tbuckley/cabot-search huggingface dataset:
Abstract 5117: Investigating the role of secreted plasminogen receptors in the establishment of the pre-metastatic breast cancer niche
Authors: Gillian Okura
Journal: Cancer Research (2025)

Abstract Introduction: Breast cancer is the most common cancer in women, with 25% of patients presentingsecondary tumors at diagnosis. Metastasis, responsible for over 90% of cancer deaths, involves cancer cellsescaping the primary tumor to colonize distant organs. This process requires the preparation of target sites, known as premetastatic niches (PMNs). PMNs undergo structural remodeling facilitated by cancer cell-secreted factors, including the protease plasmin (Pm), which aids in cancer cell escape by degrading tissuebarriers. Cancer cells utilize plasminogen receptors (PgRs) to convert the blood protein plasminogen (Plg)into Pm. Our research has shown that conditioned media (CM) from breast cancer cells can activate Plg toPm, suggesting the presence of PgRs in these secretions. While cell surface PgRs are established in tumorprogression, the roles of secreted PgRs within the breast cancer secretome remains undefined. Additionally, the involvement of the Plg/Pm system in PMN modulation is unexplored. We have found that CM frommalignant BCCs has higher Pm-activating potential than from non-malignant BCCs. Protein purification ofCM identified several soluble PgR-active fractions, with phosphoglycerate kinase-1 (PGK-1) emerging asa key PgR candidate. Methods: CM was isolated from highly and weakly metastatic BCC lines (MDA MB 231 vs. MCF7 &amp; 4T1vs. 67NR). Soluble proteins were separated by size- and charge-chromatography, and fractions wereassayed for PgR activity, measured through their ability to stimulate tPA-dependent Plg-to-Pm conversion.Active fractions were pooled and identified via mass spectrometry. Results: CM from MDA MB 231 and 4T1 cells exhibited higher PgR activity and distinct chromatographicprofiles compared to MCF7 and 67NR cells. Size-exclusion chromatography revealed multiple PgR activitypeaks. Mass spectrometry identified novel PgR candidates, including glycolytic enzymes and extracellularmatrix components, PGK-1, a glycolytic enzyme, was identified in a PgR activity peak, with recombinantPGK-1 showing significant in vitro Pm generation, confirming its PgR role. Conclusions: PGK-1 is secreted by breast cancer cells and has Pm-generating potential. Futureexperiments will validate PGK-1 and other proteins as PgRs and clarify their roles in metastasis. Citation Format: Gillian Okura. Investigating the role of secreted plasminogen receptors in the establishment of the pre-metastatic breast cancer niche [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 5117.
Abstract 5803: Computational modeling of immune cell phenotypes enhances prediction of clinical anti-cancer drug response
Authors: Gema Sanz, Réka Böröcz, Bence Czakó, Gerold Csendes, Csaba Gór, Gábor Kovács, László Mérő, Kristóf Szalay, Daniel Veres, Bence Szalai
Journal: Cancer Research (2025)

Abstract Preclinical cancer model systems, such as large-scale drug screens in cancer cell lines, are pivotal for identifying drug-sensitive indications and biomarkers of drug efficacy. However, these systems often lack the tumor microenvironment's complexity, including interactions with immune cells, which play a critical role in modulating drug response. Investigating drug-induced effects on immune cells is experimentally challenging due to the diversity of immune cell types and the complexity of co-culture systems. Computational models of immune cells can help to overcome these limitations and to guide further experiments. Leveraging public post-perturbation single-cell RNA sequencing datasets from various immune cells (including CD8 and CD4 T cells), we trained Turbine’s Simulated Cell engine to predict transcription factor (TF) activity changes in 17 immune cell types post-drug treatment. We compared the predicted, drug induced TF activity changes to immune killing effects from public co-culture experiments. Predicted activity changes of CD8 T-cell activator TFs, such as FOSL and MYC, positively correlated with tumor-killing effects (Pearson r = 0.35 and 0.42, respectively). Conversely, inhibitor TFs such as NR4A1 and IRF4 exhibited inverse correlations (Pearson r = -0.27 and -0.47, respectively).To assess clinical relevance, we analyzed oncology clinical trial data from ACTT. We calculated mean overall response rates (ORRs) for indication - drug pairs and compared it to in vitro indication specific relative IC50 values of drugs. Using a linear model to predict ORRs from in vitro cancer cell line drug response data alone, we predicted ORRs with a Pearson correlation of 0.28. Integrating simulated drug induced TF activities of CD8 T-cells improved this correlation to 0.48, showing that combining tumor-intrinsic mechanisms with immune-mediated cell killing enhances the predictive performance of the model. Our findings suggest that augmenting traditional in vitro drug screening with simulated immune cell activity significantly enhances the clinical translatability of preclinical drug response models, paving the way for improved therapeutic strategies. Citation Format: Gema Sanz, Réka Böröcz, Bence Czakó, Gerold Csendes, Csaba Gór, Gábor Kovács, László Mérő, Kristóf Szalay, Daniel Veres, Bence Szalai. Computational modeling of immune cell phenotypes enhances prediction of clinical anti-cancer drug response [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 5803.
Abstract 7020: Chemical probe discovery for PAX3::FOXO1 via small-molecule microarrays
Authors: Yichen Xiang, Marc Ramos Sala, Bocheng Wu, Diya Rana, Keisuke Motoyama, Becky Leifer, Mohammed Toure, Shelby Doyle, Angele N. Koehler
Journal: Cancer Research (2025)

Abstract PAX3::FOXO1 (P3F) oncoprotein is a driver of poor patient outcome, contributing to tumorigenesis by dysregulating protein complexes that result in altered chromatin structure and gene expression. We conducted Small-Molecule Microarray (SMM) screening of approximately 10, 000 compounds using engineered HEK293 cell lysates, identified KI-P3F-032, a compound that binds silently to the fusion protein, forming the basis for PROTACs development. With this initial results, there is a need to revalidate this preliminary screening result with biophysical data, we validated binding with SPR and developed biologically relevant high-throughput secondary assays to evaluate PROTACs efficacy. We have now developed a PROTAC with strong selective cytotoxicity against P3F positive RMS cell lines. At the same time, we also explored the possibility of indirect targeting of P3F via inhibiting and degrading other transcription regulators such as CDK9. We also developed new SMM assays to identify novel P3F binders using a library of approximately 65, 000 small molecules under native P3F positive cell lysates, identifying 90 potential binders. We then developed functional recombinant P3F protein production and purification in our lab to enable pure protein based assays. We hope our research strategy can further advance the current progress on targeting the conventionally undruggable P3F oncogenic fusion and bring insight to targeting disordered oncogenic fusions in other pediatric cancers. Citation Format: Yichen Xiang, Marc Ramos Sala, Bocheng Wu, Diya Rana, Keisuke Motoyama, Becky Leifer, Mohammed Toure, Shelby Doyle, Angele N. Koehler. Chemical probe discovery for PAX3::FOXO1 via small-molecule microarrays [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 7020.
Abstract 5157: The novel CD34 huNSG-FLT3-IL15 mouse strain, which expresses human IL15 and FLT3 ligand, enhances the development T, myeloid, dendritic, and natural killer cells
Authors: Peter Deng, Pali Kaur, Shuang Hu, Brian S. Soper, Voot Yin
Journal: Cancer Research (2025)

Abstract Cell humanized mouse models that reconstitute the human immune system are valuable in the field of immuno-oncology (IO) and IO drug development. Importantly, the development of cell humanized mouse models that recapitulate a comprehensive immune system is critical for the study of the interplay between T, myeloid, dendritic, and natural killer cells in the context of cancer. In the present study, we have developed a novel NOD-scid IL2rγnull (NSG) mouse variant (NSG-FLT3-IL15) that transgenically expresses both human IL-15 and human FLT3 ligand to enhance maturation of functional innate immune cells including human CD56+ CD16+ NK cells, CD33+ myeloid cells, CD141+ and CD1c+ conventional DC subsets, CD123+ pDCs, and CD14+ monocytes alongside adaptive immune cells such as CD4+ regulatory T cells and CD4+ and CD8+ effector T cells over a 28-week period. NSG-FLT3-IL15 mice, along with control strains NSG, NSG-IL15, and NSG-FLT3, were engrafted with human umbilical cord blood-derived CD34+ hematopoietic stem cells from three different donors, and blood samples were collected until week 28 post-transplantation. Flow cytometry revealed that hCD45+ cell engraftment and T cell subpopulations (CD3+, CD4+, and CD8+) in NSG-FLT3-IL15 mice were comparable to parental control strains. Strikingly, NSG-FLT3-IL15 mice exhibited enhanced CD56+/dim CD16+ NK cells compared to the control strains. Furthermore, levels of myeloid sub-lineage cells such as monocytes, macrophages (M1), granulocytes, dendritic cells, and neutrophils, were higher than in NSG or NSG-IL15 strains but comparable to NSG-FLT3 strain mice. Current growth kinetic studies with human patient derived tumors will assess human immune cell infiltration across NSG variants. In vivo efficacy studies are underway to demonstrate therapy induced tumor killing by the enhanced innate human immune cells developed in NSG-FLT3-IL15 mice. Overall, these results demonstrate that the NSG-IL15-FLT3 model supports enhanced development of functional human innate immune cells and serves as a novel comprehensive immune model for studying human IO. Citation Format: Peter Deng, Pali Kaur, Shuang Hu, Brian S. Soper, Voot Yin. The novel CD34 huNSG-FLT3-IL15 mouse strain, which expresses human IL15 and FLT3 ligand, enhances the development T, myeloid, dendritic, and natural killer cells [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 5157.
Abstract 2057: CG&amp;gt;TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer
Authors: Jan Budczies, Eva Romanovsky, Michael Menzel, Klaus Kluck, Susanne Beck, Markus Ball, Peter Schirmacher, Daniel Kazdal, Albrecht Stenzinger
Journal: Cancer Research (2025)

Abstract Homologous recombination deficiency (HRD) is a predictive biomarker for PARP inhibition and platinum-based chemotherapy. Copy number alteration-based scores such as HRDsum =LST+TAI+LOH are included in therapy approvals of PARP inhibition, but have limited sensitivity for HRD detection in samples of low tumor purity. Biomarkers based on single base substitutions (SBS) beyond Mutational Signatures are underinvestigated as predictors of HRD. WES data of the TCGA pan-cancer cohort and an in-house ovarian cancer cohort were annotated by genetic and epigenetic alterations of BRCA1/2 and additional genes causative of HRD. Using this reference, the new biomarker fdeam defined as frequency of C&amp;gt;T transitions at CpG sites in relation to all SBS and HRDsum were compared for the detection of HRD. In the TCGA ovarian cancer, the in-house ovarian cancer, and the TCGA breast cancer cohorts, fdeam performed non-inferior to HRDsum (AUC=0.84, AUC=0.85, and AUC=0.88). The cutpoint fdeam=13.1% maximized the balanced accuracy in the TCGA ovarian cancer cohort and resulted in sensitivity=89% and specificity=77% in the in-house cohort. In a simulation study, fdeam retained high sensitivity for HRD detection and outperformed HRDsum for tumor purity 40%, 20%, and 10%. Thus, the new biomarker overcomes the limited robustness of copy number alteration-based biomarkers against low tumor purity and offers the opportunity of a more sensitive HRD detection in clinical tumor samples. Further studies are warranted to confirm its clinical validity and utility and explore its potential for liquid biopsies. Citation Format: Jan Budczies, Eva Romanovsky, Michael Menzel, Klaus Kluck, Susanne Beck, Markus Ball, Peter Schirmacher, Daniel Kazdal, Albrecht Stenzinger. CG&amp;gt;TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and 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 2057.
Abstract 4597: Globo H affects the immune tumor microenvironment in cholangiocarcinoma
Authors: Chih Chieh Yen, Tzer Min Kuo, Chun Jung Lin, Hung Wen Tsai, Wen Lung Wang, Chien Jui Huang, Ping Jui Su, Ting Kai Liao, I Ting Liu, Li Chin Cheng, Ying Jui Chao, Yan Shen Shan, Chia Jui Yen, Ming Tain Lai
Journal: Cancer Research (2025)

Background: Cholangiocarcinoma (CCA), which is characterized by aberrant glycosylation on the surface, is a rapidly progressing cancer with an unsatisfactory response to chemoimmunotherapy. Globo H (GH) ceramide, a tumor-promoting glycosphingolipid, is expressed in various types of cancer and is correlated with poor prognosis. However, few studies have discussed the role of GH in CCA. Hence, the pathways involved and alterations in the immune tumor microenvironment (TME) have not been explored. Methods: We aimed to reveal the clinical features and immune modulatory role of tumor GH and its correlation in CCA. We evaluated the signaling-associated proteins and those coexpressed with GH. Tumor-infiltrating immune cells (TIMCs) were compared between tumors with high vs. low levels of GH synthesizing enzyme (GH-se) using open-domain databases and single-cell RNA sequencing results. Results: Surface GH expression correlated with poor prognosis and peritumor inflammation. High-GH CCA cells coexpressed GH with PD-L1, EGFR and EPCAM. While GH and its synthesizing enzymes affected immune modulation and survival, TIMCs such as neutrophils, tumor-associated macrophages, natural killer cells and foxp3 regulatory T cells were significantly altered in high-GH-se tumors. Conclusion: Tumor GH expression correlates with a poor prognosis in patients with cholangiocarcinoma. GH modulates the immune TME by promoting an immune-evasive niche. The results provide insights for combining immunotherapy with GH-targeting therapy. Citation Format: Chih Chieh Yen, Tzer Min Kuo, Chun Jung Lin, Hung Wen Tsai, Wen Lung Wang, Chien Jui Huang, Ping Jui Su, Ting Kai Liao, I Ting Liu, Li Chin Cheng, Ying Jui Chao, Yan Shen Shan, Chia Jui Yen, Ming Tain Lai. Globo H affects the immune tumor microenvironment in cholangiocarcinoma [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 4597.
Abstract 6808: DOCK1 as a therapeutic target for EGFR resistance in cholangiocarcinoma
Authors: Kishor Pant, Kory Engelstad, Estanislao Peixoto, Ainhoa Lapitz, Jesus M. Banales, Adrian Mansini, Sergio A. Gradilone
Journal: Cancer Research (2025)

Abstract Cholangiocarcinoma (CCA) is an aggressive cancer of the bile ducts, characterized by poor prognosis and limited treatment options due to late-stage diagnosis and resistance to targeted therapies. Mutations in critical pathways, including the Epidermal Growth Factor Receptor (EGFR) and Fibroblast Growth Factor Receptor (FGFR), drive CCA progression, while resistance mechanisms and mutation weaken the effectiveness of available therapies. Dedicator of Cytokinesis 1 (DOCK1), a guanine nucleotide exchange factor, has emerged as a key player in cancer progression, particularly in modulating cell signaling. In this study, we investigated the therapeutic potential of targeting DOCK1 in CCA via modulating EGFR signaling. Our assessment across five distinct patient cohorts demonstrates that DOCK1 is significantly overexpressed in CCA tumors compared to normal cholangiocytes, underscoring its pivotal role in promoting tumor growth and aggressiveness. Pharmacological inhibition of DOCK1 using the small-molecule inhibitors CPYPP and TBOPP, as well as siRNA-mediated knockdown, resulted in a marked reduction in HuCCT1 and EGI1 CCA cell lines proliferation and migration. This was accompanied by an increase in tumor suppressor proteins p53 and p21, along with a decrease in proliferation markers PCNA and cyclin D1. Moreover, siRNA-mediated reduction of DOCK1 expression significantly induced apoptosis and cytotoxicity, accompanied by elevated levels of cleaved caspase-3 and PARP1, highlighting its role in driving cell death resistance in CCA. Furthermore, DOCK1 inhibition disrupted EGF-stimulated EGFR phosphorylation and downstream signaling through Erk1/2, a critical pathway supporting tumor growth, survival, and therapeutic resistance. These findings position DOCK1 as a central enhancer of EGFR-mediated oncogenic signaling, playing a key role in the aggressive phenotype and therapeutic resistance of CCA. Targeting DOCK1 not only suppressed tumor cells proliferation but also enhanced cell death, offering a dual therapeutic advantage. Our study provides strong evidence supporting DOCK1 as a promising therapeutic target and suggests that its inhibition, particularly in combination with EGFR-targeted therapies, could overcome EGFR mutant and drug resistance mechanisms and improve clinical outcomes in CCA. By unveiling this novel therapeutic strategy, our research lays the foundation for advancing more effective and stable treatments for this aggressive and often deadly malignancy. Citation Format: Kishor Pant, Kory Engelstad, Estanislao Peixoto, Ainhoa Lapitz, Jesus M. Banales, Adrian Mansini, Sergio A. Gradilone. DOCK1 as a therapeutic target for EGFR resistance in cholangiocarcinoma [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 6808.
Abstract 6527: Ginseng polysaccharides circumvent acquired resistance to anti-pd1 immunotherapy in patients with non-small cell lung cancer
Authors: Jumin Huang, Ziming Wang, Yabing Cao, Wenhua Liang, Elaine Lai-Han Leung
Journal: Cancer Research (2025)

In 2021, we demonstrated that ginseng polysaccharides (GPs) enhance the therapeutic efficacy of anti-programmed cell death 1 (PD-1) immunotherapy by modulating the gut microbiota. GPs may serve as a beneficial dietary supplement for non-small cell lung cancer (NSCLC) patients undergoing immunotherapy. We reported GPs increased the anti-tumor response to αPD-1 mAb by increasing the microbial metabolites valeric acid, and decreasing the ratio of Kyn/Trp, which contributed to the suppression of Treg and induction of Teff cells. Besides, the microbial analysis of patients fecal samples indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders. In this study, we aim to further validate and extend these previous findings. Therefore, we designed the first World Health Organization-registered clinical trial of traditional Chinese medicine combined with immunotherapy (ChiCTR2100046431) to investigate whether oral administration of GPs can circumvent acquired resistance to anti-PD-1 immunotherapy in patients with advanced NSCLC. Eligible acquired drug-resistant patients continued the use of PD-1 inhibitors as per their initial immunotherapy regimen and initiated oral administration of GPs twice daily upon enrolling in the trial. Longitudinal stool and blood samples were systematically collected from participants. The gut microbiome was profiled through third-generation amplicon sequencing. Simultaneously, comprehensive analyses of blood samples were conducted, utilizing metabolomics and quantification of cytokines. Clinical trial results showed that five patients regained response to anti-PD-1 immunotherapy, with an objective response rate of 50%. Comprehensive analysis of the gut microbiome and blood samples revealed a significant increase in the relative abundance of Parabacteroides distasonis after treatment, along with a significant upregulation of tumor necrosis factor-α (TNF-α) and various metabolites levels in the blood. In this study, we report the first case series of patients with advanced NSCLC with acquired resistance to anti-PD-1 immunotherapy who were treated with oral administration of GPs, which resulted in overcoming acquired resistance and regaining a response to immune checkpoint inhibitors. These preliminary data provide valuable clinical clues for overcoming the acquired resistance to PD-1 immunotherapy. Citation Format: Jumin Huang, Ziming Wang, Yabing Cao, Wenhua Liang, Elaine Lai-Han Leung. Ginseng polysaccharides circumvent acquired resistance to anti-pd1 immunotherapy in patients with 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 6527.