tbuckley/cabot-search huggingface dataset:
Abstract 6279: Identification of novel secreted proteins modulating immunotherapy efficacy through spatial transcriptomics models
Authors: Beibei Ru, Lanqi Gong, Emily Yang, Kenneth Aldape, Lalage Wakefield, Peng Jiang
Journal: Cancer Research (2025)

Abstract Background: Secreted proteins, derived from around 1900 human protein-coding genes, play a crucial role in mediating intercellular communication. Despite their significance, the downstream signaling effects of most secreted proteins in shaping antitumor immunity remain largely unexplored, except for extensively studied cytokines. Spatial transcriptomics (ST), which profiles gene expression in the spatial context of intact tissues, enables us to investigate spatial relationships between secreted proteins and their downstream targets. This technology provides insights into the activity and function of secreted proteins within the tumor microenvironment. Objective: The current study aims to leverage target gene signatures trained from ST data to identify novel secreted proteins modulating the efficacy of immunotherapy. Results: We collected hundreds of tumor ST samples across over twenty cancer types. Using Moran’s I correlation, we assessed the spatial relationships between secreted proteins and potential target genes. After filtering out low-quality targets, approximately 1, 200 secreted protein signaling signatures were retained. Based on these data, we developed SecAct, a multiple regression framework to predict secreted protein signaling activity. Next, SecAct’s reliability was validated using clinical trial data from cytokine-blocking treatments. We observed that the inferred activity reduction of secreted proteins significantly correlates with patients' clinical responses in both tumor and inflammatory disease settings, demonstrating SecAct’s clinical relevance. Subsequently, we applied SecAct to analyze forty-two cancer immunotherapy cohorts treated with immune checkpoint blockades, identifying secreted proteins whose activity is strongly associated with therapeutic efficacy. This prioritized list includes both established cancer immunotherapy regulators and novel candidates without previously known roles in cancer. Several new high-ranked regulators were further validated through in vivo mouse models. Conclusion: Our framework provides a data-driven screening ground for identifying novel regulators of antitumor immunity, potentially guiding the development of new immunotherapies. Citation Format: Beibei Ru, Lanqi Gong, Emily Yang, Kenneth Aldape, Lalage Wakefield, Peng Jiang. Identification of novel secreted proteins modulating immunotherapy efficacy through spatial transcriptomics models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6279.
Abstract 6983: Innovative oral STING agonists for cancer therapy
Authors: Zhiyong Qin, Limin Jia, Chengyu Yang, Chuanyun Yu, Yang Lv, Yujie Wang, Pan Li
Journal: Cancer Research (2025)

Abstract STING, functioning as an adaptor protein, plays a pivotal role in the induction of type I interferons (IFN) and pro-inflammatory cytokines subsequent to the detection of cytosolic DNA. The development of a non-nucleotide STING agonist amenable to oral administration holds the promise of expanding the clinical utility of STING agonists among cancer patients. Leveraging computer-aided drug design strategies, a cohort of non-nucleotide STING agonists endowed with oral antitumor activities was meticulously designed and synthesized, with the overarching goal of exploring uncharted druggability domains. Among the array of investigated compounds, ZSSW21040164 manifested remarkable IFN-β (Interferon-β) activities within the tumor microenvironment. Rigorous experimental validation unequivocally demonstrated that ZSSW21040164 activates the downstream signaling cascade of STING via a STING-dependent modality. Moreover, ZSSW21040164 exhibited favorable pharmacokinetic (PK) characteristics, notably high oral bioavailability. In murine tumor models bearing H22, MC38, and CT-26 tumors, oral administration of ZSSW21040164 was well-tolerated and had a significant anti-tumor effect with more tumors achieved complete remission, which accompanied by the establishment of durable antitumor immunity. Notably, when ZSSW21040164 was co-administered with a fully murinized anti-mouse PD-1 antibody, the antitumor efficacy of single-agent therapy was substantially augmented. Collectively, these findings strongly suggest that ZSSW21040164 harbors considerable potential for development as an efficacious antitumor agent, warranting further preclinical and clinical investigations. Within this work, a series of aryl-fused heterocycles STING agonists with significant potency towards STING were investigated. The investigation comprised multiple aspects, namely, the identification methodology, pharmacokinetic (PK) properties determination, evaluation of in vitro and in vivo antitumor activities, and the elucidation of relevant structure-activity relationships (SARs). ZSSW21040164, an orally available human STING agonist, emerged as a crucial finding. It is anticipated that this compound will serve as a valuable reference for the discovery and design of human STING agonists suitable for systemic administration in a clinical setting, thereby contributing to the advancement of cancer therapeutics. Citation Format: Zhiyong Qin, Limin Jia, Chengyu Yang, Chuanyun Yu, Yang Lv, Yujie Wang, Pan Li. Innovative oral STING agonists for 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 6983.
Abstract 6789: Identification of DGKA as a regulatory factor for paclitaxel resistance in lung cancer based on CRISPR screen and transcriptome sequencing
Authors: Jiang Luo, Mini Zhang, Jiawen Tang, Qingwei Wang, Yu Yuan, Min Xia, Yufei Yan, Yushuang Tan, Conghua Xie, Yan Gong
Journal: Cancer Research (2025)

Abstract Background: Lung cancer is the second most prevalent cancer with the highest mortality rate in the world. Paclitaxel (PTX) is one of the most effective clinical chemotherapeutic agents for the treatment of lung cancer, but a variety of mechanisms induce its chemoresistance including alterations in microtubule-associated proteins, up-regulation of drug efflux systems. Lipid metabolism was reported to impact chemosensitivity, but the underlying mechanisms are to be clarified. Therefore, this study aims to exploring the molecular mechanisms of PTX resistance regulated by lipid metabolism, and to discover novel PTX resistant targets and therapeutic agents. Methods: Lipid metabolism related sgRNA library was used for CRISPR screen. PTX-resistant lung cancer cells were constructed for transcriptome sequencing. The key regulators were identified via integrating negative enriched genes in CRISPR screen and the differential ones in transcriptome sequencing. The regulation of PTX sensitivity by the key regulators was confirmed in deficient lung cancer cells. Transcriptome sequencing was applied to find downstream pathways, and immunoblotting and RT-qPCR were used to confirm the molecular mechanisms. Mouse models were used to investigate the safety and effectiveness of its inhibitors combined with PTX for lung cancer treatments in vivo. Results: DGKA is highly expressed in PTX-resistant lung cancer cells, and its deficiency significantly induced PTX sensitivity in lung cancer cells. DGKA knockdown significantly inhibited lung cancer cell proliferation, invasion and migration. In addition, DGKA depletion promoted PYX-induced cell apoptosis and G2/M-phase arrest in lung cancer cells. Transcriptomics showed that the MAPK signaling pathway was significantly enriched after DGKA knockdown, and further experiments confirmed that DGKA inhibition increased lung cancer cell sensitivity to PTX via inhibiting ERK phosphorylation. DGKA inhibitor (R59022) could induce the PTX sensitivity of lung cancer cells safely and effectively in vivo. Conclusion: DGKA promotes PTX sensitivity of lung cancer cells and alleviates PTX resistance through the MAPK pathway, providing preclinical evidence for targeting DGKA as a novel strategy for lung cancer therapy against PTX resistance. Citation Format: Jiang Luo, Mini Zhang, Jiawen Tang, Qingwei Wang, Yu Yuan, Min Xia, Yufei Yan, Yushuang Tan, Conghua Xie, Yan Gong. Identification of DGKA as a regulatory factor for paclitaxel resistance in lung cancer based on CRISPR screen and transcriptome sequencing [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 6789.
Abstract 6611: Genome-wide cfDNA fragmentomics combined with machine learning enhance non-invasive prostate cancer detection
Authors: Shuang Gan, Haoran Tang, Feng Xie, Yue Zhang, Hang Dong
Journal: Cancer Research (2025)

Abstract The liquid biopsy approach focusing on DNA molecules offers a promising non-invasive method for prostate cancer diagnosis. Next-generation sequencing (NGS) of targeted gene panels is widely used for detecting somatic mutations but is limited by confounding clonal hematopoietic variants and narrow genome coverage. We propose a solution that encompasses genome-wide DNA fragmentation features for tumor fragment evaluation. This study collected plasma samples from 209 patients with prostate cancer and 49 healthy individuals as controls. Cell-free DNA (cfDNA) was extracted and tested using PredicineSCORE™, a low-coverage whole-genome sequencing assay designed to identify tumor-specific features. Tumor content assessed by mutation-based detection assays served as the reference indicator. Fragmentomics characteristics—including regional coverage, fragment length, and end-motif features—were profiled as tumor markers. Copy number burden and tumor fragment content were refined using the expectation-maximization algorithm. An ensemble machine learning model was then developed to estimate tumor fractions. We found strong correlations between estimated tumor fraction and fragmentomics features. The absolute correlation coefficients for tumor fraction with the relative depth at LYL1 binding sites, the insert size ratio of short reads, and the CCCA end motif were higher than 0.9, 0.75, and 0.7, respectively. To validate these findings, a total of 500 simulated samples with tumor content ranging from 0.1% to 50% were generated by mimicking tumor and normal reads. The ensemble model outperformed single-method approaches, with the XGBoost algorithm achieving high predictive performance (Pearson correlation r &amp;gt; 0.9, p &amp;lt; 0.01) for predicting tumor fraction in cfDNA. The model demonstrated a limit of detection (LoD) at 2%, surpassing previously proposed models in sensitivity. This study highlights the potential of plasma cfDNA fragmentomics profiling as a highly precise and non-invasive method for quantifying and detecting prostate cancer. The findings support its utility in advancing liquid biopsy applications with improved sensitivity and accuracy. Citation Format: Shuang Gan, Haoran Tang, Feng Xie, Yue Zhang, Hang Dong. Genome-wide cfDNA fragmentomics combined with machine learning enhance non-invasive prostate cancer detection [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 6611.
Abstract 6213: T-cell receptor excision circles (TRECs) at birth and risk of childhood cancers
Authors: Jun Tao, Paul S. Albert, Nellie Gottlieb, Eric A. Engels
Journal: Cancer Research (2025)

Abstract Introduction: Acquired immunosuppression is associated with higher risk for infection-related cancers. However, cancer risk among children born with primary immunodeficiency is unknown. Circulating T-cell receptor excision circles (TRECs) are a marker of thymus production of T-cells, which is used to identify severe combined immunodeficiency (SCID) at very low levels during newborn screening. It is unknown whether TREC levels at birth are associated with cancer risk in children. Methods: The California (CA) and Texas (TX) cancer registries identified cancers in children aged 0-5 years born during 2013-2018. Controls were matched to cases by birth year and sex. TREC levels, measured at birth by the state SCID screening programs were linked to cases and controls. Conditional logistic regression was used to assess the association between tertiles (T) of TREC levels and cancer risk. Results: We included 1, 450 cancer cases and 7, 250 controls from TX and 2, 564 cases and 12, 820 controls from CA. Only 13 newborns in CA and 15 in TX had extremely low TREC level at birth. T2 levels of TREC was inversely associated with cancer risk compared to the lowest (T1), for several cancers(Table 1). However, only acute myeloid leukemia showed an inverse association for T2 and T3 in CA (odds ratio [OR] 95%CI: T2, 0.38, 0.22-0.66; T3, 0.47, 0.27-0.82), but this was not replicated in TX. Both T2 and T3 were associated with increased risk of acute lymphoblastic leukemia in TX (T2, 1.45, 1.05-1.99; T3, 1.49, 1.06-2.08) but not in CA. Conclusion: SCID is rare among children with cancer. We did not see consistent associations between TREC levels and cancer risk, either across tertile levels or between CA and TX. This indicates that differences in immune function do not contribute to the etiology of the childhood cancers examined. Alternatively, TREC assays are designed to detect children with the abnormally low TREC levels, and higher TREC levels may not reflect immune function. Citation Format: Jun Tao, Paul S. Albert, Nellie Gottlieb, Eric A. Engels. T-cell receptor excision circles (TRECs) at birth and risk of childhood 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 6213.
Abstract 6977: Development of SY-9453, a novel MAT2A inhibitor, for the treatment of MTAP-deficient cancers
Authors: Shuang Liu, Zhenbang Lou, Ying Xin, Chang Lu, Shikang Cheng, Junfen Shi, Yeliu Wang, Sheng Zhao, Yan Zhu, Hong Luo, Yinghui Sun
Journal: Cancer Research (2025)

Abstract Co-deletion of the MTAP gene with the CDKN2A gene, which is found in approximately 15% of all cancers, results in sensitization to MAT2A inhibition and provides an option for therapeutic intervention. The encouraging clinical activity of IDE397 provides further proof-of-concept for MAT2A inhibitors in the treatment of MTAP-deficient cancers. Here, we describe SY-9453 as a novel and potent MAT2A inhibitor. In the biochemical assay, SY-9453 potently inhibited the activity of MAT2A enzyme with an IC50 of 0.5 nM. In HCT116 MTAP-/- cells, SY-9453 showed very strong inhibition of the cellular SAM production and protein SDMA modification with IC50s less than 10 nM. Moreover, SY-9453 also demonstrated strong inhibitory activity on the proliferation of multiple MTAP-deficient cancer cell lines. Functionally, SY-9453 reduced cellular mRNA splicing, induced cell cycle arrest, and promoted cell apoptosis in a dose-dependent manner. In vivo studies showed that SY-9453 has robust anti-tumor activity in several CDX models of colorectal cancer, pancreatic cancer, and non-small cell lung cancer. In the HCT116 MTAP-/- xenograft model, SY-9453 displayed dose-dependent inhibition of tumor growth, and tumor regression was observed after treatment with SY-9453 at 25 mpk, QD. Furthermore, SY-9453 revealed favorable PK properties and tolerability in preclinical studies. In conclusion, the current results demonstrate that SY-9453 is a novel small molecule MAT2A inhibitor with high activity in vitro and in vivo, providing a rational option for treating cancers with MTAP deficiency. Citation Format: Shuang Liu, Zhenbang Lou, Ying Xin, Chang Lu, Shikang Cheng, Junfen Shi, Yeliu Wang, Sheng Zhao, Yan Zhu, Hong Luo, Yinghui Sun. Development of SY-9453, a novel MAT2A inhibitor, for the treatment of MTAP-deficient 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 6977.
Abstract 4834: Genomic and metabolic effects of KDM6A loss regulates differential responses to immune checkpoint therapy and chemotherapy in bladder cancer
Authors: Pratishtha Singh, Deblina Raychaudhuri, Bidisha Chakraborty, Aminah J. Tannir, Swadhin Meher, Anurag Majumdar, Jessalyn Hawkins, Yun Xiong, Philip L. Lorenzi, Padmanee Sharma, Patrick G. Pilie, Sangeeta Goswami
Journal: Cancer Research (2025)

Abstract Bladder cancer often harbors driver mutations in genes regulating epigenetic processes, yet their influence on therapeutic perturbations is understudied. One key example is KDM6A, a gene frequently mutated in bladder cancer, which encodes a histone demethylase that confers transcription permissive chromatin state. Retrospective analysis of patient cohorts demonstrated that KDM6A mutations correlate with improved response to immune checkpoint therapy (ICT) and decreased sensitivity to cisplatin-based chemotherapy. Mechanistic studies reveal that CRISPR-Cas9 deletion of Kdm6a reduced expression of critical genes including Msh2, Msh6, and Exo1 involved in DNA Mismatch repair (MMR) and double-stranded base repair (DSBR) in tumor cells with improved response to anti-PD-1 therapy. Further, KDM6A deficiency downregulated genes involved in cisplatin resistance and attenuated sensitivity to cisplatin-based chemotherapy in vitro and in vivo. Additionally, loss of KDM6A was associated with metabolic shift from glycolysis to oxidative phosphorylation. CyTOF analyses show decreased abundance regulatory T cells (Tregs) in Kdm6a-knockout tumors. Importantly, reduced lactate in the Kdm6a-knockout tumor microenvironment impaired histone lactylation (H3K9la/H3K18la) in Tregs with concurrent attenuation of expression of key immunosuppressive genes including Foxp3, Tgfß1 and Pdcd1. Collectively, this study provided insights into the role of KDM6A-mediated epigenetic regulation of DNA repair and metabolic reprogramming which could potentially govern response to chemotherapy and ICT aiding patient stratification and development of personalized treatment algorithms. Citation Format: Pratishtha Singh, Deblina Raychaudhuri, Bidisha Chakraborty, Aminah J. Tannir, Swadhin Meher, Anurag Majumdar, Jessalyn Hawkins, Yun Xiong, Philip L. Lorenzi, Padmanee Sharma, Patrick G. Pilie, Sangeeta Goswami. Genomic and metabolic effects of KDM6A loss regulates differential responses to immune checkpoint therapy and chemotherapy in bladder 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 4834.
Abstract 6483: Powerful end-to-end spatial analyses using precise spatial proteomics
Authors: Charles E. Jackson, Matthew H. Ingalls, Kayla E. Cashion, J Spencer Schwarz, Adam Northcutt, Arne Christians, Oliver Braubach
Journal: Cancer Research (2025)

Abstract Spatial biology supports our understanding of the progression and treatment of cancer by distilling complex cellular interactions into actionable spatial signatures. The most actionable targets to study with spatial methods are protein biomarkers, but non-destructive, high-plex spatial proteomics has been challenging to achieve due to technical limitations posted by available technologies. With the recent advent of enhanced photobleaching in cyclic immunofluorescence (EpicIF™) technology, multiplex immunofluorescence (mIF) can now be achieved more easily and inexpensively. EpicIF technology quickly and safely removes signal from even the brightest organic fluorophores, enabling the use of standard fluorescent antibodies in high-plex spatial proteomic protocols. We leveraged EpicIF technology to design modular mIF assay panels targeting key tumor immune microenvironment (TiME) biomarkers, tissue structural features, and markers enabling accurate cell segmentation. These assay panels were validated for performance (including sensitivity, specificity, and reproducibility) across a range of carcinoma tissues using the CellScape™ Precise Spatial Proteomics platform. Our validated panels enabled robust segmentation of immune, tumor and stromal cell types, ultimately permitting robust and comprehensive end-to-end spatial analysis of the TiME. We identified complex spatial neighborhoods composed of cellular interactions between immune infiltrates containing B-cells and T-cells, with mosaic expression of developmental and activation status markers in the TiME. Together, the use of these modular mIF panels, coined Next-Generation VistaPlex™ Assays, provided a fast foundation for accurate spatial analyses. The pairing of EpicIF technology with ready-to-use mIF assay panels provides the first simple, achievable access to spatial proteomics, including those without previous expertise in spatial biology. Citation Format: Charles E. Jackson, Matthew H. Ingalls, Kayla E. Cashion, J Spencer Schwarz, Adam Northcutt, Arne Christians, Oliver Braubach. Powerful end-to-end spatial analyses using precise spatial proteomics [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 6483.
Abstract 6679: MicroRNA cargo of extracellular vesicles of pancreatic cancer patients have immunoregulatory potential
Authors: Rupinder Kaur, Sandeep Bhoriwal, Pramod Kumar Gautam
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dismal five-year survival rate of 5-8%. Extracellular vesicles (EVs), nano-sized membrane-bound particles (30-150 nm) present in the circulatory system, play a crucial role in mediating intercellular communication, regulating immune responses, and driving tumor progression. MicroRNAs (miRNAs), integral components of EVs, function as key mediators in cellular signaling pathways. Although the role of exosomal miRNAs (exo-miRNAs) in cancer pathogenesis is well established, their comprehensive therapeutic, diagnostic, and immunomodulatory potential remains largely unexplored. This study established the differential exoMIR profile of PDAC patients using small RNA sequencing on the Illumina platform, compared with healthy controls, post-surgery and follow-up. Statistical analysis revealed hsa-miR-375-3p, hsa-miR-134-5p and hsa-miR-197-3p miRNAs were downregulated in PDAC patients than controls whereas hsa-miR-126-5p, hsa-miR-7847-3p, hsa-miR-197-3p were upregulated post-surgery. Six-month follow-up sample after surgery had hsa-miR-144-3p, hsa-miR-194-5p, hsa-miR-16-5p, hsa-miR-197-5p upregulated and hsa-miR-125b-3p was downregulated as compared to post-surgery sample. These distinct exoMIRs were identified as key regulators of cytokine translation in immune cells. The altered expression of these cytokines is well-known to significantly influence immune activity within the tumor microenvironment. Bioinformatic analyses revealed that these miRNAs, along with their protein targets, are closely involved in oncogenic pathways, underscoring their potential as valuable tools in cancer therapeutics, diagnostics, and prognosis. Citation Format: Rupinder Kaur, Sandeep Bhoriwal, Pramod Kumar Gautam. MicroRNA cargo of extracellular vesicles of pancreatic cancer patients have immunoregulatory potential [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 6679.