is generally limited, with MFS showing the highest number of positivity in clinical samples and xenograft models. Nevertheless, the observed frequency appears insufficient to support TF as suggestive therapeutic target across other subtypes of sarcomas. Citation Format: Francesca La Greca, Agnieszka Wozniak, Chao-Chi Wang, Daniël Gorgels, Flavia Paternostro, Luna De Sutter, Lore De Cock, Kimberly Verbeeck, Ulla Vanleeuw, Raf Sciot, Patrick Schöffski. Epidemiology of tissue factor expression in soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5667.

Background: OMX-0407 is an orally available spectrum-selective kinase inhibitor targeting a set of oncology-relevant tyrosine kinases (TK) as well as the salt-inducible kinase (SIK) family, demonstrating a dual mode of action (MoA) in cancer. This involves OMX-0407-induced cell cycle arrest in tumor cells by de-phosphorylation and inactivation of TKs such as Src family kinases (SFK) and the SIK family, and increased sensitivity of the tumor microenvironment to immune-mediated tumor cell killing. OMX-0407 is currently undergoing early clinical testing for the treatment of angiosarcoma (AS) and clear cell renal cell carcinoma (ccRCC) (NCT05826600). Methods: Kinase activity profiling using the PamChip® kinase array was used to quantify OMX-0407 treatment effects. Moreover, a flow-cytometry-based “phosFlow” assay was developed to assess the phosphorylation status of SFKs. Both assays revealed dose-dependent inhibition of SFK phosphorylation and activity in peripheral blood mononuclear cells (PBMCs). Hence, they were implemented as pharmacodynamic biomarkers in the ongoing first-in-human trial (NCT05826600) of OMX-0407 in patients with previously treated unresectable solid tumors. Results: As of 30th of October 2024, 24 patients have received continuous treatment with OMX-0407 administered orally in 28-day cycles in a dose escalation study at dose levels of 10, 30, 60, 90, 100, and 140 mg twice daily (BID). Treatment was well tolerated with the main safety finding being gastro-intestinal adverse reactions. One patient with secondary radiation-induced angiosarcoma achieved a complete response at doses of up to 60 mg BID, which remains ongoing at 14 months. PhosFlow analysis confirmed OMX-0407 effects on the phosphorylation of SFKs in PBMCs at doses of 60mg and above. This was associated with the inhibition of oncology-relevant TKs as determined by functional kinase activity profiling. Treatment effects were significantly correlated with PK exposure. This confirms that both phosFlow and kinase activity profiling successfully resolve dose-dependent OMX-0407 activity in peripheral patient blood as pharmacodynamic biomarkers. These findings, together with safety findings and PK profiling, contributed to the selection of 100mg BID as the recommended phase 2 dose (RP2D) for the dose expansion. Conclusions &amp; Outlook: OMX-0407 is a promising therapeutic candidate for the treatment of angiosarcoma and RCC with a potential dual MoA combining direct anti-tumor effects with modulation of the immune cell compartment towards a pro-inflammatory state. In September 2024, Ph1b expansion cohorts of the first-in-human trial (NCT05826600) were initiated for patients with unresectable/metastatic AS or ccRCC who have received at least one prior line of therapy, evaluating OMX-0407 at a dose of 100mg BID. Citation Format: Marisa Stebegg-Wagner, Ilona Petra Maser, Bettina Bauer, Andreas Schirmer, Moritz Zulley, Carmen Amerhauser, Thorsten Meyer, Tiantom Jarutat, Hannes Loferer, Stefan Bissinger. Pharmacodynamic biomarker modulation by OMX-0407, a novel, spectrum-selective kinase inhibitor for the treatment of angiosarcoma and renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4350.

BackgroundComprehensive studies on the tumor burden of soft-tissue sarcoma (STS) by anatomical site are lacking in Asian populations.ObjectiveTo investigate the anatomical distribution of STS via relative tumor density (RTD) in a Korean cohort.MethodsThe RTDs of patients with STS at a single-institution from 2007–2022 were retrospectively analyzed. To describe the STS locations, the body was divided into 4 anatomical sites, and the RTD of each was calculated to the compare topographic tumor burden.ResultsFifty-nine cases in 58 individuals, 35 male (60.3%) and 23 female (39.7%), with a mean age of 56.5±20.4 were analyzed. Overall, the most frequent STS site was the lower extremity (LE, n=22, 37.3%), and the highest RTD was in the head and neck (H&N, 2.44; 95% confidence interval, 1.39–3.77). Dermatofibrosarcoma protuberans (DFSP), Kaposi’s sarcoma (KS), and angiosarcoma (AS) accounted for 76.3% of all the cases. DFSP, KS, and AS showed significantly higher RTD on the trunk (2.55, p=0.025), LE (3.88, p<0.001), and H&N (7.42, p<0.001), respectively, than elsewhere.ConclusionEach STS displays topographic variability and produces different topographic tumor burdens by body site in an Asian population.

Efficacy of immune checkpoint inhibitors in the treatment of soft tissue sarcoma: A systematic review and meta-analysis of clinical trials.

Angiosarcoma (AS) is a rare, aggressive malignancy originating from vascular or lymphatic endothelial cells. Despite its severity, little is known about its epidemiology, and no geographical regions have previously been identified as having an exceptionally high incidence. We retrospectively analyzed medical records spanning 37 years (1987-2023) in Okinawa, Japan, identifying 135 cases of AS that were used to calculate its incidence. This incidence was compared to global data to highlight significant regional differences. Factors related to patients' survival were also assessed. The age-adjusted incidence of AS of the scalp in Okinawa was 4.1 per million per year (mpy; 2015 Japanese model population) or 2.0 per mpy (2000 US standard population), significantly higher than the global data, including in the United States (about eightfold higher) and mainland Japan (about fourfold higher). The estimated five-year survival for patients with AS of the scalp in Okinawa was 9.2%. Multivariate analysis identified surgery, chemotherapy, and radiotherapy as significant factors associated with patient survival. This study provides the first evidence of a significantly higher incidence rate of AS of the scalp in Okinawa. Given its rarity, further research is crucial to uncover the epidemiological, genetic, and environmental factors driving this cancer.

Angiosarcoma (AS) is a rare malignant tumor originating from the endothelial cells of blood or lymphatic vessels. It is characterized by an aggressive course with a high risk of generalization. The most frequent sites of metastasis include the skin, soft tissues, breasts, liver, and heart. Clinical symptoms vary depending on the site of origin. The most common include erythema, skin efflorescence, swelling, and tenderness. Diagnosis of AS is established based on histopathological examination with evidence of atypical endothelial cells and vascular structures. Imaging methods are used as supplementary examinations and help in determining the location and extent of the tumor. In this publication, we focus on the secondary type of angiosarcoma, which has been increasingly described in recent years in the irradiated breast area after breast-conserving surgery. We describe three case reports of patients comprehensively treated at our institution. A relatively long remission, spanning several years, is typical. The essential basis of AS treatment is surgical removal of the tumor with intact resection margins. Due to the size of the defect after resection, simple suturing of the skin cover is often insufficient, and collaboration with a plastic surgeon is necessary for the reconstruction of the resulting defect. Professional literature does not unequivocally state the sufficient width of the healthy tissue margin during resection. The benefit of adjuvant chemotherapy or radiotherapy is debatable. Prognosis is generally poor due to insufficient sensitivity to non-surgical treatment modalities and the speed of metastasis.