tbuckley/cabot-search huggingface dataset:
Abstract 2943: SWY2321, a novel topoisomerase I inhibitor linked bispecific ADC targeting EGFR/cMet, exhibits potent anti-tumor efficacy
Authors: Jinyu Yang, Jing Qiao, Mo Dan, Xiwu Hui, Bing Yao, Can Yuan, Miaomiao Wei, Xiao Li, Xuening Lv
Journal: Cancer Research (2025)

Abstract EGFR and cMet are two important clinically validated targets in cancer therapy. They exhibit overexpression across various cancer types with a poor prognosis. The signaling pathways of EGFR and cMet demonstrate intricate interconnections, with evidence suggesting that activation of one pathway can trigger the other. These interactions contribute to augmented cell proliferation, survival, invasion, ultimately tumor growth as well as therapeutic resistance. Consequently, targeting both EGFR and cMet has the potential to improve treatment in patients with solid tumors characterized by EGFR and/or cMet dysregulated pathways. SWY2321 is comprised of a bispecific antibody against EGFR/cMet, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent. The ADC was constructed on the backbone of the clinically validated monovalent bispecific IgG platform and was engineered with fine-tuned affinity on EGFR and cMet, with the aim of enhancing tumor inhibition capacity while reducing EGFR and/or cMet-driven toxicity in normal tissues. SWY2321 demonstrated in vitro binding to all the tested cancer cell lines with various expression of EGFR and cMet, and showed higher internalization and cytotoxicity on the tumor cells co-expressing EGFR and cMet than single targeted ADC or first in class ADC. Furthermore, SWY2321 had potent efficacies on the tumor xenograft models of different malignant types including non-small cell lung cancer (NSCLC), gastric cancer (GC), cutaneous squamous cell cancer (CSCC), and with various expression levels of these two targets, including EGFRHighcMetLow, EGFRLowcMetHigh, EGFRmoderatecMetmoderate and EGFRLowcMetLow. The tumor inhibition efficacies of SWY2321 on these models were superior to first in class ADC, and superior to or equivalent to single-targeted ADCs given at the same dose with SWY2321. Especially in EGFR/cMet co-expressed NSCLC NCI-H1975 tumor model, SWY2321 showed excellent efficacy at 1.5 mg/kg single administration. In summary, the promising efficacy of SWY2321 supports that SWY2321 can be an effective treatment targeting multiple EGFR- or cMet- expressing solid tumors. Citation Format: Jinyu Yang, Jing Qiao, Mo Dan, Xiwu Hui, Bing Yao, Can Yuan, Miaomiao Wei, Xiao Li, Xuening Lv. SWY2321, a novel topoisomerase I inhibitor linked bispecific ADC targeting EGFR/cMet, exhibits potent anti-tumor efficacy [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 2943.
Abstract 5911: The role of CD53+ subsets and the JAK/STAT3 pathway in regulating cancer stemness and immune escape in esophageal squamous cell carcinoma
Authors: Beilei Liu, Hongyu Zhou, Licheng Tan, Bowen Yao, Shuang Zhang, Jiayi Huang, Mengsu Yang, Xinyuan Guan
Journal: Cancer Research (2025)

T cell therapy has revolutionized treatment for hematologic malignancies but faces significant challenges in solid tumor applications, including esophageal squamous cell carcinoma (ESCC). In this study, we utilized a dynamic subcutaneous tumor growth model in mice to investigate how ESCC tumors modulate T cell activity through four distinct phases: initial enlargement, reduction, stabilization, and explosive growth. Single-cell sequencing revealed that CD53+ subsets were enriched in the reduction stage and showed their function in stemness regulation and immune escape. Functionally, CD53+ mouse ESCC cell lines showed a higher organoid formation ability when compared with CD53- cells. When co-cultured with T cells, CD53+ ESCC cell lines revealed their capability in regulating T cell exhaustion. Mechanically, GO enrichment analysis and western blotting demonstrated that CD53+ cells activated IL-6/JAK/STAT3 signaling pathways and upregulated their downstream genes such as C-myc and PD-L1. Furthermore, in vivo study showed that JAK inhibitor Ruxolitinib and STAT3 inhibitor C188-9 could efficiently reduce tumor growth and enhance T cell infiltration in CD53+ mouse ESCC cell lines, suggesting a role in tumor proliferation and T cell editing. This study aims to elucidate the biological function of CD53+ subset ESCC cells in tumor progression and verify their role in T cell regulation, offering new therapeutic targets for ESCC treatment. Citation Format: Beilei Liu, Hongyu Zhou, Licheng Tan, Bowen Yao, Shuang Zhang, Jiayi Huang, Mengsu Yang, Xinyuan Guan. The role of CD53+ subsets and the JAK/STAT3 pathway in regulating cancer stemness and immune escape in esophageal squamous 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 5911.
Abstract 5830: Combining DNA methylation inhibition and STING agonist in the treatment of metastatic triple-negative breast cancer
Authors: Sofiane Berrazouane, Xiaoting You, Jack Su, Margarita Bartish, Rhea Dumitrescu, Marios Langke, Young Im, Benjamin Lebeau, Sonia del Rincon, Josie Ursini-Siegel, Michael Witcher
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer associated with early metastatic events leading to a poor prognosis. According to the American Cancer Society, the 5-year relative survival rate is 91% in patients with localized TNBC but only 12% for those with metastatic TNBC. Thus, there is an urgent need to understand the mechanisms that drive TNBC metastasis to uncover more effective therapeutic approaches. In this regard, we first profiled the RNA-Seq and DNA methylation enrichment in 8 metastatic TNBC cell lines with bone, liver and lung organotropism and then compared them to 3 parental TNBC cell lines. The RNA-Seq data showed that the downregulation of IFN-type-1 pathways is associated with TNBC metastatic organotropism in the lung, liver and bone. Surprisingly, the DNA methylation profiling revealed that the IFN-type-1-related genes are under DNA methylation regulation. The inhibition of DNA methylation with decitabine increased the expression of IFNβ gene in metastatic TNBC cell lines. This supports that targeting DNA methylation and stimulating the IFN-type-1 pathway could represent a new vulnerability for metastatic-TNBC. In this regard, the use of STING agonist, a known stimulator of IFN-type-1, synergizes with decitabine in reducing the viability of 6 metastatic TNBC cell lines with lung, liver and bone organotropism. More importantly, the decitabine/STING therapy showed a potent effect in targeting TNBC metastatic lesions in vivo and improved survival. Altogether, this work suggests that the DNA methylation inhibition and the stimulation of the IFN-type-1 pathway represent a new approach to target the metastatic-TNBC. Citation Format: Sofiane Berrazouane, Xiaoting You, Jack Su, Margarita Bartish, Rhea Dumitrescu, Marios Langke, Young Im, Benjamin Lebeau, Sonia del Rincon, Josie Ursini-Siegel, Michael Witcher. Combining DNA methylation inhibition and STING agonist in the treatment of metastatic triple-negative breast cancer [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 5830.
Abstract 3505: AM105, first-in-class T cell engaging bispecific antibody for metastatic colon cancer, demonstrates strong anti-tumor activity by both neutralizing EGFR activity and engaging T cells
Authors: Hyun-Jong Lee, Dong-Wook Kim, Seong-Yeol Kim, Min Yoon, Young-ha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee
Journal: Cancer Research (2025)

Abstract Globally, colorectal cancer is a significant health concern. In 2020, there were over 1.9 million new cases and more than 930,000 deaths attributed to this disease and 5 year survival rate for distant colorectal cancer is 14.7 percent. Cetuximab, an approved anti-EGFR antibody, is effective in treating metastatic colorectal cancer with wild-type KRAS, improving survival. However, about 80% of patients develop resistance, leading to disease recurrence. To address this high recurrence rate, ongoing research focuses on developing bispecific antibodies that can overcome this resistance, aiming to improve long-term outcomes in metastatic colorectal cancer patients.AM105, a novel T cell-engaging bispecific antibody comprising a newly developed monoclonal antibody (15E3) and an affibody targeting EGFR and 4-1BB respectively. Characterized by its 2+4 architecture, it enhances selective binding to cancer cells by creating a difference in affinity between TAA and 4-1BB. It includes four Affibodies targeting 4-1BB, thereby increasing the likelihood of binding with T cells. Additionally, by enhancing the “clustering of CD137” on T cells, the T cell response is significantly amplified. In addition, AM105 was found to efficiently induce tumor cell death in CRC cell lines, even at very low effector-to-target cell ratio, in a target expression dependent manner. In vivo experiment using humanized 4-1BB mice have demonstrated excellent tumor cell elimination effects, and this therapeutic effect was still observed after newly introduction of tumor cells even in the absence of AM105 in the blood, suggesting the induction of T-cell memory function. Taken together, these results strongly suggested that AM105, a novel 4-1BB based bispecific antibody, exhibits potent anti-tumor T cell activity and could be promising therapeutic agent. Citation Format: Hyun-Jong Lee, Dong-Wook Kim, Seong-Yeol Kim, Min Yoon, Young-ha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee. AM105, first-in-class T cell engaging bispecific antibody for metastatic colon cancer, demonstrates strong anti-tumor activity by both neutralizing EGFR activity and engaging T 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 3505.
Abstract 2959: PF-08046031: A promising first-in-class antibody-drug conjugate for targeting novel tumor antigen in melanoma
Authors: Raj Giraddi, Steven Jin, Devra J. Olson, Iliyana Mikell, Eliana Moskovitz, Rebecca Mazahreh, Sharsti Sandall
Journal: Cancer Research (2025)

Abstract MFI2, also known as CD228, melanotransferrin, p97, MTf, or MELTF, is a GPI-anchored membrane protein that belongs to the iron-transporting transferrin family. CD228 expression is elevated in multiple solid tumors such as melanoma and non-small cell lung cancer (NSCLC) but has limited expression in normal tissues. Here, we have expanded our expression analysis and found that other solid tumors, including head and neck cancer (HNSCC) and esophageal cancer (ESCC), also show positivity rates of 86% and 94%, respectively. PF-08046031 is an antibody-drug conjugate (ADC) that consists of the anti-CD228 human IgG1 antibody conjugated with an average of 4 molecules of monomethyl auristatin E (MMAE) by a cleavable valine-citrine (vc) linker. The proposed mechanism of action (MoA) of PF-08046031 is to bind to CD228-expressing cells where it is internalized and transported to lysosomes to release MMAE, causing microtubule disruption and cytotoxic cell death. This drug-linker and conjugation methodology have been clinically validated and approved. In this study, pharmacological evaluations of antibody binding, internalization, cytotoxic cell death and in vivo anti-tumor activity were conducted using various in vitro and in vivo models. PF-08046031 specifically binds to human CD228 with high affinity in both high and low CD228-expressing tumor cells. In vitro studies showed that the ADC had strong cytotoxic effects on CD228-positive cell lines but not on CD228 negative or genetically modified CD228KO cells. The anti-tumor activity of PF-08046031 was tested in vivo using two cutaneous melanoma models derived from cell lines (A2058 and Colo853). After a single intravenous dose of PF-08046031 at 3 and 6 mg/kg, significant tumor growth inhibition (TGI) was observed in a dose-dependent manner compared to the untreated group. At the highest dose of 6.0 mg/kg, TGI reached 87% for A2058-derived tumors and 90% for COLO853-derived tumors. These findings support the clinical development of PF-08046031 for targeting multiple solid tumors. Citation Format: Raj Giraddi, Steven Jin, Devra J. Olson, Iliyana Mikell, Eliana Moskovitz, Rebecca Mazahreh, Sharsti Sandall. PF-08046031: A promising first-in-class antibody-drug conjugate for targeting novel tumor antigen in melanoma [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 2959.
Abstract 5876: ctDNA as predictor for systemic therapy response in patients with colorectal cancer: A systematic review and meta-analysis
Authors: Anja Holz, Bidisha Paul, Antonia Zapf, Klaus Pantel, Simon A. Joosse
Journal: Cancer Research (2025)

Abstract Background: The response to systemic therapy against metastatic colorectal cancer (mCRC) is currently assessed by radiologic imaging. However, an increasing number of studies have shown that circulating tumor DNA (ctDNA) as liquid biopsy can be used as an alternative method to assess therapy efficacy. We conducted a systematic review with subsequent meta-analysis of primary studies to assess the predictive value of sequential liquid biopsies in patients with colorectal cancer treated with systemic therapy. Methods: Randomized, non-randomized, as well as prospective observational studies, reporting on the change in ctDNA concentration in total cell-free DNA over the course of systemic therapy of patients treated for metastatic colorectal cancer to predict treatment response according to RECIST criteria were included. Results: Forty-one studies involving 4546 evaluable patients with metastatic colorectal cancer were included in the meta-analysis. ctDNA increase during systemic therapy as compared to baseline was significantly associated with progression-free survival (HR: 2.47, 95%CI: 1.97-3.10) and overall survival (HR: 2.18, 95%CI: 1.66-2.86), which were reported in 31 and 22 studies, respectively. Conclusion: Longitudinal plasma-based ctDNA liquid biopsy has prognostic value and may help to identify those patients that benefit of continuing therapy or therapy switch. Although further standardization and randomized controlled clinical trials are required, based on the available data, we recommend longitudinal ctDNA measurements to be included in clinical practice and inclusion in the RECIST criteria. Protocol registration: The protocol for this review was registered on PROSPERO (CRD42023420012). Citation Format: Anja Holz, Bidisha Paul, Antonia Zapf, Klaus Pantel, Simon A. Joosse. ctDNA as predictor for systemic therapy response in patients with colorectal cancer: A systematic review and meta-analysis [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 5876.
Abstract 5910: Characterizing spatial expression patterns and prevalence of folate receptor alpha in relation to other existing and emerging ovarian cancer biomarkers
Authors: Marian Themeles, Kevin Kolahi, Amita Mistry, Erik Huntzicker, Peter Ansell, Emily Deutschman
Journal: Cancer Research (2025)

Abstract The ovarian cancer treatment landscape has seen an emergence of biomarker-targeted therapies following accelerated approval of the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere) in November 2022 (with full US approval granted in March 2024). Many therapies in development are biomarker-directed ADCs with distinct cytotoxic payloads, which is the major effector component of the ADC. Data suggest mechanisms of resistance may be largely payload specific, meaning patients may only be able to receive a limited number of these therapies; thus making it paramount to identify the therapy from which each individual patient will derive maximal clinical benefit. Eligibility for MIRV is currently evaluated by FRα expression as assessed by the immunohistochemical VENTANA FOLR1 (FOLR1-2.1) RxDx Assay (FOLR1 CDx). FRα is expressed in roughly 95% of high-grade serous ovarian cancer, with around 36% prevalence observed at the cutoff for MIRV eligibility (PS2 ≥ 75%, or ≥75% of viable tumor cells with ≥2+ staining). The goal of this study was to characterize the spatial overlap of FRα expression and prevalence with biomarkers that are currently being or could be leveraged for targeted therapeutics in the ovarian space. FRα expression was evaluated in commercially procured, formalin-fixed, paraffin-embedded (FFPE) primary ovarian tumor specimens using the FOLR1 CDx. HER2, Muc16, Mesothelin, TROP2, CLDN6, B7-H4, CDH6, Tissue factor and Napi2B were also evaluated by immunohistochemistry from serial sections taken from the same FFPE blocks. Intensity staining for each biomarker was correlated to FRα intensity staining to identify overlapping eligible patient populations. In addition to intensity overlap, spatial expression patterns of each biomarker relative to FRα were also evaluated to understand sequencing and combinability options. These data shed light on biomarker co-expression in ovarian cancer to best match patients to the ideal targeted therapy and to best tailor optimal combination therapies in ovarian cancer patients. Citation Format: Marian Themeles, Kevin Kolahi, Amita Mistry, Erik Huntzicker, Peter Ansell, Emily Deutschman. Characterizing spatial expression patterns and prevalence of folate receptor alpha in relation to other existing and emerging ovarian cancer biomarkers [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 5910.
Abstract 5878: Landscape of tumor heterogeneity index and tumor mutational burden in non-small cell lung cancer
Authors: Jongwoo Kim, Jong Yeob Kim, Leeseul Kim, Junho Song, Liam Il-Young Chung, Young Kwang Chae
Journal: Cancer Research (2025)

Abstract Background/Aims Tumor heterogeneity and tumor mutational burden (TMB) are novel biomarkers associated with the response to immunotherapy in non-small cell lung cancer (NSCLC), but studies report conflicting results. We aim to describe the associations between these biomarkers. Methods From records of 77 NSCLC patients, tissue next-generation sequencing (NGS) data and circulating tumor DNA (ctDNA) NGS data, along with corresponding tissue TMB (tTMB) and blood TMB (bTMB) values, were obtained. PyClone was used to estimate tumor heterogeneity from tissue sequencing data. Tumors with ≥3 clusters were defined as having high tumor heterogeneity, and those with &amp;lt;3 clusters as having low heterogeneity. Mutant-allele tumor heterogeneity (MATH), another estimate of tumor heterogeneity, was calculated from tissue and blood NGS data. Results Out of the 77 NSCLC cases, 21 cases had high tumor heterogeneity, and 56 cases had low tumor heterogeneity according to PyClone. High tumor heterogeneity was statistically significantly associated with higher tTMB (p-value = 0.02) but was not significantly associated with bTMB. Tumor heterogeneity was not significantly associated with age, sex, smoking status, tumor histology, or metastasis. Tumor heterogeneity was not associated with either tissue MATH (p-value = 0.86) or blood MATH (p-value = 0.30), and there was no significant association between tissue MATH and blood MATH (p-value = 0.96). There was a statistically significant positive correlation between tTMB and bTMB (r = 0.75, p &amp;lt; 0.001). Neither tissue MATH nor blood MATH showed significant associations with tTMB or bTMB. Conclusions High tumor heterogeneity as defined by PyClone was associated with high tTMB but not bTMB. tTMB and bTMB were strongly positively correlated. There were no evident correlations between the estimates of tumor heterogeneity. Citation Format: Jongwoo Kim, Jong Yeob Kim, Leeseul Kim, Junho Song, Liam Il-Young Chung, Young Kwang Chae. Landscape of tumor heterogeneity index and tumor mutational burden in non-small cell lung cancer [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 5878.
Abstract 5974: Novel combinational therapeutic strategy in angiosarcoma through PLK1 and mTOR co-inhibition
Authors: Nimod D. Janson, Alejandra R. Alzate, Annaleigh Powell-Benton, Bozhi Liu, Ant Murphy, Jason A. Hanna
Journal: Cancer Research (2025)

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.