tbuckley/cabot-search huggingface dataset:
Abstract 3165: Leveraging chemoinformatics and high-throughput screening for the identification of novel ubiquitin specific protease 7 (USP7) inhibitors
Authors: Rita I. Oliveira, Caio Franco, Miguel Mano, Ana Leal, Karen T. Liby, Jorge A. R. Salvador
Journal: Cancer Research (2025)

Abstract Ubiquitin-Specific Protease 7 (USP7) is a member of one of the most largely studied families of deubiquitylating enzymes, proteases that play a key role in controlling the dynamics of ubiquitination within the cellular ubiquitome. USP7 plays a pivotal role in modulating the levels of multiple proteins, including tumor suppressors, transcription factors, epigenetic modulators, DNA repair proteins, and regulators of the immune response. This suggests USP7 as a promising druggable target that offers interesting new avenues for cancer therapy. Wherefore, the main goal of this study was the identification of promising small molecules that inhibit USP7 enzymatic activity. The work was conducted according to an integrated workflow combining Computer-Aided Drug Discovery (CADD) and High-Throughput Screening (HTS) of chemical libraries to discover and characterize selective USP7 inhibitors with new chemotypes and adequate pharmacological properties as potential drug candidates to be used for anticancer therapy. Such protocol screened a large set of databases, disclosing 9 novel USP7 hit compounds with in vitro USP7 inhibitory activities against both USP7 full-length and USP7 catalytic domain, displaying IC50 values between 4.5 μM to 33 μM. The dose-response curves of these compounds tested against cancer cell lines showed promising selective cytotoxicity in breast and lung cancer cells, with IC50 values ranging from low nanomolar to micromolar. These results highlight the utility of using CADD and HTS in the early steps of drug discovery and pave the way for the identification of novel USP7 inhibitors that might represent a steppingstone for cancer treatment. Citation Format: Rita I. Oliveira, Caio Franco, Miguel Mano, Ana Leal, Karen T. Liby, Jorge A. R. Salvador. Leveraging chemoinformatics and high-throughput screening for the identification of novel ubiquitin specific protease 7 (USP7) 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 3165.
Abstract 871: Quality control aspects of cell therapy products
Authors: Bettina A. Meissburger, Julian S. Thimm, Stefan B. Eichmueller
Journal: Cancer Research (2025)

Abstract Quality control of cell therapy products is critical to ensure safety and efficacy of these advanced therapeutics. Cell therapy products are characterized by their complexity and variability due to the use of patient-individual living cells as the primary therapeutic agent. Consequently, QC processes must address several unique challenges and parameters. The QC process typically involves a combination of in-process controls and final product testing. In-process controls are essential to monitor critical manufacturing steps and ensure that the process remains within predefined parameters. Final product testing is conducted to confirm that the cell therapy product meets all established quality specifications before release. Key QC criteria for a T cell product include cell number and viability, identity, potency, as well as endotoxin, mycoplasma and microbiological testing. Analytical QC methods need to be extensively validated before routine use. The application of pre-validated QC kits simplifies the validation process while at the same time ensuring fast in-house QC testing. For endotoxin testing we have established a cartridge based testing methodology, which has been validated with the final cell product enabling rapid pre-release testing. Mycoplasm testing can be performed using a Ph.Eur. compliant TaqMan-based real-time qPCR method, which ensures fast and sensitive mycoplasm detection including a DNA extraction step from the cellular product. Pre-tested freeze-dryed antibody cocktails combined with automatic gating strategies ensure robust identity testing by flow cytometry analysis. Additionally, cell counting and viability testing can be integrated into this analysis, thus omitting additional counting methods. Due to the short product shelf-life of living cells, microbiological testing poses a challenge with classical culture methods. Post-release final results might be acceptable taking into account the advantage of direct application of living cells without additional freezing steps. Novel rapid testing methods will be a promising alternative in the future. Potency of the cell product is another challenge, which is often assessed by surrogate markers such as cytokines. In case of known target antigens, killing assays or ELISpot assays are possible. Additionally, multimer staining can test for MHC-antigen recognition of the cell product. In summary, robust QC systems are indispensable for the development and clinical application of cell therapy products, safeguarding patient health and advancing the field of regenerative medicine. Citation Format: Bettina A. Meissburger, Julian S. Thimm, Stefan B. Eichmueller. Quality control aspects of cell therapy products [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 871.
Abstract 1191: Epstein-Barr virus <i>lncBART</i>s interact with BRD4 and CTCF complex to regulate EBV latent replication and promote EBV-associated oncogenesis
Authors: Jiayan Liu, Wei Dai, Honglin Chen
Journal: Cancer Research (2025)

Abstract The Epstein-Barr Virus (EBV) infects approximately 95% of the global population, with the majority of these infections being asymptomatic. However, EBV is strongly associated with the development of certain tumors affecting lymphoid or epithelial tissues, such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma (NPC), and gastric cancer (GC). In these EBV-associated cancers, the virus maintains a latent infection and expresses only a few viral proteins. There is considerable interest in understanding how EBV maintains latency in associated tumors and the role it plays in the oncogenesis of these cancers. Increasing evidence suggests that long non-coding RNAs play crucial roles in the epigenetic reprogramming of human cancer cells. We have previously characterized a family of EBV-expressed long non-coding RNAs, known as lncBARTs, in EBV-associated nasopharyngeal and gastric carcinoma. It is important to understand how EBV replicates in infected cells, and we sought to explore the role of lncBARTs in EBV replication in infected cancer cells. Our study discovered that lncBARTs co-localize in nuclear speckles and identified BRD4 and CTCF as interacting partners of lncBARTs. EBV expressed EBNA1 is essential for EBV replication, and we further confirmed that lncBARTs interact with the EBV genome via the BRD4/CTCF/EBNA1 complex. Using a combination of functional genomic analysis and gene-editing strategy, we noted a significant reduction in the tethering of EBV episomes to cell chromosomes when lncBARTs were knocked down in EBV-infected NPC and GC cells. This supports a mechanism whereby lncBARTs facilitate EBV episome tethering to the chromosome for latent replication through interaction with the EBV latent origin of replication (Orip). Our findings suggest that the interaction of lncBARTs with the BRD4-CTCF complex could impact the epigenetic reprogramming of host cells. Importantly, ATAC and transcriptome analyses indicated that lncBARTs drive tumorigenesis by aberrantly regulating the expression of MYC and BCL2 in EBV-infected cells. These findings reveal that EBV turns off the expression of viral proteins to avoid provoking an immune response and utilizes virus-encoded lncBARTs to maintain EBV latent replication in conjunction with cancer cell division. Consequently, lncBARTs-BRD4/CTCF promotes the reprogramming of the host epigenome and drives tumorigenesis in EBV-associated epithelial tumors. Citation Format: Jiayan Liu, Wei Dai, Honglin Chen. Epstein-Barr virus lncBARTs interact with BRD4 and CTCF complex to regulate EBV latent replication and promote EBV-associated oncogenesis [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 1191.
Abstract 3708: Targeting the ATG101 And ULK1 complex in pancreatic ductal adenocarcinoma: computational approach
Authors: Raasil R. Basha, Vaishnavi Kuppala, Ganji Purnachandra Nagaraju
Journal: Cancer Research (2025)

Abstract Introduction: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis (five-year survival rate around 13%). PDAC progression mainly depends on autophagy signaling for cell homeostasis. The current study holds significant importance in this context as it aims to identify the interaction between ULK2 and ATG101 and evaluate hydroxychloroquine's effect on the ULK2 and ATG101 complex. Methods: The proteins ULK2 (Q9QY01, MOUSE) and ATG101 (Q9D8Z6, MOUSE) were retrieved from the UniProtKB database. The domain region of the protein structures was carefully trimmed using BIOVIA Discovery Studio 4.5 Visualizer, and the interacting residues were identified with precision using HawkDock. The ULK2-ATG101 complex was then imported into DimPlot to recognize and display the presence of intermolecular hydrogen bonds. To validate the complex structure, we employed the Desmond Program, Molecular Dynamic (MD) Simulations, Principal Component Analysis (PCA), Root Mean Square Deviation (RMSD), and Root Mean Square Fluctuation (RMSF). To confirm the functional activity of the interaction, we conducted an in vitro pulldown assay. All samples were lysed with RIPA buffer, and the lysate (500 µg) was added to 30 µL of agarose beads and anti-ULK2. The samples were resolved on the SDS page and transferred to the PVDF membrane. The membrane was probed with ATG101, and the intensity of protein bands was quantified using the Image J program. Unpaired t-tests were conducted to acknowledge the difference between treated and untreated samples. Results: The formation of hydrogen bonds between these complexes are Arg19 vs. Glu146 and Glu150; Gln67 vs. Ser160; Arg4 vs. Thr63. Among the top 10 scoring ATG101-ULK2 PPI complex models, the highest binding energy was found at -48.13 kcal/mol. The RSMD graph displayed a stable trajectory, following 80 ns of simulation time using RMSD values ∼3.1A to ∼3.7A, depicting stabilization during 100 ns for the PPI complex. The pulldown assay results indicated hydroxychloroquine reduced the interaction between the ATG101 and ULK2, suggesting a potential impact on PDAC treatment. Discussion/Conclusion: Results suggested that the interaction of ATG101-ULK1 was strong, and hydroxychloroquine reduced this interaction. Site-directed mutagenesis is essential to understanding the molecular interaction (ATG101-ULK2) and the role of residues in PDAC. Citation Format: Raasil R. Basha, Vaishnavi Kuppala, Ganji Purnachandra Nagaraju. Targeting the ATG101 And ULK1 complex in pancreatic ductal adenocarcinoma: computational approach [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 3708.
Abstract 103: Syndecan-1 Is a key mediator of entosis and cellular competition in pancreatic cancer
Authors: Kara Li, Shigeaki Umeda, Chenyang Li, Rajya Kappagantula, Christine A. Iacobuzio-Donahue, Wantong Yao
Journal: Cancer Research (2025)

Abstract Entosis, a form of cell-in-cell (CIC) structure formation where one cell invades and becomes internalized by another, has long been observed in various malignancies and is considered a critical cellular process in cancer progression, with potential impacts on tumor heterogeneity, survival, and metastasis. Syndecan-1 (SDC1), a transmembrane proteoglycan involved in cell adhesion and communication, plays a pivotal role in these processes, yet its specific function in entosis within pancreatic ductal adenocarcinoma (PDAC) remains underexplored. This study aimed to investigate whether SDC1 facilitates entosis in PDAC cells and to assess its impact on tumor aggressiveness and patient outcomes. Using immunohistochemistry, flow cytometry, and entosis assays, our findings reveal that SDC1 prominently localizes at cell-cell contact points, facilitating stable intercellular adhesion and promoting entotic activity. Knockdown experiments reveal that reduced SDC1 expression significantly diminishes CIC formation, implicating SDC1 as a critical mediator of this process. Analysis of clinical samples revealed that high SDC1 expression correlates with increased entotic activity in PDAC tumors and is associated with decreased patient survival. These results suggest that SDC1-mediated entosis enhances tumor aggressiveness by contributing to cellular competition and heterogeneity. Our study sheds light on the critical role of SDC1 in promoting CIC formation and cancer progression, highlighting its potential as a therapeutic target to disrupt entotic mechanisms in PDAC. Citation Format: Kara Li, Shigeaki Umeda, Chenyang Li, Rajya Kappagantula, Christine A. Iacobuzio-Donahue, Wantong Yao. Syndecan-1 Is a key mediator of entosis and cellular competition in pancreatic 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 103.
Abstract 229: Oncogenic cell growth linked with hypermethylation of CpG sites within the p53 pathway, and its effects on subgroups
Authors: Roy Khalife, Ethan Grebler, Anthony Magliocco
Journal: Cancer Research (2025)

Methylation of tumor-suppressor genes is a recognized oncogenic mechanism. This study focuses on determining the extent of CpG site methylation within genes of the p53 pathway and assessing how patient sex influences these methylation patterns, which could aid in cancer identification through p53 pathway methylation analysis. Given that mutations in p53 occur in over half of all human cancers, their pro-apoptotic properties are vital for halting unchecked cell growth. We analyzed the methylation status of p53-regulated transcriptional target genes using FFPE samples from various primary brain cancers. Methylation data, generated using the Infinium MethylationEPIC v2.0 array, was visualized through heat maps. Among all samples, the most hypermethylated genes (m-value &amp;gt;2) were identified in descending order as SFN, CASP9, TP53, APAF1, GTSE1, TSC2, and SESN3. Interestingly, TSC2 and SESN3 did not exhibit hypermethylation in male samples, suggesting potential sex-specific epigenetic regulation. The observed trend of hypermethylation—exceeding 80% CpG site methylation—within key inhibitory, apoptotic, and repair genes underscores their silencing and involvement in tumor development. Additionally, the absence of hypermethylation in canonical TP53 targets such as WAF1/p21 highlights the need for further investigation into pathway-specific methylation patterns, potentially uncovering alternative or complementary mechanisms of tumor suppression evasion. Citation Format: Roy Khalife, Ethan Grebler, Anthony Magliocco. Oncogenic cell growth linked with hypermethylation of CpG sites within the p53 pathway, and its effects on subgroups [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 229.
Abstract 1070: siderGrimoire: a database of retroCNVs in human tumors and populations
Authors: Thiago Luiz Miller, Helena Beatriz da Conceição, Pedro Alexandre Galante
Journal: Cancer Research (2025)

Abstract Background: Retrocopies, also known as processed pseudogenes, are structural variations resulting from the duplication of protein-coding genes via the reverse transcription of their mature messenger RNA by the LINE-1 enzymatic machinery. These retrocopies can be fixed, present in all genomes of a given species, or unfixed—classified here as retroCNVs—when they are polymorphic, either germline or somatic. While fixed retrocopies have been extensively studied, the understanding of retroCNVs remains limited due to the lack of specialized bioinformatics tools for their detection and annotation in DNA sequencing data, as well as curated databases to share findings with the scientific community. Objective: To address this gap, we developed the sideRETRO, a robust computational tool for the identification and annotation of retroCNVs in whole-genome and exome sequencing data. The results of this tool will be made accessible through siderGrimoire, an online, curated database integrating retroCNVs from human populations and cancer samples. Methods: The sideRETRO pipeline, published in Bioinformatics, offers a dedicated approach to detecting non-fixed retroCNVs. Using datasets from the 1000 Genomes Project and The Cancer Genome Atlas (TCGA), siderGrimoire curates retroCNVs across human populations and tumor samples, providing detailed annotations and a user-friendly interface. Results: Initial analyses reveal a comprehensive landscape of retroCNVs, uncovering their prevalence and patterns of events in diverse human populations and cancer types. This resource bridges a critical gap in the availability of retroCNV-specific data for the research community. Conclusion: The siderGrimoire database represents a significant advancement in retroCNV research, providing a valuable tool for studying the role of retrocopies in genetic variation and cancer biology. By integrating large-scale data from key genomic projects, this platform enables new insights into the genomic impacts of retroCNVs, fostering further exploration in human genetics and oncology. Citation Format: Thiago Luiz Miller, Helena Beatriz da Conceição, Pedro Alexandre Galante. siderGrimoire: a database of retroCNVs in human tumors and populations [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 1070.
Abstract 2278: Correlation between DNA-methylation predicted and measured immune-cell type proportions by age in ARIC
Authors: Zhike Lin, Dominique S. Michaud, Naisi Zhao, Vernon A. Burk, Eric Boerwinkle, Jan Bressler, Devin C. Koestler, Karl T. Kelsey, Elizabeth A. Platz
Journal: Cancer Research (2025)

Abstract Background: DNA methylation (DNAm)-predicted deconvolution uses cell-specific methylation markers of leukocytes in peripheral blood to estimate immune cell type proportions. Validity is high for predicted proportions of immune cell types. Given known age-related immune system changes and changes in predicted immune cell proportions by age, we assessed whether the correlations between predicted and measured proportions differ across age. Such information is needed for cancer studies on immunoaging in cohorts without CBC differential or stored whole blood. Methods: Lymphocyte, neutrophil, monocyte, eosinophil, and basophil proportions were previously estimated using DNAm deconvolution (Salas et al., PMID: 35140201) and measured by CBC among Black participants (N=151; 62% female) without cancer in the Atherosclerosis Risk in Communities study. Pearson correlation coefficients were calculated in age tertiles (T1: 47-53, T2: 54-60, T3: 61-67 years). To minimize confounding by health factors, we stratified by more (no diabetes, BMI &amp;lt;30 kg/m2, and non-smoker) and fewer (≤ 2 of the factors) positive health factors. Correlations in age T1 and T3 were compared after Fisher’s z-transformation. Results: Correlations between predicted and measured proportion were similar across age tertiles, albeit slightly weaker in the oldest tertile (Table, except for basophils). This same pattern was present stratifying by health factors, although the correlations appeared slightly stronger for more vs. fewer positive health factors (e.g., age T1, T3 - neutrophils: more 0.81, 0.77; fewer 0.78, 0.66). However, all p-values were &amp;gt; 0.1 comparing correlations in the youngest and oldest age tertiles. Conclusion: For each common immune cell type, correlations between DNAm-predicted and measured proportion were generally similar across mid- to older adulthood, supporting use of the algorithm in immunoaging studies. Studies with participant diversity, including ages ≥ 70 yrs are needed. Citation Format: Zhike Lin, Dominique S. Michaud, Naisi Zhao, Vernon A. Burk, Eric Boerwinkle, Jan Bressler, Devin C. Koestler, Karl T. Kelsey, Elizabeth A. Platz. Correlation between DNA-methylation predicted and measured immune-cell type proportions by age in ARIC [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 2278.
Abstract 3221: Identification and characterization of FAK kinase as a novel regulator of PD-L1 stability and activity in cancer immune evasion
Authors: Asia-lily Boyd, Prem Khanal, Yawei Hao, Xiaolong Yang
Journal: Cancer Research (2025)

Abstract The PD-1/PD-L1 axis is an essential immune checkpoint that modulates T cell-mediated immune responses. Cancer cells exploit this checkpoint to inhibit anti-tumour immune activity, enabling immune evasion. Thus, blocking PD-1/PD-L1 using antibodies has become a cornerstone of cancer immunotherapies. However, despite promising results, these therapies show limited response rates in many cancer patients and often lead to adverse effects, impacting its overall efficacy. Therefore, understanding of the molecular mechanism underlying immunotherapy resistance is critical for successful cancer immunotherapy. Emerging research indicates that phosphorylation of PD-L1 by kinases significantly influence PD-L1 stability and functionality, thereby contributing to cancer cell immune evasion and influencing immunotherapy outcomes. However, although 560 kinases have been identified in the human kinome, there is no systematic screening of kinases regulating PD-L1 stability and its function in immune evasion. By using a PD-L1 NanoLuc luciferase biosensor, in this study, we performed a systematic kinome-wide screening and identified focal adhesion kinase (FAK) as a novel regulator of PD-L1 stability in cancer. Further investigation of FAK-mediated PD-L1 signalling and its role in immune evasion may provide a new therapeutic strategy for cancer treatment. Citation Format: Asia-lily Boyd, Prem Khanal, Yawei Hao, Xiaolong Yang. Identification and characterization of FAK kinase as a novel regulator of PD-L1 stability and activity in cancer immune evasion [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 3221.