tbuckley/cabot-search huggingface dataset:
Abstract 2118: ABN501: A CLDN3-targeted monoclonal antibody with proven safety, pharmacokinetics, and synergistic anti-tumor efficacy
Authors: Saehyung Lee, Jae Choi, Sunghyun Hong, Ha Yeon Park, Ho Jin Lee, Jaemun Kim, Sangin Lee, Seung Hwa Jung, Myeung Ryun Seo, Hobin Yang, Sungyoul Hong, Jun Young Choi, Na Young Kim, Young Kee Shin
Journal: Cancer Research (2025)

Abstract ABN501 is an afucosylated monoclonal antibody specifically designed to target claudin-3 (CLDN3), a protein frequently overexpressed in various solid tumors, including small-cell lung cancer (SCLC). Given the critical role of CLDN3 in cancer cell proliferation and tumorigenesis, it is recognized as a promising therapeutic target. In this study, we evaluated the preclinical safety and efficacy of ABN501, focusing on its potential for clinical development as a targeted cancer therapy. To identify suitable animal models for toxicity assessment, we investigated the cross-species reactivity of ABN501 with CLDN3. Our results confirmed that ABN501 binds to CLDN3 across human, mouse, rat, and cynomolgus monkey species. Based on these findings, rats and cynomolgus monkeys were selected for comprehensive toxicity evaluations, including single-dose and repeated-dose studies. Notably, even at the highest administered doses, ABN501 exhibited no significant changes in key toxicity markers, demonstrating its exceptional safety profile. We further assessed the therapeutic potential of ABN501 as both monotherapy and in combination with chemotherapy. Chemotherapy was shown to upregulate CLDN3 expression in lung cancer cell lines, thereby enhancing the antitumor activity of ABN501 and confirming a synergistic effect. In conclusion, our preclinical studies demonstrate that ABN501 is a safe and effective CLDN3-targeting monoclonal antibody for treating CLDN3-overexpressing cancers. Its excellent safety profile and synergistic effects in combination with chemotherapy present a promising strategy for improving treatment outcomes, particularly in cancers with limited targeted treatment options. These findings pave the way for further clinical investigation, particularly in lung cancer and other CLDN3-expressing malignancies. Citation Format: Saehyung Lee, Jae Choi, Sunghyun Hong, Ha Yeon Park, Ho Jin Lee, Jaemun Kim, Sangin Lee, Seung Hwa Jung, Myeung Ryun Seo, Hobin Yang, Sungyoul Hong, Jun Young Choi, Na Young Kim, Young Kee Shin. ABN501: A CLDN3-targeted monoclonal antibody with proven safety, pharmacokinetics, and synergistic 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 2118.
Abstract 3497: A chimeric antibody-based gamma/delta TCR targeting GPC3 overcomes low antigen expression in liver cancer therapy
Authors: Dan Li, Tianyuzhou Liang, Hsi-En Tsao, Laura Hutchins, Madilyn Gaydos, Chin-Hsien Tai, Jing Bian, Maggie Cam, Hongbing Zhang, Cheng Liu, Mitchell Ho
Journal: Cancer Research (2025)

Chimeric antigen receptor (CAR) T cell therapy is a promising approach for cancer treatment; however, its effectiveness in solid tumors is hindered by challenges such as antigen escape due to mutations, heterogenous expression, and immunosuppressive tumor microenvironment. Previously, we developed CAR-T cells targeting glypican-3 (GPC3) for liver cancer using a humanized GPC3-specific monoclonal antibody (hYP7) and human single-domain antibody (HN3). The hYP7 CAR-T cells demonstrate tumor regression in preclinical mouse models and are being used to treat liver cancer patients in a clinical trial at the NIH. In this study, we analyzed clinically-relevant mutations in GPC3 transcripts observed in hepatocellular carcinoma (HCC) patients through RNAseq analysis. Produced the GPC3 variant proteins, and tested whether these mutations may functionally reduce the effectiveness of CAR-T therapies targeting GPC3. We also developed an engineered antibody-gamma/delta TCR (AbTCR) targeting GPC3, incorporating hYP7 and HN3 antibodies against two distinct epitopes on C and N lobes of GPC3, respectively. In an HCC mouse model with low GPC3 antigen density, the GPC3-targeting AbTCR demonstrated superior tumor control and improved overall survival compared to CAR-T cells, attributable to its robust antigen-binding capacity and enhanced tumor infiltrations. Our RNA sequencing analysis revealed a unique set of upregulated genes in tumor-infiltrating AbTCR-T cells compared to CAR-T cells. These genes were associated with T cell functionality and persistence, particularly pathways involving NF-κB and NFAT signaling. The functional analysis data highlight the GPC3-targeting AbTCR as a new potent therapeutic approach for HCC. Citation Format: Dan Li, Tianyuzhou Liang, Hsi-En Tsao, Laura Hutchins, Madilyn Gaydos, Chin-Hsien Tai, Jing Bian, Maggie Cam, Hongbing Zhang, Cheng Liu, Mitchell Ho. A chimeric antibody-based gamma/delta TCR targeting GPC3 overcomes low antigen expression in liver 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 3497.
Abstract 2584: <i>In situ</i> hybridization-based validation of transcriptionally-defined stromal clusters in the prostate cancer microenvironment
Authors: Filippo Pederzoli, Hubert Pakula, Wikum Dinalankara, Jeanne Jiang, Mohamed Omar, Silvia Rodrigues, Pier Vitale Nuzzo, Fabio Socciarelli, Giuseppe Nicolò Fanelli, Luigi Marchionni, Massimo Loda
Journal: Cancer Research (2025)

Abstract Introduction: Stromal cells in the prostate tumor microenvironment (TME) affect tumor progression and exhibit both a universal response to tumorigenesis and specific ones determined by the genotype that drives the tumor (Pakula et al., Nat Commun 2024). As a result, stromal clusters associated with murine and human prostate cancer identified by single cell RNA sequencing (scRNA-seq) fall into a) common subtypes: myofibroblasts/pericytes and innate immunity-associated; as well as b) two additional ones specific to either AR positive adenocarcinomas or neuroendocrine tumors (NEPC). Here, we defined their spatial localization leveraging spatial transcriptomics and multiplex in situ RNA hybridization. Methods &amp; Results: We computationally identify the most discriminative genes able to distinguish the four stromal groups. Specifically, we first identified highly discriminatory genes representative of each cluster. We then used integer programming-based optimization to obtain small sets of genes (n&amp;lt;4) that are differentially expressed in each group compared to the remaining three. For instance, group 0, encompassing myofibroblasts and pericytes, was characterized by the expression of Rgs5 and Myh11, while group 2, whose stromal cells are characterized by the expression of Ar and Wnt signaling genes, was characterized by the expression of Wif1 and Coch. A decision-tree analysis was able to discriminate all the different stromal groups. These were validated using 1) in situ RNA hybridization + multiplex immunofluorescence panels and 2) spatial transcriptomics. Myofibroblasts/pericytes were found to be distant to tumor cells, common clusters were associated with all tumors of diverse phenotype (Tmprss2-ERG, cMYC, Pten-/-, Pten-/-/ Rb1-/- NMYC+/+), while periostin high/AR low clusters were immediately adjacent to NEPC foci in mouse models. Conclusions: Our integrated computational and experimental approach establishes a robust pipeline for validating stromal markers identified through scRNA-seq, enabling spatial mapping of stromal heterogeneity in prostate cancer. Citation Format: Filippo Pederzoli, Hubert Pakula, Wikum Dinalankara, Jeanne Jiang, Mohamed Omar, Silvia Rodrigues, Pier Vitale Nuzzo, Fabio Socciarelli, Giuseppe Nicolò Fanelli, Luigi Marchionni, Massimo Loda. In situ hybridization-based validation of transcriptionally-defined stromal clusters in the prostate cancer microenvironment [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 2584.
Abstract 4377: AN9025, an orally bioavailable pan-RAS(ON) inhibitor with potent, broad-spectrum anti-tumor activity
Authors: Shuaishuai Liu, Meng Lv, Xiangyu Fu, Chenchen Zou, Hannah Yan, Tanya Yang, Feifan Li, Zhao Sun, Xiaoli Zhu, Hongyang Zhu, Meng Chen, Junying Li, Zhiyong Yu, Nanhai He
Journal: Cancer Research (2025)

Abstract RAS mutations drive approximately 30% of human cancers, representing a critical unmet clinical need. AN9025, an oral RAS (ON) inhibitor, with best-in-class potential, demonstrates picomolar potency against RAS-dependent tumor cell lines, showing greater potency than a benchmark molecule. AN9025 binds to cyclophilin A (CypA) to form a binary complex which then engages the RAS (ON) protein to create a tri-complex that effectively inhibits downstream signaling pathways such as MAPK and PI3K/AKT. Preclinical characterization shows that AN9025 binds to CypA with high affinity (KD=3.2 nM) and selectively engages with GMPPNP-bound RAS (ON), rather than RAS (OFF), to form a tri-complex with single-digit nanomolar affinity (KD=8.8 nM). Consistent with its high binding affinity, cell-based assays showed that AN9025 disrupts the KRAS-RAF1 interaction and downregulates phospho-ERK1/2 levels in KRASG12D- and KRASG12V-mutated cells, with IC50 values of 0.068 and 0.013 nM, respectively. AN9025 also exhibited potent antiproliferative effects across a range of RAS-dependent tumor cell lines with various mutations (KRASG12C, KRASG12D, KRASG12V, KRASG12R, KRASG12A, KRASG13C, NRASQ61H, NRASQ61L, NRASQ61K), achieving IC50 values between 0.001 and 0.1 nM. Additionally, AN9025 demonstrated cytotoxic activity in cell models resistant to KRAS(OFF) G12C inhibitors sotorasib and adagrasib, while showing no cytotoxicity in BRAF-mutant, RAS-independent cell lines. In the KRASG12D-bearing HPAC xenograft model, oral administration of AN9025 at a dose of 0.125 mg/kg QD achieved ∼95% intratumoral pharmacodynamic (PD) inhibition of DUSP6 and induced deep tumor regression compared to vehicle. Notably, AN9025 demonstrated sustained PD inhibition, with 60% inhibition persisting 14 days post-treatment cessation, suggesting extended therapeutic efficacy. In summary, AN9025 is a highly potent pan-RAS(ON) inhibitor that forms a tri-complex with CypA and RAS, effectively blocking downstream signaling and demonstrating robust antitumor efficacy, including in models that are resistant to mutant-selective RAS(OFF) inhibitors. Preclinical studies support its advancement into clinical development as a promising targeted therapy for RAS-driven cancers. Citation Format: Shuaishuai Liu, Meng Lv, Xiangyu Fu, Chenchen Zou, Hannah Yan, Tanya Yang, Feifan Li, Zhao Sun, Xiaoli Zhu, Hongyang Zhu, Meng Chen, Junying Li, Zhiyong Yu, Nanhai He. AN9025, an orally bioavailable pan-RAS(ON) inhibitor with potent, broad-spectrum anti-tumor activity [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 4377.
Abstract 3998: Exploring fibroblast's influence on chemoresistance in PDAC using patient-derived organoids
Authors: Jonathan Barajas, Carolyn Ruiz, Zhi Yang, Edward Agyare, Saun-Joo Yoon, Ba Xuan Hoang, Bo Han
Journal: Cancer Research (2025)

Abstract Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year survival rate below 13%. A critical factor in this poor prognosis is the tumor microenvironment (TME), characterized by dense stroma comprising cancer-associated fibroblasts (CAFs), immune cells, and epithelial cells. CAFs secrete inflammatory cytokines like IL-6 and TGF-β and deposit ECM components, particularly collagen, leading to immunosuppression and chemotherapy resistance. This study examines the role of fibroblasts in modulating the efficacy of gemcitabine in PDAC using patient-derived organoids (PDOs). PDOs were co-cultured with either human fibroblasts and tumor cells or tumor cells with fibroblast-conditioned medium. The PDOs were cultured in collagen based matrices, which allows for manipulation of the ECM stiffness, using either a soft or stiff gel condition to mimic the heterogeneity of in vivo environments. Conditioned Medium was collected from fibroblasts grown in either soft or stiff ECM gels. Patient-derived cells were obtained from two patients: one Black (G43) and one White (G46). Results reveal significant differences in response to treatment between the two cells used. G43 is shown to be more sensitive to treatment overall in co-culture and condition medium, when compared to G46. However, when cells are compared to themselves, either in co-culture or conditioned medium, there are differences seen. In particular, G43 cells are more responsive to treatment in conditioned medium, in soft ECM, when compared to co-cultures. However, in stiff ECM conditioned media, this effect is not seen. Indicating that the stiffness of the ECM, rather than just secreted soluble factors alone, is a key driver of tumor cell behavior. The difference between co-culture and conditioned media supports the observations that fibroblast induced mechano-stress, aids in chemotherapy resistance. The results suggest that therapeutic strategies aimed at modulating the physical properties of the tumor microenvironment, such as ECM stiffness, could potentially improve treatment responses in PDAC. Citation Format: Jonathan Barajas, Carolyn Ruiz, Zhi Yang, Edward Agyare, Saun-Joo Yoon, Ba Xuan Hoang, Bo Han. Exploring fibroblast's influence on chemoresistance in PDAC using patient-derived organoids [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 3998.
Abstract 4024: Cancer research advocates: satisfaction, frustration, and opportunities
Authors: Bob Riter, Hillary Andrews
Journal: Cancer Research (2025)

Abstract Introduction: Advocates have been involved in cancer research for several decades, but little is known about their opinions regarding what is satisfying and what is frustrating. This largely qualitative study gathered feedback from a range of advocates regarding their experiences with cancer research to identify common themes and to generate hypotheses for future research. Methods: An online survey with 14 questions about the advocates’ background and experiences with research advocacy was distributed in early 2024 to cancer research advocates through multiple organizations and research advocacy networks. Thirty individuals responded, half of whom were advocates with 10+ years of experience. Results: Breast cancer was the most common cancer site of research activity (n=18/30, 60%), and clinical trials (n=29/30, 97%), and translational research (n=25/30, 83%) were the types of research of greatest interest. Respondents were generally enthused about their work and felt like they were making a meaningful contribution. The greatest frustration was being asked for letters of support at the last minute or otherwise “checking a box” for a researcher applying for a grant. Many respondents expressed difficulty in getting connected with research activities, especially at a local level. The advocates noted that the “career path” to becoming an established advocate is not always clear nor is it easy to find opportunities Conclusions and Recommendations: Our survey results demonstrate that research advocates are very engaged and satisfied with their experiences. While excellent training programs provide a solid foundation for new advocates, there should be a greater focus on continued engagement and mentoring for “mid-career” advocates. Citation Format: Bob Riter, Hillary Andrews. Cancer research advocates: satisfaction, frustration, and opportunities [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 4024.
Abstract 2553: Hypoxia-associated lncRNA-induced glycolysis and lactylation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination
Authors: Jun Zhang
Journal: Cancer Research (2025)

Abstract Peritoneal Dissemination is the main site of diffuse gastric cancer (DGC) distant metastasis and indicates an extremely poor prognosis and survival. Our previous research revealed that HIF-1a can initiate the expression of LINC01355, promoting the progression of DGC. Here, in DGC orthotopic transplantation model, we observed that overexpression of LINC01355 could accelerate peritoneal dissemination. We found that LINC01355 could directly bind to Pyruvate Kinase M1/2 (PKM), inhibiting its degradation, thereby facilitating glycolysis in GC and creating a microenvironment with accumulated lactate. Single-cell analysis reveals the presence of a hypoxia-associated subtype of cancer-associated fibroblasts (hypoxiaCAF) within TME of DGC. This distinct subtype is independent of myoCAF, iCAF, and apCAF, representing a novel CAF population. HypoxiaCAFs exhibit a slow proliferation rate and display a senescence-associated secretory phenotype (SASP). Mass spectrometry and related experimental data suggest that lactate accumulation in the TME downregulates the specific histone lysine delactylase HDAC3, promoting histone H4 lysine 12 lactylation (H4K12la). H4K12la is enriched in the promoters of SASP-related genes, driving SASP transcription and exacerbating the senescence of CAFs. Inhibition of HDAC3 blocks the increased viability of DGC cells induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry reveals the presence of fibroblasts in the ascites of patients with peritoneally disseminated DGC, with fibroblast populations displaying high levels of p16 expression and SASP factors. These findings provide insights into the role of histone lactylation in sustaining inflammation-related SASP and the involvement of senescent CAFs in DGC peritoneal dissemination. Citation Format: Jun Zhang. Hypoxia-associated lncRNA-induced glycolysis and lactylation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination [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 2553.
Abstract 5008: A multi-dimensional vision-language deep learning model for radiology and pathology imaging
Authors: Marta Ligero, Tim Lenz, Jakob Nikolas Kather
Journal: Cancer Research (2025)

Abstract Multimodal vision-language models (VLM) have shown promising biomarker classification performance in individual data modalities such as radiology and pathology. By learning joint representations of visual and textual information, these methods have shown to provide better features from medical images. However, current methods are limited to the multimodal landscape of 2D images in radiology and pathology, leaving a substantial gap for the creation of models with 3D data. In this study, we introduce a novel, multimodal VLM that can process both radiology and pathology images of varying dimensionalities. Our approach processes 3D CT reconstructions and 2D digitized hematoxylin- and eosin-stained histology slides simultaneously, learning a joint representation which is applicable for biomarker classification in either modality. Our zero-shot approach was validated using two distinct datasets, eliminating the need for model fine-tuning. The first evaluation assessed whole-body CT lesion classification across multiple organs (lung, liver, kidney, and soft tissue) in 839 patients. The second evaluation focused on distinguishing between lung adenocarcinoma and squamous cell carcinoma in 974 patients. The model achieved an average Area Under the Receiver Operating Characteristic (AUROC) curve of 0.70 for lesion detection and 0.60 for lung cancer subtyping in a zero-shot setting. Our findings demonstrate the potential of multimodal vision-language models to perform medical image analysis without task-specific training, which offers a promising direction for developing more flexible and generalizable image processing and multimodal integration towards an artificial intelligence-driven molecular tumor board. Citation Format: Marta Ligero, Tim Lenz, Jakob Nikolas Kather. A multi-dimensional vision-language deep learning model for radiology and pathology imaging [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 5008.
Abstract 2908: WEE1 as a therapeutic target in <i>TP53</i> and <i>ARID1A</i> concurrent mutant colorectal cancers
Authors: Chi Zhang, Ke Peng, Qing Liu, Yanjing Zhu, Luoyan Ai, Jingyuan Wang, Qihong Huang, Tianshu Liu
Journal: Cancer Research (2025)

The development of next-generation sequencing (NGS) technology has provided us a comprehensive mutation profile of colorectal cancer (CRC). However, large number of genetic alterations, especially tumor suppressers, remain undruggable. ARID1A, as a member of tumor suppresser complex SWI/SNF, is frequently mutated (∼9%) in CRC and its mutations contribute to the tumorigenesis of CRC. Recent evidence indicates targeting DNA damage response pathways exhibits promising efficacy in ARID1A-mutant cancers. WEE1 is a key regulator of G2/M cell cycle checkpoint, and WEE1 inhibition results in the accumulation of DNA damages and ultimately leads to cell death. Our present study demonstrates that WEE1 inhibitor (WEE1i) exhibits the highest sensitivity [ln (IC50) median difference = -1.85, P &amp;lt; 0.0001] among a panel of 199 compounds in ARID1A-mutant CRC cells based on GDSC2 dataset screening. As ARID1A mutation is considered as loss of function (LoF), ARID1A knockout was performed to simulate LoF in multiple CRC cell lines. Notably, ARID1A knockout sensitizes TP53-mutant, but not TP53-wildtype CRC cell lines, to WEE1 inhibitor MK-1775 or ZN-c3. In vivo study also indicated preferable efficacy to MK-1775 in COLO205 ARID1A knockout xenografts, compared with their wildtype counterparts. Mechanistically, TP53-wildtype cells exhibited robust rebound of P53 and P21 pathway under WEE1i treatment which significantly limited the efficacy. Besides, ARID1A deficiency enhanced replication stress (EdU incorporating assay) and DNA damage (γH2AX) through accumulation of pathological R-loops, which were detected by S9.6 nuclear intensity. Immunofluorescence colocalizing analysis also indicated that after WEE1i treatment, γH2AX signal tended to culminate in S9.6 positive loci, suggesting an R-loop associated DNA damage. These studies paralleled a phase 1b/2 clinical trial with SC0191 (a novel WEE1 inhibitor) based combination therapy in a cohort of late-line metastatic CRC patients (NCT06363552). In this cohort, one patient who had previously undergone 6 treatment regimens and harbored concurrent mutations in TP53 and ARID1A, achieved stable disease for at least five months, accompanied by tumor regression in the liver lesion. In conclusion, our research showed that targeting WEE1 is effective in TP53 and ARID1A mutant colorectal cancers. This therapeutic strategy is being tested in a phase 2 study for mCRC patients. Citation Format: Chi Zhang, Ke Peng, Qing Liu, Yanjing Zhu, Luoyan Ai, Jingyuan Wang, Qihong Huang, Tianshu Liu. WEE1 as a therapeutic target in TP53 and ARID1A concurrent mutant colorectal cancers [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 2908.