tbuckley/cabot-search huggingface dataset:
Abstract 5065: Single-cell transcriptomic profiling of longitudinal patient tumors and PDX models reveals resistance mechanisms in ALK- and EGFR-mutant LUAD
Authors: Naomi Mfonfu, Floriane Brayé, Galina Boldina, Matteo Cesaroni, Luc Fibroulet, Sergey Nikolaev, Andrey Yurchenko
Journal: Cancer Research (2025)

Abstract Resistance to EGFR and ALK tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LUAD) remains a major barrier to effective treatment. Tumor adaptation frequently involves dynamic cellular state transitions, altered signaling networks, and interactions within the tumor microenvironment (TME). Understanding the mechanisms driving resistance in EGFR- and ALK-mutant tumors is critical to developing strategies to improve patient outcomes. This study investigates transcriptomic changes underlying TKI resistance and persistance, combining patient data with functional insights from PDX models. Tumor biopsies from 11 LUAD patients were collected across three treatment stages: baseline (n=6), minimal residual disease (MRD, n=4), and relapse (n=1). Patient-derived xenograft (PDX) models were generated from pretreated tumors with EGFR and ALK mutations. Tumors were grafted into five mice per model, with three receiving treatment until stable residual disease emerged and two serving as untreated controls. Single-nucleus RNA sequencing was performed on both patient tumor samples and PDX models to comprehensively profile transcriptomic changes. Transcriptomic changes were observed in both patient tumor samples and PDX models during TKI treatment. In patients, at MRD, a novel subpopulation expressing mesenchymal and neuronal markers was identified, accompanied by altered cell-cell communication involving neuronal signaling (RELN), stromal remodeling (FGFRs), and survival pathways (MAPK). At relapse, signatures of epithelial-mesenchymal transition (EMT), ECM remodeling, and immune evasion were enriched. In PDX models, most persister cells were arrested in the G1 phase and showed suppression of canonical cancer pathways, while notable upregulation of the ciliated pathway was observed across models. This study provides a high-resolution transcriptomic map of TKI-treated LUAD tumors. Resistance mechanisms in EGFR- and ALK-mutant tumors include neuronal, EMT, MAPK signaling, ECM remodeling, and activation of the ciliated pathway. These findings offer novel therapeutic targets to combat resistance, leveraging the integration of patient-derived data and functional insights from PDX models. Citation Format: Naomi Mfonfu, Floriane Brayé, Galina Boldina, Matteo Cesaroni, Luc Fibroulet, Sergey Nikolaev, Andrey Yurchenko. Single-cell transcriptomic profiling of longitudinal patient tumors and PDX models reveals resistance mechanisms in ALK- and EGFR-mutant LUAD [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 5065.
Abstract 838: The novel eIF4A inhibitor synergizes potently with the XPO-1 inhibitor in T-cell lymphoma
Authors: So-Young Seol, Chung Hyun Park, Soo Jeong Kim, Hyunsoo Cho, Jin Seok Kim, Yu Ri Kim
Journal: Cancer Research (2025)

Abstract Malignant lymphomas are categorized into B-cell and T-cell lymphomas. While treatment outcomes for B-cell lymphoma have significantly improved with targeted therapies and cellular treatments, T-cell lymphoma remains a therapeutic challenge due to the lack of standardized first-line treatments. Consequently, T-cell lymphoma exhibits lower remission rates, higher relapse rates, and poor overall prognosis. Although T-cell lymphomas account for only 15-20% of all malignant lymphomas, their incidence is notably higher in Asia compared to Western countries, making Korea an ideal location for research on this disease. Also, T-cell lymphoma (TCL) is an aggressive malignancy with poor prognosis, characterized by high relapse rates and limited therapeutic options. Novel therapeutic approaches are urgently needed to improve outcomes for patients with TCL. Previous studies have demonstrated the efficacy of eIF4A inhibitors in downregulating oncogenic protein synthesis and inducing cell death in various lymphoma models. We hypothesized that the combination of eIF4A inhibitor (CR-1-31-B) and XPO-1 inhibitor (Selinexor) would exhibit synergistic anti-lymphoma activity in TCL and have potential clinical applications. The anti-lymphoma effects of CR-1-31-B in combination with a XPO-1 inhibitor were evaluated in TCL cell lines using flow cytometry. Cell apoptosis assays were performed at increasing concentrations of CR-1-31-B and the XPO-1 inhibitor alone, as well as in combination, over 48 hours. To investigate the molecular mechanisms underlying the observed synergistic effects in TCL, RNA-seq profiling was conducted on cells treated with single agents and the combination therapy. Gene set enrichment analysis (GSEA) was performed to identify pathways involved in the combination's mechanism of action. CR-1-31-B and the XPO-1 inhibitor demonstrated concentration- and time-dependent cytotoxicity in TCL cell lines at low nanomolar concentrations. The combination of the eIF4A inhibitor and the XPO-1 inhibitor showed strong synergistic effects in all tested TCL cell lines (p&amp;lt;0.0001). RNA-seq profiling revealed that the transcriptional signature of the combination therapy was distinct from that of single-agent treatments. The combination of eIF4A inhibitor and XPO-1 inhibitor demonstrates potent anti-lymphoma activity in T-cell lymphoma. This novel combination represents a promising therapeutic strategy for patients with TCL, warranting further preclinical investigations and potential clinical translation. Citation Format: So-Young Seol, Chung Hyun Park, Soo Jeong Kim, Hyunsoo Cho, Jin Seok Kim, Yu Ri Kim. The novel eIF4A inhibitor synergizes potently with the XPO-1 inhibitor in T-cell lymphoma [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 838.
Abstract 1863: A cytotoxic peptide designed for tumor-targeted delivery of co-injected molecules
Authors: Norio Miyamura, Chisato M. Yamazaki, Kyoji Tsuchikama, Kazuki N. Sugahara
Journal: Cancer Research (2025)

Abstract Clinical trials have highlighted its promise as a tumor-targeted delivery system and enhancer of anti-cancer therapies. In this study, we developed and analyzed an iRGD, tumor specific homing peptide, conjugate linked to monomethyl auristatin F (MMAF), a highly potent antimitotic agent. This conjugate demonstrated dual functionality as a tumor-targeted cytotoxic agent and a delivery platform for co-administered drugs. The iRGD-MMAF conjugate selectively internalized and killed tumor cells in vitro through αv integrin-dependent pathways. In vivo, systemic injection of iRGD-MMAF resulted in tumor-specific localization and widespread distribution within the extravascular tumor tissue, consistent with iRGD’s tumor-penetrating properties. Additionally, iRGD-MMAF significantly improved tumor-specific uptake of a co-injected drug, confirming its efficacy as a delivery scaffold. These findings suggest that chemically modified iRGD peptides with added therapeutic properties maintain their ability to enhance co-administered drug delivery to tumors. Citation Format: Norio Miyamura, Chisato M. Yamazaki, Kyoji Tsuchikama, Kazuki N. Sugahara. A cytotoxic peptide designed for tumor-targeted delivery of co-injected molecules [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 1863.
Abstract 80: Integrin driven adhesion in ovarian cancer
Authors: Nazia Bano, Isabelle Lewis, Malaika Amin, Eva M. Schmelz
Journal: Cancer Research (2025)

Abstract Ovarian cancer is the fifth leading cause of cancer-related deaths in women due to late-stage diagnosis, reducing the survival rate to 30%. During dissemination, ovarian cancer cellsexfoliate from the primary tumor and aggregate to form spheroids in the peritoneal cavity. Peritonealaggregation enhances the survival of cancer cells by mitophagy, reduced metabolism, andproliferation. However, as spheroids adhere to secondary sites, mitochondrial function is restoredby mitobiogenesis, with increased metabolism and proliferation. These findings strongly suggest aswitch from mitophagy in spheroids to mitobiogenesis upon adhesion. However, the mechanism bywhich adhesion induces mitobiogenesis remains unknown. Therefore, our objective is to identifykey adhesion receptors, with a focus on integrins that activate adhesion and downstream signalingcascades. To investigate changes in integrin expression, we mimicked three major stages ofovarian cancer progression by developing adherent, spheroid, and adherent spheroid stages usingmouse ovarian surface epithelial (MOSE) cell lines. These represented the benign (MOSE-E) stage, as well as slow-developing (MOSE-L) and fast-developing (MOSE-LTICv) disease in biologicallyrelevant conditions. We identified integrin and adhesion-related gene expression levels via RT-qPCR. Western blotting and confocal microscopy were used to observe protein expression andlocalization throughout ovarian cancer progression. Drug treatment was done to observe the effectof integrin inhibition on spheroid aggregation and adhesion to secondary sites. Our finding revealeddistinct expression changes of different integrins during aggregation and adhesion, as well asspecific changes of other adhesion molecules, ECM, and their regulators indicating specific rolesin metastatic dissemination and implantation. This was further confirmed with specific integrininhibitors that were effective in preventing aggregation and spheroid adhesion to secondary sitesindicating distinct roles of integrins during the metastatic stages. Overall, this project will aid inidentifying integrin and integrin drug targets to develop new metastatic treatments, ultimately aimingto reduce mortality in women with ovarian cancer. Citation Format: Nazia Bano, Isabelle Lewis, Malaika Amin, Eva M. Schmelz. Integrin driven adhesion in ovarian 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 80.
Abstract 2192: Enhancing veterinary cancer drug development with innovative bioanalytical assays
Authors: Jun Wang, Ildiko Kasza, Denise Garvin, Trish Trish, Rod Flemming, Jeff Nelson, Ngan Lam, Marjeta Urh, Mei Cong, Jamison Grailer
Journal: Cancer Research (2025)

Abstract The development of biologic drugs for veterinary health requires precise and reliable bioanalytical tools. To that end, we have developed several new assays, extending our industry-leading portfolio of human bioassays to emerging veterinary therapeutic targets. Featured here are cell-based reporter bioassays: Canine ADCC Reporter Bioassay and Canine PD-1/PD-L1 Blockade Bioassay. Additionally, we present two new Lumit Immunoassays for characterizing binding to the FcRn receptor: Canine FcRn Binding Immunoassay and Feline FcRn Binding Immunoassay. Utilizing luminescence detection, these assays offer sensitive and specific measurement of target interactions. Our assay development process involves rigorous testing for accuracy, precision, linearity, and specificity, adhering to ICH guidelines. The assays demonstrated high sensitivity and specificity, as well as robust performance in detecting and quantifying the potency of target molecules. Our cell-based bioassays are available in convenient thaw-and-use kit formats, allowing for easy adoption and highly reproducible results. These assays can be utilized from early development through lot release, supporting every stage of the drug development process. Promega’s advanced bioassays and immunoassays provide a comprehensive platform for the development and characterization of veterinary biologic drugs. These tools support the entire drug development pipeline, enhancing the efficacy and safety of veterinary therapeutics through high sensitivity, specificity, and reproducibility. Additionally, our Lumit Immunoassays significantly reduce assay time compared to traditional ELISAs, providing faster and more efficient workflows for the characterization of binding interactions to the FcRn receptor. Citation Format: Jun Wang, Ildiko Kasza, Denise Garvin, Trish Trish, Rod Flemming, Jeff Nelson, Ngan Lam, Marjeta Urh, Mei Cong, Jamison Grailer. Enhancing veterinary cancer drug development with innovative bioanalytical assays [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 2192.
Abstract 2639: Role of annexin A2 in triple-negative breast cancer metastasis
Authors: Pankaj Chaudhary
Journal: Cancer Research (2025)

Introduction: Emerging evidence indicates that AnxA2 plays a role in the invasion and metastasis of breast cancer. However, the clinical significance of AnxA2 expression in breast cancer remains unknown. Methods/Materials: The TNBC cells were purchased from the American Type Culture Collection (Manassas, VA). The expression of AnxA2 in cell lines, tumor tissues, and serum samples of breast cancer patients were analyzed by immunoblotting, immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. Results: We observed that AnxA2 was significantly elevated in the tumor tissues and serum samples of breast cancer patients compared to normal controls. High levels of serum AnxA2 were significantly correlated with tumor grade and poor survival in breast cancer patients. When we analyzed molecular subtypes, we found that AnxA2 expression was notably higher in the tumor tissues and serum samples of triple-negative breast cancer (TNBC) patients compared to those with other breast cancer subtypes. Our studies on breast cancer cell lines indicated that the secretion of AnxA2 is linked to its phosphorylation at tyrosine 23 (Tyr23). Additionally, phosphorylation of AnxA2 at Tyr23 facilitates its translocation to the cell surface in TNBC cell lines. The increased expression of AnxA2 on the cell surface enhances plasmin generation in these cell lines, and an inhibitory hexapeptide against AnxA2 can neutralize this activity. Furthermore, our analysis of AnxA2 phosphorylation in clinical samples confirmed that the phosphorylation at Tyr23 was significantly higher in the tumor tissues of TNBC patients when compared to matched adjacent non-tumorigenic breast tissues. Conclusions: These findings suggest that serum AnxA2 concentration could be a potential diagnostic biomarker for TNBC patients. Citation Format: Pankaj Chaudhary. Role of annexin A2 in triple-negative breast cancer metastasis [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 2639.
Abstract 3475: KGX103, a conditionally active prodrug of PD-1-targeting IL-15 induces antitumor activity by preferentially activating PD-1+ intratumoral T cells in cis
Authors: Jiangfeng Fan, Zhiqiang Bai, Jing Wang, Shumin Yang, Yucheng Luo, Jie Huang, Hui Chen, Haixiang Wu, Yi Wu, Weidong Jiang
Journal: Cancer Research (2025)

Abstract Interleukin-2 (IL-2) and IL-15 have both similar and contrasting functional roles in the proliferation and regulation of lymphocytes. They share the β/γ heterodimeric receptors while having distinct α-receptors. IL-15 is thought to be superior to IL-2 for the treatment of cancer in the aspects of lower vascular endothelium associated toxicity, much weaker Treg-stimulating activity and stronger expanding NK and CD8+ T cells abilities. However, the application of IL-15 in tumor immunotherapy remains challenging due to short half-life and severe adverse events caused by excessive and systemic immune activation. To address these challenges, we have developed KGX103, a PD-1-targeting non-α attenuated IL-15 prodrug fused with anti-HSA antibody. The IL-15 mutein is concealed by an inactivation domain linked with tumor-specific protease cleavable peptide, to prevent systemic immune activation. Once mask is cleaved in tumor microenvironment (TME), KGX103 could effectively stimulate intratumoral antigen-experienced CD8+ T cells with elevated PD-1 expression. With PD-1 targeting and tumor-specific activation, KGX103 could greatly potentiate tumor-specific T cell proliferation and function while ameliorating systemic immune activation. The pSTAT5 activation of either fresh or pre-activated peripheral blood mononuclear cells (PBMCs) were tested with KGX103 and unmasked KGX103. KGX103 showed almost no pSTAT5 activation signal in fresh PBMCs with low PD-1 expression and weak activation in pre-activated PBMCs with elevated PD-1 expression. Meanwhile, KGX103 showed significantly reduced potency of &amp;gt;3000-fold than the unmasked KGX103, which could be recovered after tumor-specific protease cleavage. Then we evaluated KGX103's in vivo antitumor efficacy in xenograft models using B-NDG β2m KO mice plus. Mice were subcutaneously implanted with a mixture of A375 tumor cells and hPBMCs. After grouping, mice were treated with vehicle or KGX103. Compared to the vehicle group, KGX103 demonstrated its antitumor efficacy and safety as evidenced by significant tumor growth inhibition while no obvious body weight change during the dosing period. The pilot toxic study to evaluate the safety and toxicokinetics of KGX103 is ongoing in Cynomolgus monkeys. Citation Format: Jiangfeng Fan, Zhiqiang Bai, Jing Wang, Shumin Yang, Yucheng Luo, Jie Huang, Hui Chen, Haixiang Wu, Yi Wu, Weidong Jiang. KGX103, a conditionally active prodrug of PD-1-targeting IL-15 induces antitumor activity by preferentially activating PD-1+ intratumoral T cells in cis [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 3475.
Abstract 81: FOXN3 suppresses FUT5-mediated adhesion of metastatic ovarian cancer cells to mesothelial cells
Authors: Siyu Zhou, Ayon Ahmed Hassan, Alice Sze Wong
Journal: Cancer Research (2025)

Abstract Ovarian cancer is the most lethal gynecological malignancy primarily due to widespread peritoneal metastasis at diagnosis, posing significant treatment challenges. Our previous research has indicated that fucosyltransferase 5 (FUT5) is upregulated in metastatic ovarian cancer and is a key contributor to peritoneal metastatic colonization, which represents the initial rate-limiting step in metastasis. However, little is known about the regulation of FUT5. In this study, using a microfluidic chip model with ascitic fluid shear stress perfusion, we found that FUT5 is transcriptionally upregulated in ovarian cancer cells treated with ascitic shear stress, with no changes in degradation rates of FUT5 protein and transcript. Through a comprehensive analysis involving transcriptional factor prediction, biostatistics on TCGA database expression patterns, and sequence analysis using a metastatic cancer model, we identified Forkhead Box N3 (FOXN3) as a potential regulator of FUT5 transcription. Further investigation demonstrated that FOXN3 suppresses FUT5 expression by directly interacting with its promoter. Expression of FOXN3 suppresses tumor-mesothelial adhesion, which can be reversed by FUT5 overexpression. Together, these findings suggest that the FOXN3/FUT5-axis plays a crucial role in ovarian tumor-mesothelial interaction and could serve as a potential therapeutic target (This work is supported by HMRF08192286 and RGC SRFS2223-7S05). Citation Format: Siyu Zhou, Ayon Ahmed Hassan, Alice Sze Wong. FOXN3 suppresses FUT5-mediated adhesion of metastatic ovarian cancer cells to mesothelial 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 81.
Abstract 2578: GDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases
Authors: Sathya Neelature Sriramareddy, Navya Siddarajappa, Thanh Nguyen, Jeffim Kunetsov, Stefan Kurtenbach, James Jarad Dollar, Jonathan D. Licht, Ann Y. Chen, William J. Harbour, Keiran S. Smalley
Journal: Cancer Research (2025)

Abstract Little is known about how interactions between the uveal melanoma (UM) and host cells in the tumor microenvironment (TME) drive the progression of liver metastases. Single cell RNA-seq analysis of UM samples identified marked differences in cell-cell communication between primary and metastatic UM characterized by increased signaling strength and numbers of interactions emanating from the hepatic stellate cells (HSCs) and endothelial cells in the metastatic samples. In co-culture, HSCs modulated the transcriptional heterogeneity of the UM cells, enriching for cell states that expressed genes implicated in cell survival, metabolic reprogramming and the angiogenic response. Co-culture of HSCs and UM cells also led to increased expression of growth factors and receptors implicated in angiogenesis including IL-8, VCAM1, VEGF and ICAM1. One candidate driver of HSC reprogramming was the TGF-beta family member GDF15. Increased expression of GDF15 was associated with a Class 2 metastatic UM phenotype in clinical UM samples and UM cell lines, with silencing of BAP1 in UM cells increasing both GDF15 expression and H3K27ac marks at the GDF15 promoter. Treatment of HSCs with GDF15 led to increased expression of multiple ECM proteins, inflammatory cytokines and angiogenic factors, including IL- 8. Both exogenous GDF15, IL-8 and conditioned media from UM-HSC co-cultures increased endothelial cell network formation in vitro, an effect that could be blocked by anti-GDF15 antibodies. In an eye-&amp;gt;liver metastasis model of UM, silencing of GDF15 did not prevent the seeding of UM cells to the liver, but did inhibit the outgrowth of metastatic lesions. Although the GDF15-silenced UM cells were proliferative they did not recruit endothelial cells, leading to a significant reduction in metastatic burden. In sum, we provide the first evidence that UM liver metastasis development is dependent upon GDF15-mediated remodeling of the liver microenvironment leading to an angiogenic response that supports tumor growth. Citation Format: Sathya Neelature Sriramareddy, Navya Siddarajappa, Thanh Nguyen, Jeffim Kunetsov, Stefan Kurtenbach, James Jarad Dollar, Jonathan D. Licht, Ann Y. Chen, William J. Harbour, Keiran S. Smalley. GDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases [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 2578.