tbuckley/cabot-search huggingface dataset:
Abstract 151: Spatial patterns of APOBEC mutagenesis in the tumor microenvironment of Asian breast cancer
Authors: Zi Ching Tan, Yang Wu, Zhen Wei Neo, Mai Chan Lau, Siow Wee Chang, Joe Poh Sheng Yeong, Soo-Hwang Teo, Jia Wern Pan
Journal: Cancer Research (2025)

Abstract A common germline polymorphism in chromosome 22 involves the deletion of a large portion of the APOBEC3B gene that results in an APOBEC3A-B hybrid transcript. The hybrid transcript increases APOBEC3A activity and therefore increases APOBEC-associated mutagenesis, which is a common and important mutational signature in cancers. This deletion polymorphism is found with higher prevalence in Asians and is associated with increased risk of breast cancer in Asian women, as well as development of hypermutated cancers with greater immune cell infiltration. We used Stereo-seq spatial transcriptomics to study the relationship between APOBEC3B germline deletion, APOBEC mutagenesis, and the tumor immune microenvironment in Asian breast cancers with APOBEC3B germline deletion (carriers, either A3Bdel/del or A3Bdel/WT), and compared them to non-carriers. To study APOBEC mutagenesis, we constructed new bioinformatics pipelines to conduct variant calling and neoantigen prediction from Stereo-seq data whilst retaining spatial information. Unsupervised neighborhood clustering and cell type deconvolution revealed that the carriers have overall higher immune infiltration into the tumor compared to non-carriers. Somatic C&amp;gt;T mutations, the hallmark of APOBEC mutagenesis, were more prevalent in A3Bdel/del tumors. One sample showed a high overlap between somatic YTCA mutations, which are associated with APOBEC3A activity, and cancer associated fibroblasts (CAFs). Neoantigens originating from somatic mutations, specifically those arising from C&amp;gt;T mutations, were also more prevalent in A3Bdel/del tumors, but relatively few neoantigens arose from TCA or YTCA mutations. Our data suggest that biologically meaningful spatial resolution of APOBEC-associated somatic variants and neoantigens in tumor samples is possible using Stereo-seq technology. Citation Format: Zi Ching Tan, Yang Wu, Zhen Wei Neo, Mai Chan Lau, Siow Wee Chang, Joe Poh Sheng Yeong, Soo-Hwang Teo, Jia Wern Pan. Spatial patterns of APOBEC mutagenesis in the tumor microenvironment of Asian breast 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 151.
Abstract 1600: Tracking adaptation and response to targeted therapies in EGFR-mutant non-small cell lung cancer
Authors: Regina Hoo, Aaron Tan, Dawn Lau, Komal Gupta, Kenneth Chow, Jia Chi Yeo, Lan Ying Wang, Poh Sheng Joe Yeong, Anders J. Skanderup, Daniel S. Tan
Journal: Cancer Research (2025)

Abstract Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases, with EGFR-mutant NSCLC among never smokers being particularly prevalent in Asian populations. A major clinical challenge in treating advanced NSCLC is the development of resistance to targeted tyrosine kinase inhibitors (TKIs), highlighting the need to comprehensively profile the cellular mechanisms underlying drug resistance. We propose to tackle this by investigating the adaptive features of residual cancer cells and the role of the tumour microenvironment in sustaining tumour growth, resistance, and disease progression. In this study, we utilise single nucleus and spatial transcriptome profiling to decipher the response of EGFR-mutant tumours in more than 30 NSCLC patients before and during on-TKI treatment, including those that have developed resistance. We present an analytical framework that maps individual residual cancer cell populations that persist after treatment. We then examine the functional phenotypes of neighbouring immune cells including T lymphocytes and mononuclear phagocytes on these populations, and then comparing the immune dynamics to tumours that have fully acquired resistance. Our study reveals a potential mechanism by which metabolic plasticity and paracrine signaling from myeloid cells in the lung tumour microenvironment contribute to the maintenance of cancer stem cell properties, likely driving disease recurrence. We propose to incorporate a wider range of ongoing clinical trial and preclinical data to support our current findings, and with the aim of defining novel therapeutic strategy that can selectively eliminate drug tolerant persister population in EGFR-mutant NSCLC. Citation Format: Regina Hoo, Aaron Tan, Dawn Lau, Komal Gupta, Kenneth Chow, Jia Chi Yeo, Lan Ying Wang, Poh Sheng Joe Yeong, Anders J. Skanderup, Daniel S. Tan. Tracking adaptation and response to targeted therapies in EGFR-mutant 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 1600.
Abstract 661: LAG-3 blockade enhances the anti-tumor efficacy of PD-1 blockade combined with radiotherapy in a syngeneic murine triple-negative breast cancer model
Authors: Yoomin Kim, Seung Hyuck Jeon, Nawon Park, Seongmin Kim, In Ah Kim
Journal: Cancer Research (2025)

The anti-tumor efficacy of PD-1 blockade and local radiotherapy (RT) is often limited by diverse mechanisms that suppress CD8+ T cell responses. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory receptor expressed on exhausted CD8+ T cells and regulatory T cells (Tregs), and its blockade has been shown to enhance the anti-tumor effects of PD-1 blockade. Therefore, we hypothesized that combining LAG-3 blockade with PD-1 blockade and local RT would overcome treatment resistance in triple-negative breast cancer (TNBC). Using the 4T1 syngeneic mouse TNBC model, we evaluated the anti-tumor effects and immune cell phenotypes following treatments with local RT, PD-1 blockade, and LAG-3 blockade. We found that the triple combination of local RT, PD-1 blockade, and LAG-3 blockade resulted in the greatest tumor growth delay in both irradiated (primary) and unirradiated (secondary) tumors, with a significant reduction in metastatic lung nodules. The proportion of tumor-infiltrating CD8+ T cells increased with triple combination therapy while the proportion of Tregs decreased compared to the PD-1 + RT combination in both primary and secondary tumors. Consequently, the CD8+ T cell to Treg ratio was highest in the triple combination group. The proportion of tumor-specific CD8+ T cells increased following triple combination therapy not only in tumor microenvironment but also among splenic CD8+ T cells. Interestingly, the proportions of CD8+ T cells, as well as CD4+ T cells, with an effector memory phenotype were most significantly elevated by the triple combination therapy. In tumor-draining lymph nodes, the proportion of conventional type 1 dendritic cells capable of antigen cross-presentation to CD8+ T cells was increased by the triple combination therapy. These findings suggest that LAG-3 blockade enhances the therapeutic efficacy of local RT and PD-1 blockade by promoting T cell-mediated anti-tumor immune responses. This study highlights the potential of combining LAG-3 blockade with local RT and immune checkpoint inhibitors for the treatment of TNBC. (Work supported by grant from the National Research Foundation of Korea #2023R1A2C3003782) Citation Format: Yoomin Kim, Seung Hyuck Jeon, Nawon Park, Seongmin Kim, In Ah Kim. LAG-3 blockade enhances the anti-tumor efficacy of PD-1 blockade combined with radiotherapy in a syngeneic murine triple-negative breast cancer model [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 661.
Abstract 659: Translational medicine studies of BR111, a biparatopic anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment
Authors: Qinqin Zhuang, Yan Sun, Lilv Fan, Qianqian Tao, Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Lei Nie, Gang Chen, Haibin Wang
Journal: Cancer Research (2025)

Abstract ROR1 is a type I transmembrane protein that belongs to the ROR family. It is a receptor for Wnt family signaling molecules Wnt5a, and plays a critical role in various cellular processes, such as cell proliferation, survival, and migration. Being an oncofetal protein, ROR1 exhibits limited expression in most normal tissues. However, it is abnormally expressed in various hematological and solid cancers, contributing to the development and progression of many types of cancer. Due to its overexpression in cancer, ROR1 presents as a highly attractive target for antibody-drug conjugate (ADC) therapy. The current clinical results of ROR1 ADCs have been promising in treating patients with relapsed and/or refractory (R/R) hematologic malignancies. BR111 is anti-ROR1 ADC that consists of a biparatopic antibody, stably conjugated to an antimitotic agent. The biparatopic antibodies demonstrate superior binding affinity to ROR1-expressing cancer cells compared to single epitope antibodies. Notably, our unique and innovative conjugation platform CysX™, not only prevents payload detachment during circulation and reducing the off-target toxicity, but also enables a uniformed drug-to-antibody ratio (DAR) of 4. Recent translational medicine studies showed that ROR1 is relatively highly expressed in the patients of many solid tumors including sarcoma, gastric cancer, TNBC, endometrial cancer, etc. And BR111 has demonstrated efficacy in in vitro and in vivo models of those indications. BR111 has also showed synergistic efficacy when combined with PD-1/L1 antibodies, SIRPα antibody and several chemotherapeutics. Studies have also shown that ROR1 levels increase while HER2 levels decrease in cell lines treated with DS-8201, and BR111 showed improved efficacy in DS-8201 resistant cell line as well as in combination with DS-8201. The promising outcome holds great potential as a therapeutic treatment for hematological and solid cancers, offering a better safety profile. BR111 has great potential in further clinical evaluations. Citation Format: Qinqin Zhuang, Yan Sun, Lilv Fan, Qianqian Tao, Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Lei Nie, Gang Chen, Haibin Wang. Translational medicine studies of BR111, a biparatopic anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment [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 659.
Abstract 2837: Mechanisms promoting chromosomal instability following the loss of p53 and Rb
Authors: Risha Banerjee, David G. Kirsch
Journal: Cancer Research (2025)

Abstract p53 and Rb co-mutations are common in several human cancers and are associated with the onset of aggressive tumors with complex karyotypes. Canonically, these tumor suppressors respond to DNA damage and cellular stress by inducing cell cycle arrest, activating pro-apoptotic and anti-proliferative signalling, and promoting cellular senescence. While these pathways are sufficient to partially explain the tumor suppressive abilities of p53 and Rb, recent studies in genetically engineered mouse models suggest additional, non-canonical means of tumor suppression, including modulation of cellular differentiation and DNA topology, and interestingly, influencing cellular response to chromosomal instability. Chromosomal instability (CIN) is a hallmark of aggressive, therapy-resistant cancers and is associated with mitotic dysfunction, faulty DNA damage responses, immune evasion, and cellular stress response pathways. While it is known that p53 and Rb maintain the integrity of the genomic landscape, the mechanisms by which they prevent CIN remain understudied. Here, we use mouse embryonic fibroblasts (MEFs) to show that p53 + Rb double knock-out (DKO) causes a dramatic increase in ploidy at very early passages, which stabilizes at tetraploid levels. These cells also harbour high levels of CIN, indicated by the presence of micronuclei, DNA double-stranded breaks, and lagging chromosomes. Additionally, we observed CIN in p5325, 26 transactivation domain (TAD) mutant MEFs that are unable to activate most canonical p53 targets yet retain the ability to suppress tumorigenesis in vivo, raising the possibility that the maintenance of chromosomal stability is dispensable to the tumor suppressive functions of p53. Using a combination of bulk and scRNA sequencing of aneuploid and diploid DKO MEFs, in future experiments we will identify p53- and Rb-dependent changes in gene expression associated with the onset and progression of CIN. Overall, the results of this study are expected to provide critical insights into the molecular mechanisms by which tumor suppressors p53 and Rb work together to repress CIN. Citation Format: Risha Banerjee, David G. Kirsch. Mechanisms promoting chromosomal instability following the loss of p53 and Rb [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 2837.
Abstract 123: Induced natural killer cells: A next-generation platform for allogeneic immune cell therapies
Authors: Han-Seop Kim, Jae Yun Kim, Binna Seol, Ji Eun Choi, Ji-Young lee, Yee Sook Cho
Journal: Cancer Research (2025)

Abstract Background: Natural Killer (NK) cells hold significant promise for effective and safe allogeneic immune cell therapies, primarily due to their ability to selectively target and eliminate cancer and other abnormal cells. Key advantages, including off-the-shelf availability and a low risk of graft-versus-host disease, cytokine release syndrome, and immune effector cell-associated neurotoxicity syndrome, make them ideal candidate for immunotherapy. However, conventional NK cell sources derived from blood or stem/progenitor cells face challenges such as high heterogeneity, limited scalability, and high production costs, underscoring the need for innovative and robust NK cell sources. Methods: We previously developed induced NK (iNK) cells via OSKM transcription factor-mediated direct reprogramming as an alternative allogeneic NK cell source. To explore their therapeutic potential, we compared the phenotypic and functional characteristics of iNK cells, including receptor expression, cytotoxicity, degranulation, cytokine production, and antibody-dependent cellular cytotoxicity (ADCC), with those of control NK cells (PBMC-NK cells and NK-92). Furthermore, CRISPR/Cas9 screening was performed on pancreatic cancer (PC) cells using a human whole-genome dual-gRNA knockout library to identify genes critical for NK cell-mediated targeting and killing. Results: iNK cells demonstrated high purity (CD56+CD16+, 93.1±3.4%) and homogeneity, along with elevated expression of activating receptors (CD69, NKG2D, DNAM-1) and natural cytotoxicity receptors (NKp30, NKp44, and NKp46) while showing reduced KIR expression (2DL1, 2DL2 and 3DL1) compared to control NK cells. Functionally, iNK cells displayed robust cytotoxicity against a broad range of human solid cancers, including PC, through cytokine secretion (IFN-γ, granzyme B, and TNF-α), CD107a degranulation, and ADCC. CRISPR/Cas9 screening identified 500 depleted genes in PC cells, with key targets such as EIF2AK3, PRKAA1, IRAK3, and NEK2, validated as contributors to NK cell-mediated cytotoxicity. Conclusions: iNK cells represent a scalable and homogeneous alternative to conventional NK cell sources, overcoming limitations such as donor dependency, variability, and production inefficiencies. With their enhanced cytotoxic potential and the identification of key gene targets critical for NK cell-mediated killing, induced NK cells provide a robust and promising platform for the development of “off-the-shelf” allogeneic immunotherapies. Citation Format: Han-Seop Kim, Jae Yun Kim, Binna Seol, Ji Eun Choi, Ji-Young lee, Yee Sook Cho. Induced natural killer cells: A next-generation platform for allogeneic immune cell therapies [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 123.
Abstract 1225: Phenotypically-relevant patient-derived 3D cell models to interrogate personalized medicine approaches at scale
Authors: Thomas Grundy, Peilin Tan, Joanna Wasielewska, Christine Yee, Tania Fowke, Sean Porazinski
Journal: Cancer Research (2025)

Abstract The complexity and heterogeneity of cancers both intra- and inter-patient have led to the precision medicine paradigm of cancer therapy where treatment is personalized to the individual patient. Recent clinical trials such as the I-PREDICT study [1] have underscored the benefits of approaches matching combination therapies to the patient’s molecular alterations, leading to improved disease control and survival rates. Tumoroids are patient-derived cancer cells that grow as 3D self-organized, multicellular organoids that maintain key characteristics of the patient tumor of origin including molecular features such as genotype and gene expression, and biological behaviors. Whilst these models serve as valuable tools for studying tumor biology and responses of patient-derived cells to various anti-cancer therapies, the establishment and maintenance of tumoroids has historically been difficult and labor intensive, limiting more widespread use. Here, we utilize the Inventia RASTRUMTM platform and OncoProTM colorectal cancer (CRC) Tumoroid Cell Lines (ThermoFisher Scientific [2]) to easily create plug and play patient-derived 3D cell models based on synthetic PEG-based hydrogel matrices, which were tuned to mimic the tissue stiffness and ECM composition of CRC tumors. We used this workflow to evaluate how these 3D models maintain the clinicopathological features of patient-derived tumoroid cells, as well as molecular features and cellular signaling native to the tumor and its microenvironment. We further demonstrate the utility of this approach for throughput drug screening and predicting personalized therapy responses. Overall, our approach provides a scalable framework for evaluating precision medicine approaches using clinically-relevant patient-derived tumoroids. Future work will focus on the development of processes to support direct dissociation and generation of patient-derived models from biopsies from a variety of cancer types and larger scale utility of the RASTRUM platform in workflows that could be leveraged to inform treatment decision making. References [1] Sicklick JK et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med. 2019 May;25(5):744-750.[2] Paul CD et al. Long-term maintenance of patient-specific characteristics in tumoroids from six cancer indications in a common base culture media system. bioRxiv 2024. doi: https://doi.org/10.1101/2024.06.10.598331 Citation Format: Thomas Grundy, Peilin Tan, Joanna Wasielewska, Christine Yee, Tania Fowke, Sean Porazinski. Phenotypically-relevant patient-derived 3D cell models to interrogate personalized medicine approaches at scale [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 1225.
Abstract 1104: Identifying pancreatic cancer subtypes by a novel meta-learning model
Authors: Nick Boos Peterson, Mengtao Sun, Jieqiong Wang, Shibiao Wan
Journal: Cancer Research (2025)

Abstract Due to the difficulty of both early diagnosis and treatment, pancreatic cancer (PC) is the third leading cause of cancer related deaths in the United States and is projected to become the second by 2030. As a heterogeneous disease, PC can be divided into four main subtypes, with each having differing molecular pathways, survival rates, and responses to therapy. Traditional wet lab approaches to identify PC subtypes, such as histopathological studies or molecular profiling, are costly, laborious, and time-consuming. Previous studies indicate that predicting PC subtypes based on transcriptomic profiling is a feasible and promising method. However, these methods are unable to capture the full complexity of the data and may lead to biased and unstable results. To this end, we present a novel meta-learning algorithm for PC subtype identification based on RNA-seq data only. Specifically, after some basic gene filtering and preprocessing, the transcriptome-based feature vectors were classified by multiple base machine learning (ML) classifiers like logistic regression, linear support vector machine (SVM), and radial basis function (RBF) SVM, whose outputs were then combined with the initial filtered feature vectors to constitute a new set of ensemble feature vectors for a meta-learning model. Our meta-learning model could learn and leverage the diversity of different base classifiers to boost the prediction performance beyond any single ML model. Results based on 100 times leave-one-out cross validation tests on a dataset with 96 PC patients demonstrated that our proposed method could achieve an average AUC of 0.99, which was significantly better than existing state-of-the-art methods. In addition, our meta-learning model remarkably outperformed each individual base classifier, demonstrating that our model could combine diverse results from multiple base classifiers to boost the ensemble performance. We expect that our method will provide a complementary way to characterize different PC subtypes, bringing positive impacts on downstream pancreatic cancer risk stratification and tailored treatment design. Additionally, we believe our meta-learning model can also be extensible to identify subtypes of other types of cancer. Citation Format: Nick Boos Peterson, Mengtao Sun, Jieqiong Wang, Shibiao Wan. Identifying pancreatic cancer subtypes by a novel meta-learning model [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 1104.