tbuckley/cabot-search huggingface dataset:
Abstract 2677: Multi-omics profiling identifies two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics
Authors: Carine Ngo, Leo Colmet-Daage, Julien Vibert, Clémence Henon, Riwan Brillet, Jia Xiang Jin, Daniel Pissaloux, Clémence Astier, Jean-Yves Blay, Axel Le Cesne, Charles Honore, Matthieu Faron, Thomas Grünewald, Franck Bourdeaut, Franck Tirode, Sophie Postel-Vinay
Journal: Cancer Research (2025)

Abstract Background: Epithelioid sarcoma (EpS) is an aggressive sarcoma, characterized by the loss of SMARCB1 expression. EpS is traditionally classified as distal or proximal according to clinicopathological features, but its molecular bases remain largely unknown. Methods: To establish an EpS molecular classification, we combined multiple bulk omics profiling approaches to systematically characterize the genomic, transcriptional and methylome landscapes of EpS. We further investigated inter- and intra-patient heterogeneity and explored molecular subtype-specific transcriptomic signatures, using single-cell RNA sequencing on fresh samples. Results: We identified two molecular subtypes of EpS: “distal-like” and “proximal-like”. Distal-like tumors include all morphological distal subtypes and a subset of proximal and hybrid EpS. They express a specific single-cell derived epithelial-to-mesenchymal transition signature, which associates with improved patient survival and includes Desmoglein 2 (DSG2), which we identify as a potential routine immunohistochemichal biomarker to improve diagnosis. Distal-like EpS also display higher peri-tumoral CD8+ T cell infiltrates with specific tumor-immune cell interactions. Conversely, proximal-like EpS harbor a higher inter-tumoral molecular heterogeneity, with some cases resembling other SMARCB1-deficient tumors by DNA methylation profiling, and high intra-tumoral pro-tumoral macrophage infiltrates. Conclusion: Our study introduces a novel molecular classification of EpS with prognostic value, potential diagnostic markers and distinct tumor immune microenvironments, that extends beyond traditional clinicopathological classification. These insights pave the way for more personalized and effective treatment strategies for patients with EpS. Citation Format: Carine Ngo, Leo Colmet-Daage, Julien Vibert, Clémence Henon, Riwan Brillet, Jia Xiang Jin, Daniel Pissaloux, Clémence Astier, Jean-Yves Blay, Axel Le Cesne, Charles Honore, Matthieu Faron, Thomas Grünewald, Franck Bourdeaut, Franck Tirode, Sophie Postel-Vinay. Multi-omics profiling identifies two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics [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 2677.
Abstract 3015: EGFR x MET tsAb: Differentiated MET biparatopic design with optimal MET inhibitory activity to pursue best-in-class opportunity
Authors: Yanzhou Zhang, Ming Jiang, Hongyu Chen, Mengran Qian, Renke Li, Huang Yan, Huan Li, Xiaona Sun, Sujuan Huang, Xuechun Zhang, Ming Fang, Yue Wu, Fan Wang, Mingchao Kang, Xiaomin Song, Xi Wu
Journal: Cancer Research (2025)

Abstract Acquired resistant mutation after small molecule inhibitor treatment in non-small cell lung cancer (NSCLC) develops invariably through mutations in EGFR or through activation of compensatory pathways such as MET. BG-T187 is a tri-specific antibody (TsAb) targeting EGFR and MET with a differentiated MET biparatopic designation designed to treat tumors driven by activated EGFR and/or MET signaling. Stronger antiproliferative effects and MET signaling inhibition by BG-T187 compared to traditional EGFR/MET bi-specific antibody were observed in vitro. Additionally, potent in vivo anti-tumor activity was observed upon BG-T187 treatment of human tumor xenograft models driven by EGFR activation mutation and/or MET amplification. Interestingly, stronger anti-tumor activity of BG-T187 than that of traditional EGFR/MET bi-specific antibody was observed in xenograft models with MET amplification. Through a comprehensive assessment of EGFR on-target toxicity risk, we demonstrated that BG-T187 show better HEKn selectivity than EGFR/MET bi-specific antibody, indicating potential lower on-target toxicity risk of BG-T187. Collectively, our findings represent a novel EGFR/MET tri-specific antibody with differentiated MET biparatopic and pursue best-in-class potential. Citation Format: Yanzhou Zhang, Ming Jiang, Hongyu Chen, Mengran Qian, Renke Li, Huang Yan, Huan Li, Xiaona Sun, Sujuan Huang, Xuechun Zhang, Ming Fang, Yue Wu, Fan Wang, Mingchao Kang, Xiaomin Song, Xi Wu. EGFR x MET tsAb: Differentiated MET biparatopic design with optimal MET inhibitory activity to pursue best-in-class opportunity [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 3015.
Abstract 2986: Genomic amplification of MCL1 as a therapeutic target for osteosarcoma
Authors: Satoshi Takagi, Tianyi Huang, Ryohei Katayama
Journal: Cancer Research (2025)

Osteosarcoma (OS) is the most common primary malignant bone tumor that predominantly occurs in children, adolescents, and young adults. The treatment for OS that combines surgery with chemotherapy, which consists of a four-drug combination of doxorubicin (DOX), cisplatin (CDDP), high-dose methotrexate (MTX), and ifosfamide, was established in 1970s, and it is still used as a standard therapy. The lack of progress in drug development for OS is partly due to unidentified actionable oncogenic drivers common to OS. In this study, we demonstrate that copy number gains of MCL1 frequently occur in OS, leading to increased vulnerability to therapies based on Mcl-1 inhibitors. Fluorescence in situ hybridization analysis of formalin-fixed paraffin-embedded specimens revealed MCL1 amplification in 46.3% of patients with OS at the JFCR hospital (N = 41). Furthermore, analysis of the TARGET OS dataset, which comprises pediatric patients with OS (N = 81), found that the frequency of MCL1 amplification was notably higher, at 70.4%. Genetic inhibition of MCL1 induced significant apoptosis in MCL1-amplified OS cells. Pharmacological inhibition of MCL1 demonstrated a negative correlation between MCL1 copy numbers and sensitivity to Mcl-1 inhibitors, including MIK665 and AZD5991, with a Pearson’s r value of -0.65 (p = 0.03) across OS cell lines. The chromosome 1q21.2-3 region, where MCL1 is located, contains multiple genes related to the IGF-1R/PI3K pathway, including PIP5K1A, TARS2, OUTD7B, and ENSA, which also showed increased copy numbers in MCL1-amplified OS cells. Additionally, the combination of MIK665 with IGF-1R inhibitors, including OSI906, AEW541, and AZD3463, induced synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling in OS cells. In a NOS-10 (which has 16 copies of MCL1) xenograft model, MIK665 significantly suppressed tumor growth, and its antitumor effect was remarkably enhanced by combining with OSI906. This trend was also observed in a NOS-1 (with 5 copies of MCL1) xenograft model, but the enhancement was more modest than in the NOS-10 model. Moreover, the combination therapy of AZD5991 with OSI906 also reduced tumor growth in the NOS-10 xenograft model. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, observed in nearly half of OS patients, may act as a predictive biomarker for combination therapy with an Mcl-1 inhibitor and an IGF1-R inhibitor. Citation Format: Satoshi Takagi, Tianyi Huang, Ryohei Katayama. Genomic amplification of MCL1 as a therapeutic target for osteosarcoma [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 2986.
Abstract 2851: YAP1-TFE3 fusion protein promotes EndMT in epithelioid hemangioendothelioma
Authors: Ant Murphy, Sam Hartzler, Paula Carranza, Madison Yates, Nimod Janson, Shyaman Jayasundara, Majid Kazemian, Jason A. Hanna
Journal: Cancer Research (2025)

Abstract Epithelioid Hemangioendothelioma (EHE) is an ultra-rare vascular cancer driven by chromosomal translocations resulting in the TAZ-CAMTA1 or YAP1-TFE3 fusion transcription factors. Despite some knowledge of the disease defining fusion proteins, the mechanisms driving tumorigenesis remain largely unclear. To study the effects of EHE fusion protein expression on the biology of endothelial cells, we generated EHE cell models using the murine endothelial cell line MS-1 and the human endothelial cell line HUVEC. Expression of TC and YT led to increased Hippo target gene expression, as expected. However, we observed a striking phenotype in YT-expressing endothelial cells associated with morphologic changes, enhanced migratory potential, and anchorage independence growth. These phenotypic changes are consistent with a process known as endothelial-to-mesenchymal transition (EndMT). EndMT is a physiological process where endothelial cells lose their endothelial identity and become more mesenchymal-like. Indeed, we observe transcriptional changes consistent with EndMT such as the reduction in expression of multiple endothelial-specific markers and a significant increase in transcription of mesenchymal marker, Acta2. We utilize several gain- and loss-of-function approaches to further investigate the mechanisms and impact of EndMT in tumorigenesis. Citation Format: Ant Murphy, Sam Hartzler, Paula Carranza, Madison Yates, Nimod Janson, Shyaman Jayasundara, Majid Kazemian, Jason A. Hanna. YAP1-TFE3 fusion protein promotes EndMT in epithelioid hemangioendothelioma [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 2851.
Abstract 1833: Assessment of shifts in tumor-specific frequencies on the proliferation of hepatocellular carcinoma cells
Authors: Callum T. McGrath, Preeya F. Achari, Carl Blackman, Janaka P. Liyanage, Hugo Jimenez, Boris C. Pasche
Journal: Cancer Research (2025)

Abstract Background: Radiofrequency Electromagnetic Fields Amplitude-Modulated at tumor-specific frequencies (AM RF EMF) are FDA approved for the treatment of advanced hepatocellular carcinoma (HCC) and have been shown to inhibit cancer growth in vitro, in vivo, and in clinical trials. The mechanism behind AM RF EMF induced proliferative inhibition is intracellular Ca2+ influx via the Cav3.2 T-type calcium ion channel exclusively within malignant cells. However, it is unknown how AM RF EMF opens the Cav3.2 channel. We hypothesize that the tumor specific frequencies are the natural frequencies of the malignant Cav3.2 channels and thus AM RF EMF is a resonance phenomenon. To test this, we first assessed the impact on proliferative inhibition from the RF carrier wave and ambient magnetic fields. We then shifted base HCC treatment frequencies from +0.1 Hz to +0.0001 Hz logarithmically and compared proliferative inhibition to base treatment frequencies. Methods: Huh7, Hep3B and SNU-423 HCC cell lines were treated with HCC-specific AM RF EMF under two conditions: normal incubator conditions, and within a magnetically shielded metal box. Growth inhibition relative to control was measured between the two groups via thymidine incorporation assay. Next, Huh7 and Hep3B cells were exposed to the unmodulated 27.12 MHz RF carrier wave and growth inhibition compared to control via thymidine incorporation assay. Lastly, Huh7 and Hep3B cells were treated with HCC AM RF EMF frequencies shifted by either +0.1 Hz, +0.01 Hz, +0.001 Hz, or +0.0001 Hz. Growth inhibition relative to standard treatment was measured via thymidine incorporation assay. Results: There was no change in growth for Huh7 and Hep3B cells exposed to the unmodulated carrier wave compared to their respective controls. There was no change in proliferative inhibition between normal and magnetically shielded conditions for Huh7, Hep3B, and SNU-423 cells. All frequency shifts resulted in significantly decreased treatment efficacy relative to base frequencies (+0.0001 Hz: p = 0.0021, +0.001 Hz: p = 0.0172, +0.01 Hz: p = 0.0145, and +0.1 Hz: p = 0.0279) Conclusion: Neither the unmodulated carrier wave nor ambient magnetic fields contribute to AM RF EMF induced proliferative inhibition. AM RF EMF is not a resonance phenomenon but is highly sensitive to small fluctuations in treatment frequencies, highlighting the specificity required for optimal treatment. Citation Format: Callum T. McGrath, Preeya F. Achari, Carl Blackman, Janaka P. Liyanage, Hugo Jimenez, Boris C. Pasche. Assessment of shifts in tumor-specific frequencies on the proliferation of hepatocellular carcinoma cells [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 1833.
Abstract 3013: GSC000829, a novel selective FGFR2/3 inhibitor, displays superior antitumor activity in preclinical FGFR-driven neoplasms models
Authors: Tian Han, Donglin Fu, Tao Cheng, Yuanfeng Xia, Zhilong Hu, Fanglong Yang
Journal: Cancer Research (2025)

Fibroblast growth factors (FGF) and their receptors (FGFRs) are pivotal in a myriad of cellular functions. Tumorigenesis onset due to FGFR genomic alterations is commonly observed across diverse solid tumors. Although several FGFR inhibitors targeting FGFR1-3 or FGFR1-4 have gained approval for treating various solid tumors, their widespread application is hindered by the development of resistant gatekeeper mutations in FGFR proteins and toxicities linked to FGFR1 and/or FGFR4, necessitating precise dosing or even drug withdrawal. Here, we report the discovery of a novel pre-clinical candidate compound GSC000829 with a strong inhibition towards FGFR2/3 and a significantly improved selectivity over FGFR1 and FGFR4. Furthermore, GSC000829 shows excellent efficacy in various biochemical and cellular assays corresponding to different FGFR fusions or mutations. It also demonstrates enhanced antitumor activity at lower dosage in FGFR3-driven CDX models compared to the pan-FGFR inhibitor Erdafitinib, as well as other FGFR3-selective inhibitors such as TYRA300 and LOXO-435. GSC000829 exhibits favorable physicochemical and pharmacokinetic properties along with an excellent preclinical toxicity profile with no obvious phosphate increase at quite high exposure level in rats. Taken together, these findings bolster the rationale for advancing GSC000829 into clinical trials as a potential best-in-class FGFR isoform-selective inhibitors, offering an approach for treating advanced solid tumors harboring FGFR2/3 aberrations. Citation Format: Tian Han, Donglin Fu, Tao Cheng, Yuanfeng Xia, Zhilong Hu, Fanglong Yang. GSC000829, a novel selective FGFR2/3 inhibitor, displays superior antitumor activity in preclinical FGFR-driven neoplasms models [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 3013.
Abstract 2676: Single cell spatial profiling reveals ERBB2 and EGFR co-expression in primary esophageal adenocarcinoma and brain metastasis tumors
Authors: Nora Lawson, Lingqun Ye, Chae Yun Cho, Bo Zhao, Thomas Mitchell, Ines Martín, Andy Futreal, Kadir Akdemir
Journal: Cancer Research (2025)

Abstract Esophageal adenocarcinoma is a prevalent and serious disease, ranking eighth globally, with a low survival rate of 15-25% and a rising incidence in the United States. However, the occurrence of brain metastasis in esophageal adenocarcinoma (EAC) is rare, affecting only approximately 2-6%. Despite its rarity, brain metastasis in EAC is associated with a poor prognosis, compounded by the limited availability of effective treatment options. Due to the infrequent occurrence of brain metastasis in EAC patients, our understanding of the tumor composition in these cases and how they differ from those in primary sites remains limited. To address these gaps, we analyzed the tumor microenvironment of brain metastasis tumors and their matched primary tumors using spatial transcriptomic data generated by the 10x Xenium Analyzer. By employing a brain tumor panel, an immune panel, and a custom panel, we characterized the tumor microenvironment, including neuronal and immune cell populations present in these samples. Overall, primary samples contained a higher proportion of immune cells such as macrophages, T cells, B cells, dendritic cells, plasma cells, and mast cells, compared to brain metastases, which had a greater composition of neuronal cells. We additionally investigated the oncogenic expression patterns at the single-cell level within these matched samples, revealing areas with high ERBB2 and EGFR expression density within malignant cell populations. Notably, brain metastasis samples contained a higher proportion of malignant cells co-expressing ERBB2 and EGFR than primary samples, suggesting clonal evolution during disease progression from primary to metastatic sites. Our findings indicate that ERBB2 and EGFR amplifications may represent potential targets for therapeutic interventions in these patients. These findings enhance our understanding of brain metastasis in EAC, offering insights into the tumor microenvironment that may guide future therapeutic strategies and improve clinical management for this previously understudied metastatic type. Citation Format: Nora Lawson, Lingqun Ye, Chae Yun Cho, Bo Zhao, Thomas Mitchell, Ines Martín, Andy Futreal, Kadir Akdemir. Single cell spatial profiling reveals ERBB2 and EGFR co-expression in primary esophageal adenocarcinoma and brain metastasis tumors [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 2676.
Abstract 1500: Inhibition of tumor hypoxia response with synthetic transcriptional repressors
Authors: Long Chi Nguyen, Zeyu Qiao, Dongbo Yang, Christopher Dann, Deborah Thomas, Madeline Henn, Andrea Valdespino, Colin Swenson, Scott Oakes, Marsha Rich Rosner, Raymond Moellering
Journal: Cancer Research (2025)

Abstract Hypoxia, a hallmark of aggressive solid tumors, promotes metastasis and therapy resistance by activating factors such as hypoxia-inducible factors (HIFs) that support cellular adaptation and tumorigenesis. Under hypoxic stress, transcription factors like HIFs and X-box-binding protein 1 (XBP1) are activated and bind to unfolded protein response element (UPRE) and hypoxia response element (HRE) motifs, regulating oncogenic gene expression. We identified that the core HRE motif (5’-ACGTG-3’) is embedded within the canonical UPRE motif (5’-TGACGTGG-3’), and prior research shows overlap in the binding patterns of HIF1α/ARNT and XBP1. We propose a novel strategy to target the tumor hypoxia response by using fully synthetic transcriptional repressor (STR) peptides that mimic the basic leucine zipper DNA-binding domain of XBP1. These peptides effectively bind to UPRE and HRE DNA elements. Our lead peptide, STR22, inhibits the DNA binding of both XBP1 and HIF1A, resulting in global suppression of the hypoxia response transcriptional program in vitro and in triple-negative breast cancer (TNBC) tumor models. STR22 has shown no observable toxicity with either intratumoral or intravenous administration and significantly inhibits tumor growth and metastasis in TNBC-bearing mice. Our findings validate STRs as a safe and promising approach for targeting DNA motifs, including tumor hypoxia response elements, through direct DNA binding competition with oncogenic transcription factors. This strategy offers potential to outperform single-factor therapies, presenting a novel option for clinical applications. Citation Format: Long Chi Nguyen, Zeyu Qiao, Dongbo Yang, Christopher Dann, Deborah Thomas, Madeline Henn, Andrea Valdespino, Colin Swenson, Scott Oakes, Marsha Rich Rosner, Raymond Moellering. Inhibition of tumor hypoxia response with synthetic transcriptional repressors [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 1500.
Abstract 2687: Exploring the synergistic mechanisms of VEGFR and immune checkpoint inhibitors in clear cell renal cell carcinoma metastases
Authors: Stefan Maksimovic, Nina Costanza Boscolo, Matthew T. Campbell, Eleonora Dondossola
Journal: Cancer Research (2025)

Abstract M.C. and E.D. equally contributed. Clear cell renal cell carcinoma (ccRCC) is the most common malignancy originated from the kidney, with bone and lungs as the main sites of distant spread in vast majority of patients. A key feature of ccRCC is the loss of function of the von Hippel-Lindau (VHL) protein leading to enhanced angiogenesis; in addition, ccRCC exhibits a rich and heterogeneous immune infiltrate. Consequently, different anti-angiogenic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)have emerged as standard of care for these patients, as single agents or in combination. Yet, limited data are available on their efficacy in different metastatic sites, and their impact on the immune infiltrate is unclear. We hypothesized that modulation of the microenvironment with a TKI provides an additive impact on ICI, and the outcome of combinational treatments depends on metastatic sites, treatment doses and tumor size. To this purpose, we implanted a luciferase-GFP-positive RENCA-VHL- cell line in the tibia of immunocompetent mice, resulting in synchronous bone and lung metastases. Cabozantinib (C), as one of the most potent TKIs, anti-programmed cell death protein 1 (Anti-PD1) and anti-CTLA4 antibodies, were used as single agents or in combination. The outcomes were monitored by macroscopic bioluminescence detection in vivo, and 3D multiparametric spatial analysis of bones and lungs, ex vivo. Compared to control-treated mice, all agents significantly reduced tumor progression at both tumor sites. Although all these treatments are clinically applied at stage IV of disease development, differences in their efficacy were noted once treatment was withdrawn. Spatial analysis of tumor cells, immune infiltrate and blood vessels revealed significant changes dependent on treatment, tumor site and time, with potential synergistic mechanism by TKIs when used in combination with ICI. We proved the efficacy of standard of care for bone and lung lesions of ccRCC in an immunocompetent mouse model and identified differences between treatments at the cellular level in the tumor microenvironment. We believe our studies may provide important insights and efficacy predictions for therapeutic applications in metastatic ccRCC patients. Citation Format: Stefan Maksimovic, Nina Costanza Boscolo, Matthew T. Campbell, Eleonora Dondossola. Exploring the synergistic mechanisms of VEGFR and immune checkpoint inhibitors in clear cell renal cell carcinoma metastases [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 2687.