tbuckley/cabot-search huggingface dataset:
Abstract 2871: Comparative anti-tumoral efficacy of endoglin-targeting ADCs harbouring different payloads for the treatment of gastric cancer
Authors: Isabel Egaña, Patricia González-Callejo, Alvaro González, Cristina Ferrer, Roland Kontermann, Oliver Seifer, Klaus Pfizenmaier, Myriam Fabre
Journal: Cancer Research (2025)

Endoglin (CD105), a TGFb-RII co-factor, overexpressed in tumor microvasculature and endothelial-derived CAFs, has been extensively validated as a therapeutic target for cancer treatment. Endoglin-targeting ADCs have been developed in this work, using a human IgG1 antibody, OMTX003, conjugated to different microtubule inhibitors such as eribulin (OMTX603-3) or MMAE (OMTX103), with DAR values between 4 and 8. Target binding was maintained within subnanomolar values for each ADC, similar to the unconjugated antibody. Internalization was efficient, with 75% intracellular localization within 60 minutes, regardless of the conjugated payload. In vitro activity in Endoglin-expressing HT1080 cells was target- and concentration-dependent, with IC50 values of 6 and 95.5pM, respectively. ADCs were tested for their in vivo anti-tumor efficacy in a gastric cancer PDX murine model. Complete tumor regression was observed. No re-growth occurred up to 40 days after treatment end, showing the lack of resistance to treatment. ADCs were well tolerated with no weight loss. These encouraging results are postulating these anti-ENG ADCs for further development. Citation Format: Isabel Egaña, Patricia González-Callejo, Alvaro González, Cristina Ferrer, Roland Kontermann, Oliver Seifer, Klaus Pfizenmaier, Myriam Fabre. Comparative anti-tumoral efficacy of endoglin-targeting ADCs harbouring different payloads for the treatment of gastric 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 2871.
Abstract 2502: Biologically informed cell typing in the tumor microenvironment with lightweight LLMs
Authors: Yooeun Kim, Jiwon Kim, Hongyoon Choi
Journal: Cancer Research (2025)

Background: The tumor microenvironment (TME) is a complex ecosystem of diverse cell types that interact dynamically, influencing tumor development and therapy response. Accurate cell type annotation in the TME is challenging due to partial overlap among marker genes, scarcity of representative reference datasets, and emergence of novel cell phenotypes. Our approach uses open-source Large Language Models (LLMs) including Llama 3.2 to provide a reference-free, efficient, and controllable method for cell type classification based on marker genes. Unlike tools that depend on curated reference datasets, this method demonstrates consistent performance across a wide range of cell types. By generating rationale for predicted cell types, our method offers a practical and interpretable framework for annotating diverse cellular populations while offering adaptability to the complexities of the TME. Methods: LangChain is a “Swiss-knife” platform for LLM applications. We developed a framework identifying cell types in the TME leveraging marker gene contexts. This approach combines structured outputs with predefined constraints to ensure biological plausibility and marker-based reasoning for interpretable cell type identification. Prompt engineering and schema-enforced validation ensure robust, biologically informed outputs, offering flexibility in ambiguous contexts while minimizing hallucinations. Results: Our method successfully identifies cell types in several cancer datasets, demonstrating high interpretability and reduced misclassification compared to competing methods, such as ScType and GPTCelltype. By employing a de novo cell typing approach, the model effectively resolves ambiguities in overlapping marker genes and adapts well to complex cell populations. The method also achieves superior performance in terms of agreement scores, TTFT (time-to-first-token), and TPOT (time-per-output-token), highlighting its efficiency in time-critical tasks. Explanations provided by the LLM support biological relevance and enhance user confidence in cell typing tasks. Conclusion: This study highlights the potential of light-weighted LLM for heterogeneous cell typing in complex environments like the TME. By circumventing the limitations of other cell typing methods, including those of reference-dependent and independent, this approach offers a flexible, robust, and interpretable solution for identifying diverse cell types in challenging biological contexts. Citation Format: Yooeun Kim, Jiwon Kim, Hongyoon Choi. Biologically informed cell typing in the tumor microenvironment with lightweight LLMs [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 2502.
Abstract 4480: Novel targeting API@API nanomedicines for synergistic molecular signaling modulation in head and neck cancer and the microenvironment
Authors: Li-Xing Yang, Ru-Fen Chen, Yan-Wei Wu, Pei-Wen Wang, Chih-Chia Huang, Dar-Bin Shieh
Journal: Cancer Research (2025)

Head and neck cancer (HNC) has become a prominent health concern in Taiwan, particularly among young males, with rising socioeconomic implications due to traditional treatments’ limited success in preventing recurrence and metastasis. Our study introduces a novel API@API nanoformulation strategy that combines multiple active pharmaceutical ingredients (APIs) to synergistically target signaling pathways, aiming to overcome limitations of current HNC therapies and reduce toxicity. The API@API nanoformulation leverages natural nanoparticles derived from Cordyceps sinensis, incorporating key drugs such as FTY720 and Perifosine. The formulation optimizes amphipathic drug properties, allowing for higher bioavailability and targeted therapeutic action. By evaluating API@API nano cocktails in preclinical HNC models, we observed increased efficacy, with enhanced cytotoxicity and downregulation of critical pathways in HNC cells. The formulation demonstrated selective cytotoxicity across cancer stages, effectively targeting the tumor microenvironment (TME) through dual-drug-loaded nanoparticles. We also accessed the in vitro and in vivo efficacy of API@API nano cocktails in suppressing tumor growth, modulating immune responses, and reducing cancer cell migration. The platform demonstrated improved pharmacokinetics, enhanced tumor accumulation, and prolonged retention at tumor sites. Further immunological analyses indicated an immunosuppressive-to-immunomodulatory shift within the TME, with increased dendritic and M1 macrophage activity and reduced immunosuppressive cell populations. Spatial proteomic analyses confirmed enhanced immune cell distribution with reducing tumor associate neutrophiles, indicating that API@API formulations may improve HNC sensitivity to immunotherapy. In conclusion, the API@API nanoformulation platform has shown potential as an effective therapeutic strategy for HNC, offering significant advantages in efficacy, reduced side effects, and TME modulation. This platform supports broader biopharmaceutical applications, aligning with the global need for advanced cancer treatments. Citation Format: Li-Xing Yang, Ru-Fen Chen, Yan-Wei Wu, Pei-Wen Wang, Chih-Chia Huang, Dar-Bin Shieh. Novel targeting API@API nanomedicines for synergistic molecular signaling modulation in head and neck cancer and the microenvironment [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 4480.
Abstract 3193: Overcoming glioblastoma heterogeneity and plasticity through the development of novel chimeric antigen receptor (CAR)-T cells targeting PTPRZ1
Authors: Aditya A. Mohan, Barbara Lipes, Charla Gentry, Rushil Yerrabelli, Daniel Wilkinson, Kisha Patel, Emily Blandford, Andrew Hardigan, Peter Fecci, Michael Gunn, Anoop Patel
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is an aggressive and heterogeneous brain tumor characterized by extensive plasticity, which contributes to resistance against conventional therapies. To address this challenge, we generated a unique single nuclei RNA sequencing atlas, integrating GBM, normal brain tissue, and developmental brain datasets. Utilizing single-cell RNA sequencing (scRNA-seq) analysis methods, we comprehensively characterized GBM heterogeneity and plasticity, focusing on identifying homogeneous cell surface antigens suitable for chimeric antigen receptor (CAR) T-cell targeting. scRNA-seq analysis revealed PTPRZ1 as a promising candidate antigen, uniformly expressed across tumor cells, offering a compelling therapeutic target for CAR-T cell therapy. Following antigen identification, we initiated mouse immunization campaigns to stimulate antibody production, coupled with phage display technology to generate a diverse library of single-chain variable fragments (scFvs). A rigorous cell-based positive and negative selection protocol was employed to isolate scFvs that specifically bind to PTPRZ1 while avoiding binding to closely related proteins from the same family, thereby minimizing off-tumor effects. Protein language models were used and experimental site-directed mutagenesis was performed to affinity mature and humanize selected scFv clones. Once PTPRZ1-specific scFvs were identified, they were incorporated into novel CAR constructs designed to overcome the low surface antigen density challenge commonly observed with GBM antigens. These CARs incorporated several signaling domains and structural modifications to enhance sensitivity and efficacy in low antigen-density settings. Our approach integrates cutting-edge single-cell sequencing, phage display technologies, and CAR-T cell design principles to address the heterogeneity of GBM and develop precision-engineered CAR-T cells targeting PTPRZ1. This study presents a step forward in overcoming GBM's plasticity, offering a potential therapeutic strategy with translational potential. Citation Format: Aditya A. Mohan, Barbara Lipes, Charla Gentry, Rushil Yerrabelli, Daniel Wilkinson, Kisha Patel, Emily Blandford, Andrew Hardigan, Peter Fecci, Michael Gunn, Anoop Patel. Overcoming glioblastoma heterogeneity and plasticity through the development of novel chimeric antigen receptor (CAR)-T cells targeting PTPRZ1 [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 3193.
Abstract 5090: Bioinformatics analysis of the role of asymmetric self renewal associated genes in the cancer progression
Authors: Seokyoung Hwang, Minju Lee, Jayhyun Cho, Minkyu Kim, Sang Kook Lee, Minsoo Noh
Journal: Cancer Research (2025)

Abstract Adult stem cells possess a unique ability for asymmetric self-renewal, enabling the simultaneous production of non-stem cell progenitors and self-renewing stem cells, distinguishing them from symmetrical cell division. In cancer cells, the regulation of cell division is often disrupted to sustain proliferation. However, specific patterns might be essential for evading cell death and adapting to the tumor microenvironment. In this study, transcriptomic data from engineered p53-expressing and p53-null mouse fibroblasts were re-analyzed to identify expression signatures of asymmetric self-renewal associated (ASRA) and p53/IMPDH2-related self-renewal patterns associated (SRPA). Pathway analysis revealed that ASRA signatures were enriched in immune regulation and angiogenesis pathways, in addition to cell cycle regulation. Genomic analysis using The Cancer Genome Atlas (TCGA) database demonstrated correlations between ASRA signatures and survival outcomes, as well as molecular properties across various cancer types, including stomach adenocarcinoma (STAD). Additionally, public single-cell RNA sequencing (scRNA-seq) and clinical dataset analyses revealed the role of ASRA genes in the interactions between tumor cells and surrounding immune and stromal cells. These findings suggested that targeting ASRA signatures is a promising strategy for developing novel cancer therapies. Citation Format: Seokyoung Hwang, Minju Lee, Jayhyun Cho, Minkyu Kim, Sang Kook Lee, Minsoo Noh. Bioinformatics analysis of the role of asymmetric self renewal associated genes in the cancer progression [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 5090.
Abstract 4481: Targeting Xkr8 via nanoparticles-mediated codelivery of siRNA and chemotherapy drugs for cancer immunochemotherapy
Authors: Yuang Chen
Journal: Cancer Research (2025)

Abstract Activation of scramblases is one of the mechanisms that regulate the exposure of phosphatidylserine to the cell surface, a process that plays an important role in tumor immunosuppression. Here we show that chemotherapeutic agents induce overexpression of Xkr8, a scramblase activated during apoptosis, at the transcriptional level in cancer cells, both in vitro and in vivo. Given this finding, we developed a nanocarrier for co-delivery of Xkr8 siRNA and the FuOXP pro-drug to tumors. Intravenous injection of our nanocarrier led to significant inhibition of tumor growth in colon and pancreatic cancer models along with increased antitumor immune response. Targeting Xkr8 in combination with chemotherapy may represent a novel strategy for the treatment of various types of cancers. Citation Format: Yuang Chen. Targeting Xkr8 via nanoparticles-mediated codelivery of siRNA and chemotherapy drugs for cancer immunochemotherapy [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 4481.
Abstract 5113: Elucidating the biological effects of platinum adduct-containing cell-free DNA
Authors: Sri Meghana Yerrapragada, M. Alexandra Carpenter, Michael G Kemp
Journal: Cancer Research (2025)

Abstract Cisplatin is a widely used chemotherapeutic agent for cancers such as lung, breast, esophageal, ovarian, and pancreatic. However, its effectiveness is constrained by its cytotoxicity to healthy tissues and the rapid development of cancer cell resistance. Cisplatin binds to the N7 position of purines in DNA, forming intra- and inter-strand crosslinks, which are potentially mutagenic and lethal if not removed by the nucleotide excision repair (NER) system. When DNA repair mechanisms are overwhelmed, cisplatin-DNA adducts can trigger caspase-dependent apoptosis, leading to degradation of the damaged DNA. Interestingly, the ultimate fate of this damaged DNA remains unclear. Our study, using differential centrifugation and DNA immunoblotting, has identified that cisplatin-adduct-containing DNA are released into extracellular spaces upon treating with lethal doses of cisplatin. Notably, caspase inhibition blocks this release, while inhibition of NER enhances it. Further, our research demonstrates that non-damaged bystander cells can uptake the cisplatin-DNA adducts, potentially activating DNA damage checkpoints or innate immune responses. This process can also alter the sensitivity of bystander cells to cisplatin. Given the role of cell-free DNA (cf-DNA) in intercellular communication, our findings suggest that damaged DNA could be transferred to distant organs, contributing to cisplatin resistance, toxicity, and systemic side effects. Understanding the mechanism by which cisplatin-DNA adducts influence cell signaling and treatment outcomes could open new avenues for using cf-DNA as biomarkers to monitor therapeutic responses and minimize long-term genomic risks associated with chemotherapy. Citation Format: Sri Meghana Yerrapragada, M. Alexandra Carpenter, Michael G Kemp. Elucidating the biological effects of platinum adduct-containing cell-free DNA [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 5113.
Abstract 5112: Tumor cell expression of a distinct TME gene signature defines differential drug sensitivities to EGFR/MEK/SRC targeted agents
Authors: Mingli Yang, Michael V. Nebozhyn, Lance Pflieger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Andrey Loboda, W. Jack Pledger, Timothy J. Yeatman
Journal: Cancer Research (2025)

Abstract Recently, we serendipitously identified a pair of distinct 10-gene signatures, one associated with epithelial cells (EPIS) and one the tumor microenvironment(TMES). When we classified 2373 colorectal cancer (CRC) tumors into the consensus molecular subtypes (CMS1-4), the EPIS signature score was predominantly related to the TME-poor CMS2/CMS3 classes and was highly predictive of EGFRi outcomes in two clinical trial datasets and a large, real-world clinico-genomics dataset. By contrast, the TMES signature score was strongly associated with the immune/stromal CMS1/CMS4 subtypes and was highly correlated with the gene expression signature scores portending EMT, SRC activation and MEK inhibitor resistance (MEKi-R). To understand the cellular features underpinning the TMES correlation, we further analyzed the cellular origins of 61 SRC signature genes and 13 MEKi-R signature genes, as well as 8 EMT genes using an independent public scRNASEQ dataset (n=62). All of the 13 MEKi-R genes and all of the 8 EMT genes, as well as most of the SRC activation genes, were predominantly expressed in various immune/stromal TME cells, supporting a key role of the TME gene expression. Remarkably, when the signature scores were analyzed in a dataset of ∼150 heterogenous CRC cell lines that do not have a TME, a similar strong correlation among the TMES, EMT, SRC activation and MEKi-R scores was also observed. These data suggest that the CRC epithelial cells may have adopted the TME gene expression features important in modulating the drug sensitivities. Spatial transcriptomics of 8 CRC samples confirmed that the EPIS genes were predominantly expressed in epithelial cells. By contrast, the signature genes of the TMES linked to EMT/SRC activation/MEKi-R were diffusely expressed across epithelial/invasive cancer mixed with the TME, indicating an interactive tumor-TME cellular feature. Our data suggest that the TME through its impact on epithelial cell gene expression may define drug sensitivities to targeted therapies. Citation Format: Mingli Yang, Michael V. Nebozhyn, Lance Pflieger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Andrey Loboda, W. Jack Pledger, Timothy J. Yeatman. Tumor cell expression of a distinct TME gene signature defines differential drug sensitivities to EGFR/MEK/SRC targeted agents [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 5112.
Abstract 4500: Exploring site-specific activation of kinase inhibitors via AKR1C3-mediated prodrug strategy
Authors: Esther Elonga, Zhengnian Li, Michael Martinez, Anuradha Tathireddy, Stephen M. Hinshaw, Nathanael S. Gray
Journal: Cancer Research (2025)

Targeted therapies such as kinase inhibitors have significantly advanced cancer treatment. However, targeting pan-essential kinases remains challenging due to the side effects associated with a narrow therapeutic window. To address this issue, we propose developing prodrugs that can be site-specifically activated by Aldo-keto reductase 1C3 (AKR1C3). Specifically, a kinase inhibitor prodrug will be selectively activated by AKR1C3 to release the active parent compound in tissues with overexpression of AKR1C3. In this study, we designed prodrugs of the kinase inhibitor OTS964, a potent inhibitor of the pan-essential kinase CDK11, modeled after the AKR1C3-activated prodrug OBI3424. Using rational design principles, our prodrugs were engineered for selective activation by AKR1C3. Enzymatic assays confirmed AKR1C3-mediated reduction of the prodrugs, liberating the parent compound OTS964. Subsequent in vitro assays demonstrated that these prodrugs retained comparable activity to the parent compound in cell viability, immunoblotting, and NanoBRET assays. This study introduces a promising strategy to enhance the therapeutic window of pan-essential kinase inhibitors by concentrating their effects in affected tissues while sparing normal cells. Citation Format: Esther Elonga, Zhengnian Li, Michael Martinez, Anuradha Tathireddy, Stephen M. Hinshaw, Nathanael S. Gray. Exploring site-specific activation of kinase inhibitors via AKR1C3-mediated prodrug strategy [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 4500.