tbuckley/cabot-search huggingface dataset:
Abstract 900: Melanoma immune escape controlled by cancer cell-intrinsic STING signaling is linked to MHC-I suppression
Authors: Lea Skovmand Jensen, Anne Weiss, Arianna Draghi, Shawez Khan, Aida Solhøj Hansen, Anders Etzerodt, Bent Winding Deleuran, Marco Donia, Martin Roelsgaard Jakobsen
Journal: Cancer Research (2025)

Abstract Background: A crucial aspect of anti-tumor immunity is the infiltration of cytotoxic CD8+ T cells, which eliminate tumor cells by recognizing tumor antigens presented on major histocompatibility complex (MHC) class I molecules. The innate immune pathway regulated by Stimulator of Interferon Genes (STING) plays a significant role in modulating tumor immunity, and pathway activation is evident to impact T cell priming. In cancer cells, genomic instability leads to the accumulation of cytosolic DNA, activating the STING pathway and triggering a cytokine-driven immune response, which supports tumor control. However, to evade immune detection cancer cells continuously evolve mechanisms to evade immune recognition, such as downregulating MHC-I surface expression, thereby reducing the efficacy of CD8+ T cell-mediated cancer cell elimination. Methods: We utilized a syngeneic mouse model of the murine YUMM.G/YUMMER.G melanoma cells that present high or low somatic mutational burden (SMB), along with a cohort of human melanoma patient-derived cell lines. We investigated the modulating role of cancer cell-intrinsic STING signaling in tumor immunity, focusing on its impact on antigen presentation and immune cell infiltration under varying levels of SMB both in vitro and in vivo. Results: We observed that cancer cell-intrinsic STING signaling strongly associates with MHC I expression in our murine melanoma models. Similar correlations were found in a large group (n=76) of human melanoma patient-derived cancer cell lines. Our in vivo tumor models demonstrated that loss of STING expression significantly affected tumor control in melanoma models with high SMB. Notably, high SMB melanoma tumors deficient in STING expression escaped immune control by reducing infiltration and activation of cytotoxic CD8+ T cells. Conversely, STING depletion in low SMB melanoma cells had limited impact. Conclusion: Our findings advocate that STING expression status in melanoma plays a critical role in determining tumorigenicity, with its influence being dependent on the somatic mutational burden of the cancer cells. This highlights the potential of STING expressions within cancer cells as a critical factor for tumor immunogenicity and should be considered as an exploratory biomarker in immunotherapy settings combined with tumor mutational burden. Citation Format: Lea Skovmand Jensen, Anne Weiss, Arianna Draghi, Shawez Khan, Aida Solhøj Hansen, Anders Etzerodt, Bent Winding Deleuran, Marco Donia, Martin Roelsgaard Jakobsen. Melanoma immune escape controlled by cancer cell-intrinsic STING signaling is linked to MHC-I suppression [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 900.
Abstract 3409: T cell receptors and antibodies targeting shared indel-derived neoantigens
Authors: Kazuma Kiyotani, Peng Zhao, Xiaojing Wu, Yusuke Nakamura
Journal: Cancer Research (2025)

Abstract T cells play a pivotal role in cancer immunotherapy by recognizing neoantigens presented on HLA molecules, which are specifically expressed by cancer cells. While neoantigens are generally unique to individual cancers, shared antigens that are common in a subset of cancer patients, represent promising immunotherapeutic targets. Since frameshift insertions or deletions (indels) are reported to generate highly immunogenic neoantigens through novel open reading frames. However, few studies have explored shared neoantigens from frameshift indels, which are shred among multiple cancer patients. In this study, we analyzed frameshift neoantigens from frameshift indels in TCGA exome sequencing data, identifying 760 recurrent frameshift mutation clusters (FSCs) that shared frameshifted open reading frames and premature stop codons. Among these, we focused on two FSCs in the APC gene, which generate potential neoantigens (AS3 and AS10) presented the HLA-A24 molecule. We successfully identified the T cell receptor (TCR) sequences for APC frameshift neoantigens from healthy donor’s blood. Genetically engineered T cells expressing these TCRs demonstrated recognition and cytotoxic activity against target cells presenting these APC frameshift neoantigens. Additionally, we explored the development of an antibody targeting a complex formed by the APC shared neoantigen AS10 and the HLA-A24 molecule. Using phage display library screening, we isolated single-chain variable fragments (scFvs) that specifically recognized the AS10-HLA-A24 complex. A bispecific antibody (BsAb) was then designed to connect T cells via an anti-CD3 scFv to the AS10 neoantigen on HLA-A24. We found that the AS10 BsAb specifically recognized both the AS10-HLA-A24 complex and CD3 protein, and showed significant IFN-γ release and cytotoxicity against target cells expressing frameshift neoantigens. By focusing on recurrent frameshift mutations and shared neoantigens, this study provides compelling evidence for the development of more effective and broadly applicable immunotherapeutic strategies. Citation Format: Kazuma Kiyotani, Peng Zhao, Xiaojing Wu, Yusuke Nakamura. T cell receptors and antibodies targeting shared indel-derived neoantigens [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 3409.
Abstract 4341: Association of <i>HapB3 1129-5923C&amp;gt;G</i> and <i>1236G&amp;gt;A</i> with severe fluoropyrimidine toxicity: A systematic review
Authors: Samantha J. Embley, Jaime L. Natoli, Pang F. Xiong, Ryan S. Nelson
Journal: Cancer Research (2025)

Abstract Introduction: The DPYD HapB3 haplotype includes a decreased-function intronic variant (1129-5923C&amp;gt;G) as well as a benign variant (1236G&amp;gt;A). Although it was thought that the variants were in complete linkage disequilibrium and testing for only 1236G&amp;gt;A was an accurate proxy, new evidence suggests otherwise. In addition, evidence suggests that drug-related toxicity associated with HapB3 may be less likely compared to no-function DPYD variants. The primary objective of this study was to evaluate the association between HapB3 variants and severe fluoropyrimidine toxicity and to compare this to associations for other variants with functional impact. Methods: We conducted a systematic review (date: Nov 2024) to identify studies that evaluated the association between DPYD variants and severe (grade ≥3) toxicity among patients undergoing fluoropyrimidine-based chemotherapy. Direct comparisons were made for each HapB3 variant (1129-5923C&amp;gt;G and/or 1236G&amp;gt;A) vs wild-type (WT) as well as for other decreased-function (2846A&amp;gt;T) and no-function variants (e.g., *2A) vs WT. Findings were quantitatively combined using Excel to calculate an odds ratio (OR). Indirect comparisons of ORs made across variants using WT as a common comparator. Results: HapB3 vs WT: Each HapB3 variant was compared to WT data with results summarized in the included table. Direct Comparison: HapB3 variants were directly compared to other decreased-function or no-function alleles within the same studies with results summarized in the included table. Indirect Comparison: HapB3 variants were indirectly compared to other decreased-function or no-function alleles from populations outside of HapB3 studies as summarized in the included table. Conclusions: HapB3 variants 1129-5923C&amp;gt;G and 1236G&amp;gt;A were not strongly associated with increased toxicity compared to wild-type. Both HapB3 alleles showed less risk of grade 3 or higher toxicity compared to other decreased-function and no-function variants. Citation Format: Samantha J. Embley, Jaime L. Natoli, Pang F. Xiong, Ryan S. Nelson. Association of HapB3 1129-5923C&amp;gt;G and 1236G&amp;gt;A with severe fluoropyrimidine toxicity: A systematic review [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 4341.
Abstract 3408: Cancer-specific anti-HER2 monoclonal antibodies demonstrate antitumor activities in human breast cancer xenograft models
Authors: Yukinari Kato, Tomokazu Ohishi, Tomohiro Tanaka, Hiroyuki Suzuki, Mika K. Kaneko
Journal: Cancer Research (2025)

Abstract Monoclonal antibody (mAb) therapy represents cutting-edge strategies for cancer treatment. In contrast, safety concerns persist due to the potential targeting of normal cells that express reactive antigens. Developing cancer-specific mAbs (CasMabs) that bind to cancer-specific antigens and exhibit antitumor activity in vivo is critical for reducing the risk of adverse effects. Herein, we selected mAbs targeting human epidermal growth factor receptor 2 (HER2) and successfully established an anti-HER2 CasMab (clone H2CasMab-2; mouse IgG1, kappa). We investigated both the in vitro and in vivo antitumor efficacy using three types of H2CasMab-2: the mouse IgG2a type of H2CasMab-2 (H2CasMab-2-mG2a), the mouse-human chimeric H2CasMab-2 (H2CasMab-2-hG1), and the humanized H2CasMab-2 (humH2CasMab-2). H2CasMab-2 showed lower reactivity to HER2-overexpressed Chinese hamster ovary-K1 (CHO/HER2) and breast cancer cell lines (BT-474 and SK-BR-3) than trastuzumab in flow cytometry. Every format of H2CasMab-2 also showed lower antibody-dependent cellular cytotoxicity (ADCC) against CHO/HER2 and the breast cancer cell lines than trastuzumab. In contrast, every format of H2CasMab-2 exhibited significantly higher complement-dependent cellular cytotoxicity (CDC) in CHO/HER2 and breast cancer cells than trastuzumab. Furthermore, every format of H2CasMab-2 demonstrated compatible in vivo antitumor effects against breast cancer xenografts with trastuzumab. These findings highlight the distinct roles of ADCC and CDC in the antitumor effects of H2CasMab-2 and trastuzumab and suggest a potential direction for the clinical development of H2CasMab-2 for HER2-positive tumors. Citation Format: Yukinari Kato, Tomokazu Ohishi, Tomohiro Tanaka, Hiroyuki Suzuki, Mika K. Kaneko. Cancer-specific anti-HER2 monoclonal antibodies demonstrate antitumor activities in human breast cancer xenograft 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 3408.
Abstract 4464: A large language model for diverse 2D molecular generation (2DMG) and its application in focused library generation and rational design
Authors: Zihao Liu, Qingbo Xu, Zhenyu Wu, Hongbo Zhang
Journal: Cancer Research (2025)

Abstract AI-driven large language models for molecular generation are gaining significant interest in structure-based drug design. However, challenges such as dataset quality, molecular diversity, and synthesizability still persist. To address these challenges, we introduce StoneWise 2DMG, an advanced model that sparks creativity in medicinal chemistry experts, accelerating the drug discovery process by generating diverse 2D molecular structures. The model is pre-trained on a vast dataset comprising 30 million commercial compound structures (covering most global commercial compounds), 8 million patent-derived compound structures (spanning from the 1960s to 2023), 11 million building block structures, and billions of easily synthesizable molecular structures. This large-scale training enables the generation of drug-like molecules suitable for focused library generation and rational design. The 2DMG model can be utilized for focused library generation. By analyzing the structures of molecular glues that have been published or advanced into clinical trials, we selected glutarimide as a seed molecule for focused library design. Utilizing the 2DMG model, we are able to rapidly generate a diverse, rational, synthesizable, and drug-like molecular library. This molecular glue library is currently under synthesis in the laboratory and will be employed for high-throughput screening in the future. We then extended the application of our model to tackle a more advanced challenge in rational drug design. In a case study involving ABBV-CLS-484 (a molecule targeting both tumor and immune cells; PDBID: 7UAD), we analyzed the key binding fragment, thiadiazolidin-3-one, in the crystal structure. The model then used this critical fragment as a seed to generate a focused library of over 100, 000 compounds, which were docked and further selected by medicinal chemistry experts. Ten compounds were chosen for synthesis, and four showed acceptable activity, making them suitable for lead optimization. In summary, StoneWise 2D Molecular Generation model, trained on billions of data points, offers a robust platform for generating diverse and structurally rational molecules. The model supports focused library design for high-throughput or virtual screening and facilitates rational design to explore and expand chemical space, thus accelerating the drug discovery process. Citation Format: Zihao Liu, Qingbo Xu, Zhenyu Wu, Hongbo Zhang. A large language model for diverse 2D molecular generation (2DMG) and its application in focused library generation and rational design [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 4464.
Abstract 3407: Development of bispecific antibodies targeting claudin-6 for precision cancer therapy
Authors: Siret Tahk, Paule Hermet, Anu Ustav, Robin Pau, Ana Shahpazir, Mario Plaas, Gaily Kivi, Andres Männik, Joan Teyra, Tanel Mahlakōiv, Mart Ustav
Journal: Cancer Research (2025)

Abstract Background: Claudin 6 (CLDN6), a tight junction protein, is an oncofetal antigen with limited expression in adult tissues but aberrantly overexpressed in several cancers, including ovarian, testicular, and gastric tumors. Its tumor-specific expression and critical role in maintaining cell adhesion make CLDN6 a compelling target for cancer therapy. Recent studies have linked CLDN6 to tumor progression, metastasis, and chemoresistance, highlighting its potential as both a biomarker and a therapeutic target in precision oncology. This study presents the development of bispecific antibodies for the treatment of CLDN6-positive tumors. Methods: Monoclonal antibodies specific to CLDN6 were generated using virus-like particles (VLPs) displaying CLDN6 as immunogens. Chickens were selected for immunization due to their ability to produce antibodies against highly conserved, multi-transmembrane proteins. Antibody discovery was performed using HybriFree B cell cloning technology and phage display platforms. Results: Bispecific antibodies that specifically recognize CLDN6 and CD3 were developed and evaluated for their effectiveness in killing CLDN6-positive cells while sparing CLDN6-negative cells. Various bispecific antibody formats were assessed, showing differences in non-specific T-cell activation. These findings underscore the importance of selecting appropriate bispecific antibody modalities to achieve maximum therapeutic potency while ensuring a favorable safety profile. The functionality and potency of these novel bispecific antibodies were further demonstrated in vivo using ovarian cancer xenograft models. Conclusions: This study highlights the development of novel bispecific antibodies targeting CLDN6 and CD3, emphasizing their superior safety profile. The use of specifically engineered antibody modalities and highly selective CLDN6 binders ensures minimal cross-reactivity with other homologous family members. These findings support the potential of these bispecific antibodies as a promising therapeutic approach for CLDN6-positive cancers. Citation Format: Siret Tahk, Paule Hermet, Anu Ustav, Robin Pau, Ana Shahpazir, Mario Plaas, Gaily Kivi, Andres Männik, Joan Teyra, Tanel Mahlakōiv, Mart Ustav. Development of bispecific antibodies targeting claudin-6 for precision cancer therapy [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 3407.
Abstract 3924: <i>in vitro- in vivo</i> model correlations and cross-species comparisons in osteosarcoma
Authors: Emma N. Vanderboon, Geoffrey A. Wood, Courtney R. Schott
Journal: Cancer Research (2025)

Abstract Osteosarcoma (OS) is the most common primary malignant bone cancer of both humans and dogs, characterized by its high rate of metastasis. Despite decades of research, treatment strategies for OS have seen limited advancements in over 40 years. This stagnation highlights the critical need for accurate preclinical models to investigate metastasis and develop relevant therapeutic approaches. Understanding the utility and limitations of in vitro and in vivo OS models is paramount to deriving meaningful conclusions that can guide future research and inform clinical strategies. This study aims to develop an in vitro assay pipeline to investigate mechanisms of metastasis and to characterize a panel of human OS cell lines previously characterized using orthotopic amputation and intravenous murine metastasis models, allowing us to examine in vitro- in vivo correlations. Furthermore, the study seeks to characterize a diverse panel of canine OS cell lines, enabling cross-species comparisons since canine OS serves as an important model for human disease and vice versa. By correlating findings between species and in vitro and in vivo models, this investigation seeks to bridge gaps in understanding how metastatic behaviors observed in the laboratory translate to the complexities of metastasis in living organisms. The human panel includes eight patient-derived xenograft (PDX)-derived cell lines (5 primary, 3 metastatic) and two commercial OS cell lines (MG63, SJSA). The canine panel includes commercial cell line D17 and 13 primary cell lines (11 primary, 2 metastatic). The in vitro pipeline comprises six assays designed to mimic key steps of the metastatic cascade: migration (via scratch and transwell assays), invasion (using a spherical invasion assay), anchorage-independent survival (anoikis assay), and colony formation (clonogenic assay). Additionally, doubling-time will be measured to assess proliferation. Results show differences between in vivo and in vitro metastatic behavior for individual cell lines. By establishing a robust and reproducible cross-species in vitro assay pipeline, this study aims to enhance our understanding of OS metastasis and provide a platform for future mechanistic studies. The ultimate goal is to facilitate the accurate interpretation of in vitro and in vivo findings, ensuring that conclusions drawn from these models are relevant and actionable in the context of future OS research and therapeutic development. Citation Format: Emma N. Vanderboon, Geoffrey A. Wood, Courtney R. Schott. in vitro- in vivo model correlations and cross-species comparisons in 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 3924.
Abstract 5673: Identification of potential therapeutic targets by in vivo CRISPR screening on xenograft models
Authors: Ce Zhong, Lu Bai, Tongtong Wang, Yiying Shao, Lingyun Zhang, Lu Zhang, Jingqi Huang
Journal: Cancer Research (2025)

Abstract Introduction: CRISPR screens have been successfully used to identify targetable genes for anti-cancer research and drug development. Typically, CRISPR screens are conducted in vitro on cell lines, which do not fully capture the influence of the in vivo physiological environment. It is well known that any genetic editing might trigger the adjustment of gene balance to compensate for the modifications in the target cells and tissues. To address the complexity of cellular interactions and the immunological response, in vivo CRISPR screening on a xenograft model is a compelling approach to unravel biological processes where cells are targeted within their natural physiological conditions. Methods: We have conducted a CRISPR screening approach using the human non-small cell lung cancer cell line A549 by knocking out tumor suppressor genes using a library of 3, 188 single guide RNAs (sgRNA). Subsequently, in vivo testing was carried out with the genetically edited A549 cells with or without treatment with the kinase inhibitor Trametinib. At the study endpoint, tumor samples were isolated and analyzed. Amplicon sequencing was used to capture residual sgRNA. MAGeCK was used to calculate the gene enrichment score. Results: After CRISPR editing, 37 sgRNA corresponding to 20 genes were captured in the edited A549 cell line. In the vehicle-treated A549 xenograft tumors, 45 sgRNA corresponding to 27 genes were captured, of which 17 genes were overlapping with engineered A549 cell culture, 8 upregulated and 9 downregulated. In comparison, in the A549 xenograft tumors of the Trametinib treated group, 38 sgRNA corresponding to 23 genes were discovered, with 15 overlapping genes, 9 upregulated and 6 downregulated. The change in expression levels was abundant. Of the 3, 188 sgRNA, the majority of sgRNAs were filtered out in the A549 cell line, under in vivo evolution and the influence of Trametinib treatment. We believe that the pathways related to this small set of identified genes may reveal potential new targets for anti-cancer research and drug development. Conclusion: The in vivo CRISPR approach offers a valuable and translational tool for discovering novel targets in cancer research, providing insights for new anti-cancer therapies. Citation Format: Ce Zhong, Lu Bai, Tongtong Wang, Yiying Shao, Lingyun Zhang, Lu Zhang, Jingqi Huang. Identification of potential therapeutic targets by in vivo CRISPR screening on xenograft 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 5673.