tbuckley/cabot-search huggingface dataset:
Abstract 4070: Demonstrating analytical performance of Agilent Avida Duo utilizing novel multiomic reference standards
Authors: Michael Ruvolo, Yingmin Wang, Grace Zhao, Heng Wang, Kyeong-Soo Jeong, Yun Bao, Shengrong Lin, Bram Herman, Mistuni Ghosh
Journal: Cancer Research (2025)

Abstract Measuring both genetic and epigenetic status by target enrichment NGS workflows is critical for high-sensitivity oncology applications using cell-free samples (cfDNA). Conventional workflows accomplish this by splitting a sample into multiple tests, potentially limiting sensitivity. The Agilent Avida target enrichment technology enables high-efficiency enrichment of native DNA fragments, preserving epigenetic markers such as methylation. This method, termed Avida Duo, measures both mutation and methylation status, maximizing the information that can be obtained from any single cfDNA sample. Multiomic assays have become increasingly important in research applications and determining their analytical performance is key to ensure they are fit for purpose. Currently, standards with known variants or methylation levels are available, however, there is a lack of multiomic standards for evaluation of more advanced dual modalities. We utilized commercially available mutation and methylation standards to create a combined reference to assess the performance of the Avida Duo workflow. To create this reference, the mutation status of the methylation-specific reference and the methylation profile of the mutation-specific reference was determined. We blended these fully characterized references in defined ratios to achieve known variant allele frequencies and methylation levels similar to real-world cfDNA samples. Using this combined reference standard, we demonstrated the analytical performance of the Avida Duo technology across an input range of 5-20ng using a 55.2kb mutational panel that combines hotspot and full-gene enrichment and a 173.9kb methyl panel that covering relevant differentially methylated regions (DMRs). From this, we were able to demonstrate robust detection of variants down to &amp;lt;0.5% VAF and 1% methylation of DMRs. The Avida Duo technology offers a single workflow for a combined interrogation of genetic and epigenetic information of cfDNA and as such, requires new tools to appropriately characterize the performance. Here we demonstrate an approach for generating reference samples for assay development, QC, and benchmarking the analytical performance of multiomic assays. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Michael Ruvolo, Yingmin Wang, Grace Zhao, Heng Wang, Kyeong-Soo Jeong, Yun Bao, Shengrong Lin, Bram Herman, Mistuni Ghosh. Demonstrating analytical performance of Agilent Avida Duo utilizing novel multiomic reference standards [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 4070.
Abstract 6785: MicroRNA-lincrna cross-talk in BRCA1-mutated breast cancer and its therapeutic implications
Authors: Olalekan Fadebi, Zodwa Dlamini, Rahaba Makgotso Marima
Journal: Cancer Research (2025)

Abstract Breast cancer remains one of the leading causes of cancer-related mortality, characterized by its complexity and resistance to therapy. Triple-negative breast cancer (TNBC), a particularly aggressive subtype, lacks targeted therapies, making it challenging to treat. Long intergenic non-coding RNAs (lincRNAs) have emerged as critical regulators in cancer biology, with lincRNA-BC7 identified as a potential modulator of BRCA1. However, the exact mechanisms through which lincRNA-BC7 interacts with BRCA1. This study investigated the functional role of lincRNA-BC7 in regulating BRCA1 activity and its contribution to the biological response of TNBC cells to Olaparib. Using in breast cancer in vitro models. The cell biological response of TNBC cell line (MDA-MB-231) to Olaparib compared to the control group was evaluated. Gene expression analyses by RT-qPCR was done using LincRNA-BC-7 and BRCA1 specific primers. Furthermore, in silico bioinformatics analysis to map the molecular pathways involved was employed. This study revealed that miR-663a (has-miR-663a) could act as a sponge for lincRNA-BC7, thereby influencing its stability and expression levels. This interaction leads to alterations in the expression of target genes involved in key cancer hallmarks such as epithelial-mesenchymal transition (EMT), invasion, and metastasis. The competitive endogenous RNA (ceRNA) networks provide a framework for understanding how these non-coding RNAs interact at the post-transcriptional level, potentially affecting the progression of BRCA1-related breast cancer. Notably, both LincRNA-BC7 and BRCA1 gene expression levels were downregulated in Olaparib treated TNBC cells. Understanding the interplay between miR-663a and lincRNA-BC7and how this ceRNA network affects BRCA1 mutated TNBC may open avenues for novel therapeutic interventions. Citation Format: Olalekan Fadebi, Zodwa Dlamini, Rahaba Makgotso Marima. MicroRNA-lincrna cross-talk in BRCA1-mutated breast cancer and its therapeutic implications [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 6785.
Abstract 7032: The role of general control nonderepressible 2 (GCN2) kinase in leukemogenesis and therapeutic response to L-asparaginase
Authors: Rodney Claude, Sankalp Srivastava, Minghua Zhong, Can Chen, Sandeep Batra, Utpal Dave, Chi Zhang, Yue Fang, Kirk Staschke, Ronald A. Wek, Ji Zhang
Journal: Cancer Research (2025)

Abstract Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, affecting the lymphoid cells of both B and T lineages. Most ALL cells are auxotrophic for asparagine, a nonessential amino acid for protein synthesis, due to the low expression of asparagine synthetase (ASNS), a rate-limiting enzyme for de novo biosynthesis of asparagine. Standard ALL treatment takes advantage of this vulnerability by giving patients L-asparaginase, a bacterial enzyme that depletes the circulating asparagine. However, previous work from our lab and others has shown that some ALL cells become resistant to L-asparaginase treatment through the induction of ASNS expression. Mechanistically, amino acid starvation activates the general control of nonderepressible 2 (GCN2) kinase, leading to the accumulation of the ATF4 transcriptional factor. ATF4, in turn, is recruited to the promoter of the ASNS gene to activate its transcription. However, the role of GCN2 kinase in the process of leukemogenesis under nutrient limiting environment has not been established. Here, we found that, in a mouse T-ALL model driven by a KRas(G12D) mutation, ATF4 and ASNS expression were strongly elevated in leukemic tissues. However, germline deletion of the Gcn2 did not delay leukemogenesis in primary T-ALL and secondary T-ALL generated by transplanting the pre-leukemic bone marrow cells into Gcn2 wildtype recipient mice. Although GCN2 inactivation does not affect leukemogenesis, it sensitizes T-ALL cells to L-asparaginase treatment in vitro and in vivo. In addition, a small molecule inhibitor of GCN2, GCN2iB, synergistically inhibits leukemic growth and survival in the mouse T-ALL model and human T-ALL lines where the basal expression of ASNS is low. Finally, we tested a newly developed inhibitor of ASNS (ASX-173), which selectively killed leukemic cells in the absence of exogenous asparagine even though their basal level expression of ASNS is high. Taken together, our results suggest that targeting GCN2 or ASNS will have therapeutic implications in ALL patients who become resistant to L-asparaginase treatment. Citation Format: Rodney Claude, Sankalp Srivastava, Minghua Zhong, Can Chen, Sandeep Batra, Utpal Dave, Chi Zhang, Yue Fang, Kirk Staschke, Ronald A. Wek, Ji Zhang. The role of general control nonderepressible 2 (GCN2) kinase in leukemogenesis and therapeutic response to L-asparaginase [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 7032.
Abstract 6369: Perivascular niche-resident alveolar macrophages confer interstitial pneumonitis related to trastuzumab deruxtecan
Authors: Qing Wei, Teng Yang, Ziwen Zhang, Jiayu Zhu, Xiru Xue, Jieer Ying, Peng Guo, Xiangdong Cheng
Journal: Cancer Research (2025)

Abstract Background: T-DXd, a HER2-targeting antibody-drug conjugate (ADC), has shown transformative potential in cancer therapy but is implicated in causing fatal interstitial lung disease (ILD) in clinical trials. The mechanistic basis for these ADC-induced adverse effects remains unclear. This study aimed to investigate whether T-DXd-induced ILD represents an off-target adverse event (AE) and to explore the underlying cellular and molecular mechanisms. Methods: We analyzed HER2 antigen expression in a panel of 98 normal human lung tissues to determine whether T-DXd-induced ILD is on-target or off-target. To study the mechanisms of ILD, we developed an immunocompetent murine model that replicates T-DXd-induced lung toxicity. Using single-cell RNA sequencing, we identified alveolar macrophages (AMs) as the primary cell type affected by T-DXd in the lung microenvironment. Intravital microscopy was employed to visualize how perivascular AMs engulf T-DXd via Fc-FcγR engagement. To mitigate T-DXd-induced toxicity, a pre-conditioning strategy using IgG1 or the parental antibody of T-DXd was tested in the murine model. Results: Analysis of HER2 expression in normal lung tissues revealed minimal expression, confirming that T-DXd-induced ILD is an off-target AE. Single-cell RNA sequencing and intravital microscopy identified perivascular AMs as the key mediators of lung toxicity, driven by Fc-FcγR engagement with T-DXd. This interaction triggered a phenotypic shift in AMs toward an inflammatory, pro-ILD state, characterized by activation of the SPP1 pathway. Pre-conditioning AMs with IgG1 or the parental antibody of T-DXd effectively reduced ADC uptake, alleviating lung inflammation and immune activation in the murine model. Conclusion: T-DXd-induced ILD is an off-target AE mediated by Fc-FcγR-driven phagocytosis of T-DXd by perivascular alveolar macrophages. This interaction promotes an inflammatory SPP1high phenotype in AMs, leading to lung inflammation and immune activation. Pre-conditioning strategies targeting AMs offer a potential clinical approach to reduce nonspecific ADC uptake and mitigate lung toxicity. These findings provide significant insights into the mechanisms of ADC-induced toxicities and potential intervention strategies. Citation Format: Qing Wei, Teng Yang, Ziwen Zhang, Jiayu Zhu, Xiru Xue, Jieer Ying, Peng Guo, Xiangdong Cheng. Perivascular niche-resident alveolar macrophages confer interstitial pneumonitis related to trastuzumab deruxtecan [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 6369.
Abstract 3798: Branched-chain amino acid metabolism and histone propionylation in pancreatic cancer
Authors: Christina Demetriadou, Michael Noji, Erick Mitchell-Velasquez, Sharan Venkatesh, Austin Good, Taku Harada, Daniel Kantner, Zoltan Arany, Irfan Asangani, Ben Stanger, Nathaniel Snyder, Kathryn Wellen
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer for which development of effective therapies is urgently needed. Metabolic programs are vastly remodeled in pancreatic cancer to favor the production of certain metabolites that support tumor progression. Previous studies reported that catabolism of branched-chain amino acids (BCAAs) is the major carbon source for energy production in healthy pancreatic acinar cells. However, in PDA cells, BCAA metabolism is reprogrammed and its contribution to the TCA cycle is suppressed. Our labs recently showed that BCAAs, primarily isoleucine, are a primary supplier of propionyl-CoA (pr-CoA), which accumulates in the nuclei of cancer cells and is utilized for site-specific histone lysine propionylation (Kpr). Yet, the metabolic route through which BCAA catabolism supplies pr-CoA to the nucleus, as well as the distinct function of BCAA-derived Kpr in promoting tumor growth, are currently unknown. Here, we find that disrupting BCAA catabolism in PDA cells by either nutrient deprivation or genetic manipulation significantly decreases pr-CoA pools and the global levels of selective Kpr marks. Loss of BCAA-derived Kpr downregulates the expression of specific genes associated with lipid metabolism and immunosuppression. Accordingly, defective BCAA oxidation inhibits PDA tumor growth in vitro and in vivo, signifying the potential of targeting BCAA metabolism to attenuate PDA progression. Remarkably, we show that, in addition to their expected location in the mitochondria, BCAA metabolic enzymes also are detectable in the nuclear compartment of PDA cells and primary patient tissues, suggesting on-site synthesis of pr-CoA for Kpr. Overall, our findings support a novel link between metabolism and epigenetics in which segregation of a nuclear specific BCAA metabolic sub-network is harnessed by PDA cells to boost histone propionylation and shape malignant gene expression signatures. Citation Format: Christina Demetriadou, Michael Noji, Erick Mitchell-Velasquez, Sharan Venkatesh, Austin Good, Taku Harada, Daniel Kantner, Zoltan Arany, Irfan Asangani, Ben Stanger, Nathaniel Snyder, Kathryn Wellen. Branched-chain amino acid metabolism and histone propionylation 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 3798.
Abstract 6377: TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway
Authors: Alissa D. Guarnaccia, Thijs J. Hagenbeek, Wendy Lee, Noelyn Kljavin, Meena Choi, Gözde Ulas, Vasumathi Kameswaran, Daniel Le, Sayantanee Paul, Samir Vaidya, Jason R. Zbieg, James J. Crawford, Bence Daniel, Anwesha Dey, Jennie R. Lill
Journal: Cancer Research (2025)

Abstract The Hippo signaling pathway is a major regulator of cellular growth and is frequently deregulated in cancer. TEAD proteins are the main transcriptional effectors of the Hippo pathway and a pharmacological target in oncology. Most TEAD-targeting small molecules act by binding to the conserved lipid binding pocket of TEAD and allosterically disrupting interaction between TEAD and the oncogenic transcriptional activators YAP and TAZ. However, the molecular details of how TEAD-binding small molecules function beyond YAP and TAZ is not fully understood. Using unbiased, mass spectrometry-based proteomic profiling we find an alternative mechanism for TEAD lipid pocket-binding molecules whereby certain sulfonamide-containing compounds act as molecular glues to induce the TEAD interaction with the transcriptional repressor VGLL4. The chemically induced VGLL4-TEAD interaction occurs in a variety of cell types and can be biochemically recapitulated in vitro. Additionally, small molecule activation of VGLL4-TEAD complexes counteracts YAP activity at chromatin to repress pro-growth gene networks, including genes involved in cellular proliferation and mechanosignaling. Thus, enhanced interaction between TEAD and VGLL4 stimulates a small molecule-mediated cofactor switch from YAP to VGLL4. Cells that do not express VGLL4 are not sensitive to this class of compounds, but become sensitive upon exogenous overexpression of VGLL4. Additionally, genetic deletion of VGLL4 causes resistance to these molecules in cells and in in vivo tumors. These results demonstrate that VGLL4 is the required factor that mediates an anti-proliferative response to these sulfonamide-containing TEAD lipid pocket-binding compounds. Our data reveal a suite of molecules that act as molecular glues toward the repressive VGLL4-TEAD interaction and open up new understandings for curbing the oncogenic activity of Hippo pathway deregulation. Citation Format: Alissa D. Guarnaccia, Thijs J. Hagenbeek, Wendy Lee, Noelyn Kljavin, Meena Choi, Gözde Ulas, Vasumathi Kameswaran, Daniel Le, Sayantanee Paul, Samir Vaidya, Jason R. Zbieg, James J. Crawford, Bence Daniel, Anwesha Dey, Jennie R. Lill. TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway [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 6377.
Abstract 3435: B cell TuLibs: Immortalized tumor-derived B cell libraries for the interrogation and unbiased discovery of novel therapeutic targets and antibodies from patients
Authors: Casper Marsman, Jurgen Heinen, Kelly Maijoor, Arjen Bakker, Rob Roovers, Michael Koslowski, Stefano Gulla, Alessandra Micaela Villa
Journal: Cancer Research (2025)

Abstract The use of B cell repertoires for antigen and antibody discovery is on the rise due to the emergence of new techniques to tap into the human antigen-experienced B cell repertoire. Recently, many research groups have shown that the presence of tumor-infiltrating B cells or Tertiary Lymphoid Structures (TLS) at tumor sites correlate with improved survival and response to Immune Checkpoint Inhibitors. Here, we present Kling Biotherapeutic’s platform that enables the discovery of novel therapeutic targets and antibody-pairs. We overcome the limited proliferative lifespan of primary human and animal B cells by transduction with a proprietary vector to express Bcl6 and Bcl-xL, which prevents both terminal differentiation and apoptosis. Through the highly efficient isolation and immortalization of tumor- or TLS-derived B cells, our approach captures the B cell diversity and all Ig-isotypes from all tissues. As opposed to the labour intensive and costly approach of ex vivo BCR sequencing and subsequent recombinant antibody production and validation, our B-cell Tumor Libraries (TuLibs) secrete antibodies into the culture supernatant while retaining indefinite expansion capabilities, allowing for immediate functional screening of antibodies and rapid identification of unique tumor-specific B cell clones. Moreover, our immortalized B cells retain the ability to undergo somatic-hypermutation, allowing for in vitro affinity maturation of immortalized B cell clones against targets of interest. Altogether, Kling Biotherapeutic’s proprietary platform allows the comprehensive functional screening and affinity maturation of human and animal B cell repertoires from multiple tissues sources. TuLibs represents a significant advancement in our ability to identify new immuno-functional targets and antibodies for biopharmaceutical development of tumor targeted therapies. Citation Format: Casper Marsman, Jurgen Heinen, Kelly Maijoor, Arjen Bakker, Rob Roovers, Michael Koslowski, Stefano Gulla, Alessandra Micaela Villa. B cell TuLibs: Immortalized tumor-derived B cell libraries for the interrogation and unbiased discovery of novel therapeutic targets and antibodies from patients [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 3435.
Abstract 6425: Evaluation of a plasma cell-free DNA methylation-based multi-cancer detection test
Authors: Rachel Gittelman, Alan Selewa, Yupeng He, Jordan Burke, Victoria M. Raymond, Sven Duenwald, Craig Eagle, AmirAli Talasaz, Darya Chudova
Journal: Cancer Research (2025)

Abstract Introduction: Blood-based multi-cancer detection (MCD) tests hold promise for early cancer detection. MCDs should demonstrate high specificity, clinically meaningful sensitivity, and provide information to guide clinical diagnostic evaluation. Methods: We developed an MCD test that leverages a next-generation sequencing epigenomics hybrid capture assay (Shield™) to measure DNA methylation in regions differentially methylated across cancers. We then implemented a two-step classification algorithm. First, a regression model (multi-cancer classifier) was trained to distinguish cancer from non-cancer samples at 98% target specificity. Next, a cancer signal of origin (CSO) model was trained to predict 10 solid tumors (Table 1) in samples predicted to be cancer. The test was evaluated in a blinded case-control cohort of plasma samples (3mL; Streck) from adults with treatment naïve cancer, or who were self-reported cancer free with 1 year of follow-up (NCT05334069). Results: Final evaluable dataset was 778 participants (excluding 18 (2.3%) that failed QC). Median age was 62 years (range: 40-78). 55% were female. Self-reported race was 79% White. Specificity was 98.5% (397/403). Overall sensitivity for the 10 cancers was 59.7% (224/375); 34.6% Stage I/II (64/185), 84.2% Stage III/IV (160/190) and ranged from 96% for esophageal-stomach to 21% for prostate. Primary or secondary CSO prediction was 89% accurate. Sensitivity in cancers without average risk standard-of-care screening was 73% and was 74% in the 6 most aggressive cancers (shortest survival rates; Table 1). Conclusions: In this cohort, this MCD has 59.7% sensitivity, 98.5% specificity, and 89% primary or secondary CSO accuracy. Ongoing development is aimed at expanding CSO calling range. Integrating an MCD with an FDA approved blood-based CRC screening test may increase the MCD clinical value in the intended use population. A version of this MCD is being studied in a prospective, interventional study evaluating MCD testing feasibility. Citation Format: Rachel Gittelman, Alan Selewa, Yupeng He, Jordan Burke, Victoria M. Raymond, Sven Duenwald, Craig Eagle, AmirAli Talasaz, Darya Chudova. Evaluation of a plasma cell-free DNA methylation-based multi-cancer detection test [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 6425.