tbuckley/cabot-search huggingface dataset:
Abstract 2220: Gut microbiome impacts the tumor microenvironment and enhances the effectiveness of anti-PD1 therapy in head and neck cancer
Authors: Po-Han Lin, Ya-Hui Chen, Chi-Maw Lin, Jessica Tien Yu Ho, Chih-Hao Yu, Chen-Yi Wang, Yuan-Chia Chu, Chun-Yu Liu, Ying-Cheng Chiang, Ruey-Long Hong
Journal: Cancer Research (2025)

Abstract Although the Food and Drug Administration has approved anti-PD1 as an effective therapy for recurrent head-and-neck squamous cell carcinoma (HNSCC), its response rate remains limited to approximately 10-30%, and the prognosis for patients is still poor. In this study, we seek to enhance the therapeutic efficacy of anti-PD1 for recurrent HNSCC. First, we compared the pathology of responders and non-responders to pembrolizumab treatment for HNSCC. Immunohistochemical staining revealed a significantly higher abundance of CD8 T cells in responders, and RNA sequencing, through Gene Set Enrichment Analysis (GSEA), demonstrated a significant activation of CD8 T cell pathways in responders compared to non-responders. Second, 16S full-length sequencing of stool DNA identified an enrichment of Eggerthella lenta (E. lenta) in responders. Furthermore, the presence of E. lenta was positively correlated with CD8 T cell activation and cytotoxic activity. Third, to assess the impact of E. lenta on the anti-tumor response to anti-PD1 therapy in vivo, we implanted HNSCC tumors subcutaneously in antibiotic-induced microbiome depletion mice. The mice were treated with anti-PD1 monoclonal antibody and oral E. lenta administration, resulting in significant tumor regression compared to that of the controls (no treatment), anti-PD1 alone, or E. lenta alone. The excised xenograft HNSCC tumors were analyzed by flow cytometry, revealing that the combination of anti-PD1 therapy and oral E. lenta synergistically increased tumor-infiltrating CD8 T cells and enhanced their activation, as evidenced by elevated interferon-gamma and TNF-alpha expression. Metabolomic analysis identified changes in fatty acid pathways linked to CD8 T cell activation, E. lenta administration, and responders. Our results suggest that E. lenta enhances the response to anti-PD1 therapy, offering new insights into the connection between the microbiome and cancer immunotherapy. Citation Format: Po-Han Lin, 1 Ya-Hui Chen, 1 Chi-Maw Lin, 1 Jessica Tien Yu Ho, 2 Chih-Hao Yu, 1 Chen-Yi Wang, 1 Yuan-Chia Chu, 1 Chun-Yu Liu, 3 Ying-Cheng Chiang, 1 Ruey-Long Hong1. Gut microbiome impacts the tumor microenvironment and enhances the effectiveness of anti-PD1 therapy in head and neck 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 2220.
Abstract 6138: Generation of humanized C1Q mice for antibody-mediated CDC therapy research
Authors: James Jin, Ruili Lv, Zan Zhang, Jinyi Ma, Jiangfeng Yuan, Xuan Yu, Zhi Zhang, Jiansu Zhang, Xiaofei Zhou
Journal: Cancer Research (2025)

Abstract The complement system is an essential part of innate immunity, consisting of more than 30 proteins. A critical element in the pathway is C1q (Complement 1 q), an important recognition molecule in the classical pathway of the complement system that can initiate the classical pathway and plays a major role in bridging innate and adaptive immunity. C1q is also vital in monoclonal antibody (mAb) therapy, as it attaches to the Fc region of antibodies, initiating complement-dependent cytotoxicity (CDC). Here, we generated a humanized C1Q model (B-hC1Q mice), by replacing the murine C1qa, C1qb, and C1qc genes that encode the full-length protein with the corresponding human C1QA, C1QB, and C1QC coding regions. We confirmed the exclusive expression of human C1Q in the serum of the humanized model at levels comparable to those of wild-type murine C1Q. We also performed classical pathway complement activity analysis on B-hC1Q mice, and the results showed that humanized C1Q performed the proper complement function in mice. To evaluate the CDC effector of monoclonal antibodies in eliminating cancer cells, we conducted tumor efficacy experiments using B-hCD38-luc E.G7-OVA cells, engineered to express human CD38, injected via the tail vein into B-hC1Q mice. Treatment with Daratumumab analog effectively abolished tumor growth in humanized C1Q mice. Together, the B-hC1Q mice provide in vivo platforms to evaluate complement system-related disease and CDC effector functions in tumor therapy. Citation Format: James Jin, Ruili Lv, Zan Zhang, Jinyi Ma, Jiangfeng Yuan, Xuan Yu, Zhi Zhang, Jiansu Zhang, Xiaofei Zhou. Generation of humanized C1Q mice for antibody-mediated CDC therapy research [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 6138.
Abstract 5480: Live cell real-time quantification of drug-target engagement for rapid drug discovery
Authors: Ivan Babic, Nikolas Bryan, Claire Cunningham, Avery Sampson, Daniel Starczynowski, Elmar Nurmemmedov
Journal: Cancer Research (2025)

Abstract Drug discovery for challenging drug targets necessitates the proteomic complexities of the cellular milieu for proper folding and function. Therefore, the conventional biophysical methods are not sufficient due to the artificial acellular environment they impose on the target. Cell target engagement is a powerful paradigm in drug discovery, as measures transitions in the thermodynamic state of target protein during engagement with drug molecules. The currently available luminescence-based cell target engagement methods are limited to measurement of end-point signal, poor utility across multiple challenging target families and insufficient resolution and integration for kinetic and mechanistic readouts. We have developed a highly sensitive and versatile fluorescence-based cell target engagement strategy designed for challenging drug targets. The technology enables interrogation of drug targets without interfering with folding, localization and function - all within the physiological milieu of the cell. Importantly, this new method allows for quantitation and monitoring of cell target engagement in real time using live cells. The system seamlessly integrates with readily available real-time systems such as QuantStudio, thus making it highly sensitive and scalable. We share data on challenging drug targets such as Myc, MAPK1, UBE2N and KRAS, and we demonstrate utility of this new methodology for future drug discovery. Citation Format: Ivan Babic, Nikolas Bryan, Claire Cunningham, Avery Sampson, Daniel Starczynowski, Elmar Nurmemmedov. Live cell real-time quantification of drug-target engagement for rapid drug discovery [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 5480.
Abstract 1394: Apoptosis of pancreatic cancer cells after co-treatment with eugenol and tumor necrosis factor-related apoptosis-inducing ligand
Authors: Hyun Hee Kim, Dae-Hee Lee
Journal: Cancer Research (2025)

Abstract Pancreatic cancer is a refractory cancer with limited treatment options, and resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) poses a significant therapeutic challenge. This study aimed to investigate whether eugenol, the main component of clove oil with known anticancer, anti-inflammatory, and antioxidant properties, could enhance TRAIL sensitivity by upregulating death receptor (DR) expression levels in pancreatic cancer cells. To explore this, we treated pancreatic cancer cells with eugenol and TRAIL, individually and in combination, and evaluated apoptosis and cell proliferation rates. Expression levels of key proteins, including DR5, FLICE-inhibitory protein (FLIP), and p53, were assessed. Additionally, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, and C/EBP-homologous protein (CHOP) involvement were analyzed using siRNA knockdown approaches. Our findings revealed that combined treatment with eugenol and TRAIL significantly increased apoptosis and inhibited cell proliferation compared with eugenol alone. Eugenol upregulated DR5 expression, downregulated the anti-apoptotic protein FLIP, and increased levels of the tumor suppressor protein p53. Furthermore, eugenol induced ROS generation and caused ER stress, with CHOP playing a critical role. CHOP knockdown decreased DR5 expression and reduced the synergistic apoptotic effects of eugenol and TRAIL, confirming the ROS-mediated ER stress-CHOP pathway as a key mechanism. These results demonstrate that eugenol enhances TRAIL-induced apoptosis by upregulating DR5 through ROS-mediated ER stress and CHOP activation, which further enhances ER stress via p53 induction and FLIP downregulation. This suggests that eugenol has the potential to serve as a novel TRAIL sensitizer and offers a promising approach to overcoming TRAIL resistance in pancreatic cancer treatment. Citation Format: Hyun Hee Kim, Dae-Hee Lee. Apoptosis of pancreatic cancer cells after co-treatment with eugenol and tumor necrosis factor-related apoptosis-inducing ligand [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 1394.
Abstract 4064: Transcriptome-Wide Association Study of Alternative Polyadenylation Identifies Susceptibility Genes in Non-Small Cell Lung Cancer
Authors: Xiaohang Xu, Sicong Wang, Hanyi Zhou, Qilong Tan, Zeyong Lang, Yun Zhu, Huadi Yuan, Zixiang Wu, Ling Zhu, Kejia Hu, Wenyuan Li, Dan Zhou, Ming Wu, Xifeng Wu
Journal: Cancer Research (2025)

Abstract Alternative polyadenylation (APA) plays a crucial role in cancer development and prognosis. However, the molecular characteristics of APA related to non-small cell lung cancer (NSCLC) susceptibility remain understudied especially in East Asian populations. In this study, we constructed an atlas of APA-regulated 3' untranslated region (3'UTR) and profiled its genetic regulation in 747 lung tissue samples (including tumors and paired normal tissues) from 417 Chinese NSCLC patients. We verified a significant global shortening of 3'UTRs in tumor samples compared to normal samples and underscored the value of APA-regulation as prognostic markers. The 3'UTR APA quantitative trait loci (3'aQTL) was identified by regressing the percentage of distal poly(A) site usage index (PDUI) value on genetic variants. We found that a significant proportion 3'aQTL are independent of genetic regulation of expression and are specific in Chinese. We also conducted a 3'UTR APA transcriptome-wide association study (3'aTWAS) by integrating the APA regulation atlas with a genome-wide association studies (GWAS) for NSCLC involving 7, 035 cases and 185, 413 cancer-free controls. We identified NSCLC-associated genes. Combining the consistent results from colocalization analysis, differential APA analysis, and survival analysis, we provide novel evidence for the role APA regulation in NSCLC and identified potential upstream regulators. Overall, our study profiled the APA regulation and highlighted the substantial role of APA in NSCLC carcinogenesis and prognosis. Citation Format: Xiaohang Xu, Sicong Wang, Hanyi Zhou, Qilong Tan, Zeyong Lang, Yun Zhu, Huadi Yuan, Zixiang Wu, Ling Zhu, Kejia Hu, Wenyuan Li, Dan Zhou, Ming Wu, Xifeng Wu. Transcriptome-Wide Association Study of Alternative Polyadenylation Identifies Susceptibility Genes 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 4064.
Abstract 4184: Development of a homogenous poly(ADP-ribose) assay for screening and profiling PARP inhibitors
Authors: Mahbbat Ali, Ha Pham, Anibal Ramos-Martinez, Robert Lowery, BellBrook Labs, Madison WI
Journal: Cancer Research (2025)

Abstract Poly(ADP-ribose) polymerases (PARPs) initiate DNA damage repair (DDR) by binding to double strand breaks and creating a scaffold of poly(ADP-ribose) (pADPr) chains for assembly of other DDR proteins. The use of PARP inhibitors for ovarian tumors with BRCA-1 mutations was the first clinical exploitation of synthetic lethality, and PARP inhibitors are now used for breast, prostate, pancreatic, and ovarian cancers. New types of PARP inhibitors are being sought to broaden the scope of indications. To facilitate this effort, we developed a high throughput screening (HTS) assay for PARPs that enables quantitative detection of pADPr formation in a homogenous format. The assay relies on enzymatic conversion of pADPr to AMP, which is then detected using the Transcreener AMP/GMP assay with a fluorescence polarization (FP) or time-resolved Förster resonance energy transfer (TR-FRET) readout. To minimize interference from screening compounds, we first optimized the concentration of coupling enzymes to ensure that the pADPr will be completely converted to AMP even if the conversion reaction is inhibited by as much as 80%. Using this optimized system, the assay generated a robust signal (Z’ &amp;gt; 0.8) using 0.8 nM PARP1 with sub-saturating NAD (100 μM) and saturated sheared salmon sperm DNA (0.25 mg/mL) under initial velocity conditions. The assay was validated for HTS using a 1, 280 compound bioactive library, resulting in 18 hits, 5 of which proved to be interference. We also screened a 3, 200 compound diversity library, resulting in 44 hits, 3 of which were identified as interference. Four known PARP1 inhibitors, Olaparib, PJ 34 HCl, Veliparib, and Rucaparib Camsylate, were detected in the bioactive screen and tested in dose response mode with both FP and TR-FRET readout; the measured IC50 values (0.45 nM, 29 nM, 1.4 nM and 0.4 nM, respectively) were consistent with published values. By enabling sensitive, quantitative detection of pADPr formation in a simple, mix-and-read format, the Transcreener pADPr assay should facilitate efforts to develop more effective PARP inhibitors. Citation Format: Mahbbat Ali, Ha Pham, Anibal Ramos-Martinez, Robert Lowery. Development of a homogenous poly(ADP-ribose) assay for screening and profiling PARP inhibitors [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 4184.
Abstract 3352: Profiling impact of genomic alterations on the BCL2-family protein interactions in acute myeloid leukemia using the SPID platform
Authors: Saem Hong, Yunseo Lee, Byungsan Choi, Hee-Je Kim, Byung-Sik Cho, Hongwon Lee
Journal: Cancer Research (2025)

Abstract Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy, leading to varied therapeutic outcomes with targeted therapies. Venetoclax, a BCL2 inhibitor, has shown efficacy in treating AML patients by disrupting BCL2 functions. Genomic mutations like TP53, IDH1/2, PTPN11, and NRAS are associated with response rates to venetoclax. However, profiling the association between these mutations and BCL2-family protein interactions remains limited in clinical specimens. This study utilized the single-molecule protein interaction detection (SPID) platform to map BCL2-family interactions and examine their links to TP53, IDH1/2, PTPN11, FLT3, and NRAS mutations. Methods: Bone marrow mononuclear cells (BMMCs) from AML patients were retrospectively analyzed using the SPID platform to measure BCL2-family protein expression and complex levels. 10 assays evaluated Active BAX, Active BAK, BCL2, BIM levels, and complexes like BCL2-BAX and BCLxl-BAK. A BIM-BH3 mimicking probe quantified unoccupied anti-apoptotic protein levels. Mutational status was determined using next-generation sequencing, and Mann-Whitney U tests compared protein profiles between wildtype and mutant groups. Results: Among 80 patients (median age: 65 years), 43 (48.75%) had TP53, IDH1/2, PTPN11, FLT3, or NRAS mutations. IDH1/2 mutations were linked to higher BCL2-BAX complexes and unoccupied BCL2 levels (p&amp;lt;0.05). TP53 mutations were associated with reduced Active BAX and BCL2-BAX complex levels (p=0.015 and p=0.003). NRAS mutations led to reduce BCLxl-BAK (p=0.0019) and MCL1-BAK (p=0.0504) complexes, while PTPN11 mutations lowered BIM-el and MCL1-BAK levels (p&amp;lt;0.05). No significant biomarkers were linked to FLT3 mutations. Conclusion: This study reveals how genomic alterations in AML impact BCL2-family signaling, influencing venetoclax response. IDH1/2 mutations enhance BCL2-BAX complexes, potentially associating with favorable venetoclax sensitivity. Conversely, TP53 mutations reduce pro-apoptotic signaling, conferring resistance to venetoclax. NRAS and PTPN11 mutations affect anti-apoptotic complexes, further influencing therapeutic outcomes. Taken together, these discoveries provide how genomic alterations can impact on the BCL2-family signaling. Citation Format: Saem Hong, Yunseo Lee, Byungsan Choi, Hee-Je Kim, Byung-Sik Cho, Hongwon Lee. Profiling impact of genomic alterations on the BCL2-family protein interactions in acute myeloid leukemia using the SPID platform [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 3352.
Abstract 5477: Cell avidity - the next-gen cell binding to understand the mechanism of action through cell-cell and cell-protein interaction
Authors: Zhou Zhong, Keith Bailey, Justin Moser, Bella Perez, Brian Kierce, Michael Savage
Journal: Cancer Research (2025)

Abstract Traditional assays such as affinity measurements, cytokine secretion, and cytotoxicity provide informative insights but are insufficient for comprehensively characterizing and selecting the most effective cell therapy candidates. The complexity of cell-cell interactions that drive functional outcomes remains inadequately understood. Cell avidity, defined as the aggregate strength of interactions between effector and target cells, serves as a novel pivotal metric for uncovering the mechanism of action behind therapeutic candidates. The z-Movi Cell Avidity Analyzer, part of our versatile Cell Avidity platform, leverages the integration of fluorescence microscopy with precise acoustic force application to measure cell binding under physiologically relevant conditions. This approach allows for a detailed analysis of binding profiles, encompassing cell surface receptors and ligands, cell phenotype, cell status, and more to elucidate potency, safety, sensitivity, and binding kinetics essential for robust therapeutic evaluation. Our platform is designed to support the characterization and screening of a wide array of therapeutic modalities, including molecular binders like antibodies and small molecules, as well as cell-based therapies. By providing extensive insights into the mechanism of action and functional performance, Cell Avidity enables the development of next-generation therapeutics with enhanced safety and efficacy profiles. Citation Format: Zhou Zhong, Keith Bailey, Justin Moser, Bella Perez, Brian Kierce, Michael Savage. Cell avidity - the next-gen cell binding to understand the mechanism of action through cell-cell and cell-protein interaction [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 5477.
Abstract 2198: Platform for purifying antigen-presenting myeloid cells based on frequency of interactions with T cells
Authors: Eric Ferguson, Zhixuan Huang, John M. Beierle, Behrad Azimi, Kenneth H. Hu
Journal: Cancer Research (2025)

Abstract Cell-cell interactions' underlying biology drives many promising therapeutic opportunities in treating cancer. However, studying cell-cell interactions is challenging because the cells are alive and remain motile, and the complexity of downstream analysis increases with every observed interaction event. Today, researchers study cell-cell interactions using a variety of commercially available spatial approaches on fixed tissue samples. While these approaches can help study regions of interest or groups of cells based on their location within the tissue sample, they don’t offer single-cell resolution and fail to provide information on the more complex behavior of said cells, including the frequency and temporal nature of their interactions. Narwhal Bio Inc.’s A1 instrument, software, and consumable platform allow for real-time cell identification, tagging, and downstream characterization of live cells in cell mixtures. The live-cell-in, live-cell-out process enables the purification of live cells based on cell behaviors for use in downstream multiomics analyses. Here, we apply this platform to study the clinically relevant T-cell activating interactions between myeloid and T cells. We screen myeloid cells presenting various concentrations and types of antigens and monitor interactions with T cells over days. Myeloid cells are tagged by the platform when in contact with T cells at multiple time intervals resulting in the ability to stratify highly involved antigen-presenting cells (APCs) from less involved APCs. The cells are then isolated live, stratified based on their level of T-cell interactions, and then subjected to further downstream characterization and assay. At the core of the presented application is the tenet that a better understanding of cell-cell interactions will expose important underlying biological pathways, thereby increasing the chance of discovering targets for therapeutic intervention. Citation Format: Eric Ferguson, Zhixuan Huang, John M. Beierle, Behrad Azimi, Kenneth H. Hu. Platform for purifying antigen-presenting myeloid cells based on frequency of interactions with 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 2198.