tbuckley/cabot-search huggingface dataset:
Abstract 1702: OBI-992, a novel TROP2 antibody-drug conjugate, exhibits distinct resistance profiles compared to other TROP2 targeting ADCs
Authors: Lifen Shen, Tzer-Min Kuo, Yu-Hsuan Tsao, Ya-Chi Chen, Ming-Tain Lai
Journal: Cancer Research (2025)

Abstract BACKGROUND/AIM: Trophoblast cell surface antigen-2 (TROP2), a transmembrane glycoprotein often overexpressed in a variety of cancers, has been proposed as a potential cancer driver in colorectal cancer (CRC) cells. As a result, several antibody-drug conjugates (ADC) have been developed targeting TROP2, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-Dxd). One of the major challenges in the development of ADC is the emergence of resistance via different mechanism of actions. This study aims to characterize the potential resistant mechanisms of TROP2 ADCs, including a novel TROP2 ADC OBI-992 in CRC cells. METHODS: DLD1 CRC cells resistant to OBI-992, SG, and Dato-Dxd analogs were established with sequential increase of respective ADC concentrations. Cytotoxicity of three ADCs and their payloads, including exatecan, SN-38, and Dxd, was evaluated to assess the fold of resistance. Cell surface and total TROP2 protein were measured by flow cytometry and western blotting. DNA mutation and gene expression profiling were conducted by whole exome sequencing (WES) and RNA sequencing (RNA-seq). RESULTS: TROP2 reduction and multidrug resistance proteins (MRPs) enhancement were not detected in OBI-992-induced resistant cells. Notable different DNA mutations in ATRX, BRCA2, and PALB2 of OBI-992 resistant cells were detected compared to those found with Dato-Dxd and SG-selected resistant cells. A TOP1 inhibitor-resistant mutation, TOP1 R364H, was identified as 100% variant allele frequency (VAF) in Dato-Dxd and SG resistant cells, whereas lower percentage of VAF was observed in OBI-992 resistant cell lines (29 % and 48.6 % in 0.5 uM and 2uM of OBI-992, respectively). OBI-992 resistant cells showed a clear divergence in differential expression gene (DEG) profiles, whereas Dato-Dxd and SG resistant cells were similar. c-MET and REG4 levels were greatly increased in cells with Dato-Dxd and SG resistance but not with OBI-992. Extracellular matrix (ECM) receptor interaction pathway was enriched in OBI-992 resistant cells. CONCLUSION: OBI-992, a novel TROP2 targeting ADC, emerges as a potential promising therapeutic option for patients who are resistant to other TROP2 targeting ADCs such as SG and Dato-Dxd. OBI-992 exhibits distinct resistance profiles compared to other TROP2 targeting ADCs. Understanding of potential mechanisms of resistance can provide potential combination options for TROP2-targeting ADCs to combat the drug resistance. Citation Format: Lifen Shen, Tzer-Min Kuo, Yu-Hsuan Tsao, Ya-Chi Chen, Ming-Tain Lai. OBI-992, a novel TROP2 antibody-drug conjugate, exhibits distinct resistance profiles compared to other TROP2 targeting ADCs [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 1702.
Abstract 3832: Modeling metastatic ER+ breast cancer in rats
Authors: Carstyn F. Joiner, Gui Ma, Sydney Schjoneman, Patrick Colegrove, James Shull, Wei Xu
Journal: Cancer Research (2025)

Abstract Estrogen receptor-positive (ER+) breast cancer makes up over 70% of all breast cancer and is treated with frontline endocrine therapy. However, the five-year survival rate for metastatic patients is only 27%. At this stage, patients are treated with a combination of endocrine and CDK4/6 inhibitors (e.g., palbociclib), but the development of drug resistance often arises. Genetically engineered mouse models are largely ER-negative. We developed a first-in-class ER+ metastatic breast cancer rodent model to enable a mechanistic understanding of organotropism of metastasis and the development of new treatment regimens. Following estrogen implantation in the female August Copenhagen Irish (ACI) rats, the physiological levels of estrogen are sufficient to induce ER+ mammary tumors at an incidence of 100%. RNA-sequencing revealed that rat tumors recapitulate human luminal B tumors. We subsequently derived MG-1, an ER+ rat breast cancer cell line, from ACI rat tumors. The growth of MG-1 is estrogen-dependent and inhibited by fulvestrant and CDK4/6 inhibitors. However, MG-1 does not frequently metastasize following orthotopic injection. When MG-1 cells were tail-vein injected into female ACI rats, colonization to the lung, liver, lymph nodes, and bone, all the human-relevant metastatic organs, were observed. Cells were disassociated from these tissues, flow-sorted, and cultured. Although MG-1 metastatic sublines derived from different organs exhibit distinct gene expression profiles, they all display epithelial-to-mesenchymal (EMT) signatures and are more resistant to endocrine or CDK4/6 inhibitors. In clinical trials, fibroblast growth factor receptor (FGFR) amplification/overexpression is frequently associated with endocrine and CDK4/6 inhibitor resistance. Compared with parental MG-1, MG-1 metastatic liver sublines overexpress FGFR1, elicit enhanced migration and colony formation capabilities, and are resistant to fulvestrant and CDK4/6 inhibitors. Knockdown of FGFR1 partially restored CDK4/6 inhibitor sensitivity and decreased the metastatic phenotype. Since two pan-FGFR1 inhibitors are FDA-approved for the treatment of cancers with FGFR abnormality, our immunocompetent MG-1/ACI rat model is well-suited for testing different combinations of CDK4/6 inhibitors and pan-FGFR inhibitors in treating metastatic disease. The results will inform the treatment strategy for metastatic ER+ breast cancer patients harboring FGFR alterations. We acknowledge funding support R01CA268183 to W.X. and T32 CA009135 to C. J. Citation Format: Carstyn F. Joiner, Gui Ma, Sydney Schjoneman, Patrick Colegrove, James Shull, Wei Xu. Modeling metastatic ER+ breast cancer in rats [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 3832.
Abstract 1367: Antigen recognition induces chemokine secretion to promote universal CAR-T cell infiltration
Authors: Ruxuan Li, Youngbin Cho, Matthew Laird, Walter Kaminski, Elisa Ruffo, Jason Lohmueller, Ioannis Zervantonakis
Journal: Cancer Research (2025)

The lack of CAR-T cell infiltration and immune-mediated cancer cell destruction is a dominant mechanism of immunotherapy failure. The characteristics and mechanisms of cognate recognition induced CAR-T cell infiltration have yet to be revealed. In this study, we developed an in-vitro 3D collagen droplet co-culture system to simulate CAR-T cell infiltration in the tumor microenvironment and track T cell motility and interactions with tumor cells in real-time under different micro physiological environments. We employed CAR-T cells overexpressing the SNAP tag (SNAP-CAR T cells), where the contacts between CAR-T cells and HER2+ breast tumor cells can be initiated by adding benzyl guanin-conjugated Herceptin (BG-Herceptin). Quantification of infiltrating cell numbers showed that 3D collagen matrices with HER2+ breast tumor cells significantly recruited a higher number of SNAP CAR-T cells compared to cell-free matrices. Upon initiating the contacts between target and effector cells by adding BG-Herceptin, CAR-T cell infiltration to HER2+ breast cancer matrices were significantly increased. To investigate whether chemokine secretion mediates this process, we employed chemokine arrays. Chemokine secretion such as CCL2 were significantly higher with antigen-specific interactions. Further, CAR-T cell infiltration was inhibited by CCL2 neutralization, which indicates CCL2 plays a major role in cognate induced CAR-T cell infiltration. By analyzing CAR-T cell motility patterns, we found that CAR-T cell infiltration and interaction with tumor cells are dependent on cognate recognition. With BG-Herceptin, CAR-T cell interaction with and swarming around HER2+ breast tumor cells were significantly higher. By inhibiting CCL2, CAR-T cell motility was significantly impaired. Our findings suggest that CAR-T cell infiltration towards the solid tumors is dependent on antigen-specific interactions. Moreover, we demonstrated cognate induced chemokine secretion as a crucial factor in CAR-T cell infiltration and motility. Citation Format: Ruxuan Li, Youngbin Cho, Matthew Laird, Walter Kaminski, Elisa Ruffo, Jason Lohmueller, Ioannis Zervantonakis. Antigen recognition induces chemokine secretion to promote universal CAR-T cell infiltration [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 1367.
Abstract 5097: Single cell analysis reveals upregulation of immune stimulatory pathways in quiescent metastatic castration resistant prostate cancer cells
Authors: Kristina G. Ibrahim, Julie Boerner, Steven Zielske, Frank C. Cackowski
Journal: Cancer Research (2025)

Abstract Quiescent, or G0 cell cycle phase, cells are common in most prostate cancer (PCa) cases, yet are relatively resistant to many treatments, especially cytotoxic chemotherapy. They also play key roles in tumorigenesis, and dormancy and recurrence after curative intent therapy, but are difficult to identify when viable. To identify characteristics of quiescent prostate cancer cells, we used previously published FACS methods to isolate cancer cells from bone or bone marrow of eight metastatic castration resistant prostate cancer (mCRPC) patient samples and generated single cell RNA sequencing (scRNA-seq) gene expression data of individually sorted cells. We also generated scRNA-seq data from six PCa cell lines and two normal (cancer free) bone marrow samples as positive and negative controls for cell identification. We eliminated a priori any potentially contaminating cells based on tSNE cluster location, expression of a 12 gene panel of PCa markers, and lack of expression of bone marrow markers (PTPRC / CD45, and GYPA / CD235a), leaving 297 high confidence PCa cells. To identify characteristics of G0 cells, we separated the patient PCa cells into quiescent and cycling groups based on expression of MKI67 (Ki67). GSEA analysis of KEGG pathways revealed enrichment of primarily immune related pathways in quiescent cells with the top 3 pathways; “allograft rejection, ” “autoimmune thyroid disease, ” and “intestinal immune network for IgA production.” Similarly, for GSEA analysis using gene ontology (GO) groups, “beta-2-microglobulin binding” was the second most enriched group in quiescent cells. Type 1 HLA genes, were common among multiple pathway groups suggesting potential differences in antigen presentation. In subsequent validation experiments, induction of quiescence in LNCaP, C4-2B, PC3, and RM1 PCa cell lines increased cell surface HLA class 1 or Mhc-1. Overall, these results suggest that antigen presentation is increased in quiescent PCa cells, which may be important for their elimination by the immune system, or useful for future immunotherapy approaches. Citation Format: Kristina G. Ibrahim, Julie Boerner, Steven Zielske, Frank C. Cackowski. Single cell analysis reveals upregulation of immune stimulatory pathways in quiescent metastatic castration resistant prostate cancer 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 5097.
Abstract 1391: The role of lysosomal membrane permeabilization in ECM-detached cancer cells
Authors: Hannah M. Tanczos, Lauren Young, Paulina Harnisch, Isabella Gomez, Jianping He, Jordan Cockfield-Iratishe, Zachary T. Schafer
Journal: Cancer Research (2025)

Abstract The progression of metastatic cancer invariably leads to a lower 5-year survival rate compared to patients diagnosed with primary tumors alone, so the elimination of metastasizing cells is crucial to improve patient outcomes. A barrier to cancer metastasis is anoikis, an apoptotic form of cell death induced when a cell loses attachment to the extracellular matrix (ECM). However, cells that do successfully metastasize develop anoikis resistance and are able to survive in ECM-detachment. The survival of ECM-detached metastatic cancer cells can result from a variety of changes including elevated antioxidant activity and altered metabolism. Many of these adaptive changes rely on lysosomes, which are acidic, membrane-bound organelles that are responsible for degradation of materials. Therefore, we hypothesize that lysosomal dynamics contribute to anoikis resistance. We have found that lysosomes in non-cancerous mammary epithelial cells grown in ECM-detached conditions exhibit signs of lysosomal membrane permeabilization (LMP) and dysfunction, suggesting that LMP is caused by ECM-detachment and contributes to anoikis. In support of our hypothesis, we have found that some breast cancer cell lines and oncogenically transformed cells are able to maintain intact, functional lysosomes during ECM-detachment. Preliminary data also demonstrate that the downstream effects of LMP, specifically the release of lysosomal protease cathepsin B into the cytosol, may contribute to anoikis signaling. Ongoing work aims to elucidate the mechanism(s) by which ECM-detachment causes LMP in normal cells and understand the changes in this mechanism that confer LMP resistance in cancer cells. In a translational setting, this information could lead to a therapy that prevents metastasis by sensitizing resistant cancer cells to LMP-mediated cell death, thus improving patient outcomes. Citation Format: Hannah M. Tanczos, Lauren Young, Paulina Harnisch, Isabella Gomez, Jianping He, Jordan Cockfield-Iratishe, Zachary T. Schafer. The role of lysosomal membrane permeabilization in ECM-detached cancer 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 1391.
Abstract 5067: Concurrent spatial transcriptomics and metabolomics map differential effects of drug across brain cancer tissues
Authors: Tuan Vo, Cedric Cui, Andrew Causer, Xiao Tan, Eunju Kim, Zherui Xiong, Hani Vu, Mark Hodson, Tianyao Lu, Saskia Freytag, Jenny Fung, John Lee, Quan Nguyen
Journal: Cancer Research (2025)

Abstract The spatial heterogeneity of tumors poses significant challenges for effective treatment, resulting in varied therapeutic responses across different regions of the same tumor. This challenge is especially pronounced in brain cancers, where uneven drug distribution—largely due to biological barriers like the blood-brain barrier—complicates treatment. Techniques that overlay drug distribution with transcriptional profiles would enable a comprehensive, unbiased investigation of drug effects. In this study, we present a spatial multiomics approach that integrates spatial metabolomics and spatial transcriptomics within the same tissue section of mouse brain samples treated with Palbociclib, a selective CDK4/6 inhibitor with potential for targeting various cancers, including breast cancer and medulloblastoma (MB). Our high-resolution (2-55 µm) concurrent multiomics maps reveal that the differential distribution of Palbociclib results in heterogeneous effects, promoting differentiation and reducing proliferation in specific tumor regions. Through this approach, we identified tissue regions exhibiting distinct transcriptional and metabolic signatures, including areas unaffected by drug treatment, which could contribute to recurrence. To support this analysis, we developed SpaMTP, a state-of-the-art software package providing a comprehensive pipeline for in-depth analysis of spatial metabolomics for integrating spatial multiomics data. This package bridges processing functionalities for metabolomic data from Cardinal with user-friendly cell-centric analyses implemented in Seurat. SpaMTP’s comprehensive analysis pipeline covers (1) automated mass-to-charge ratio (m/z) metabolite annotation, (2) a wide range of downstream statistical analyses including differential metabolite expression and metabolic pathway analysis, and (3) integrative spatial-omics analysis. For broad implementation and interoperability, SpaMTP includes various functions for data visualisation, data object conversion and data import/export. Overall, our work describes novel experimental and analytical methods to map drug distribution and its transcriptional impacts directly, offering critical insights into the heterogeneous effects of Palbociclib across brain tumor tissues. Citation Format: Tuan Vo, Cedric Cui, Andrew Causer, Xiao Tan, Eunju Kim, Zherui Xiong, Hani Vu, Mark Hodson, Tianyao Lu, Saskia Freytag, Jenny Fung, John Lee, Quan Nguyen. Concurrent spatial transcriptomics and metabolomics map differential effects of drug across brain cancer tissues [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 5067.
Abstract 4338: SYS6042, a novel anti-TROP2 pH-sensitive antibody-drug conjugate (ADC) with improved therapeutic window
Authors: Yancui Wang, Xiao Gao, Mo Dan, Xiwu Hui, Bing Yao, Yang Zhang, Congcong Niu, Can Yuan, Xiaoque Zhu, Zhaopeng Sun, Bin Kang, Miaomiao Wei
Journal: Cancer Research (2025)

TROP2 is a ubiquitously expressed tumor-associated antigen. Its expression in normal tissues such as skin, oral mucosa, esophagus, liver, and cornea severely limits the development of anti-TROP2 ADCs. It is difficult to balance the efficacy and toxicity to obtain a larger therapeutic window. In clinical, Dato-DXd, Trodelvy and SKB264 showed obvious on-target toxicity or off-target toxicity, which affect clinical development and patient benefit. To address the unmet needs, we developed the SYS6042, an ADC composed of an anti-TROP2 pH-sensitive antibody, a tetrapeptide-based stable linker, and a topoisomerase I inhibitor payload, with a drug-to-antibody ratio (DAR) of 8. It binds TROP2 with nanomolar affinity at pH 6.0 but hardly binds the target at pH 7.4, thereby reducing on-target toxicity. In several cell line-derived xenografts (CDX) models, a single dose of SYS6042 at 0.4 - 4.0 mg/kg exhibited remarkable tumor growth inhibition. Notably, the antitumor activity of SYS6042 was superior to homemade Dato-DXd and SKB264. In exploratory toxicology study, SYS6042 showed favorable PK and good safety profiles with toxic findings unrelated to on-target toxicity(hematotoxicity) despite high levels of TROP2 expression in normal tissues of cynomolgus monkey. The highest non-severely toxic dose (HNSTD) for monkeys was defined as 30 mg/kg for repeating dosing. Based on these results, it demonstrates that the novel design of SYS6042 leads to an improved therapeutic window, which would help address unmet needs in the treatments of TROP2-positive tumors. Citation Format: Yancui Wang, Xiao Gao, Mo Dan, Xiwu Hui, Bing Yao, Yang Zhang, Congcong Niu, Can Yuan, Xiaoque Zhu, Zhaopeng Sun, Bin Kang, Miaomiao Wei. SYS6042, a novel anti-TROP2 pH-sensitive antibody-drug conjugate (ADC) with improved therapeutic window [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 4338.
Abstract 392: Pyrimethamine inhibits NRF2Mut in esophageal squamous cell carcinoma as a molecular glue
Authors: Zhaohui Xiong, Chorlada Paiboonrungruang, Boopathi Subramaniyan, Candice Bui-Linh, Yahui Li, Huan Li, Francis Spitz, Xiaoxin Chen
Journal: Cancer Research (2025)

Abstract Esophageal squamous cell carcinoma (ESCC) is a deadly disease and one of the most aggressive cancers of the gastrointestinal tract. As a master transcription factor regulating the stress response, nuclear factor erythroid 2-related factor 2 (NRF2) is often mutated and becomes hyperactive, and thus causes chemo-radioresistance and poor survival in human ESCC. In our previous study, we have identified pyrimethamine (PYR) as an NRF2 inhibitor using a small molecule screening, and further validated it as an inhibitor of NRF2 expression in NRF2Mut ESCC cells in vitro and Nrf2E79Q-driven esophageal phenotype in mice. As a result, PYR has moved into a Phase I window of opportunity trial (NCT05678348). This study is aimed to investigate the molecular and phenotypic consequences of NRF2 hyperactivation in ESCC, and elucidate the mechanism of action of PYR. We first generated isogenic human ESCC cells through CRISPR-Cas9 knockout for comparison with its parental cells. RNAseq and Western blotting showed that NRF2Mut overexpression downreulated the expression of squamous differential markers and upregulated the expression of proliferation markers, while NRF2WT overexpression showed different patterns. Flow cytometry and live cell imaging further showed that NRF2 activation modulated cell cycle distribution and proliferation, but not apoptosis of human ESCC cells. PYR increased chemosensitivity and radiosensitivity in NRF2Mut ESCC cells. Co-immunoprecipitation (Co-IP) and proximity ligation assay (PLA) suggested that PYR promoted NRF2-KEAP1 binding as a molecular glue in NRF2Mut ESCC cells, but not in NRF2WT ESCC cells. In summary, NRF2 hyperactivation differentially modulated squamous differentiation and cell proliferation in NRF2Mut and NRF2WT ESCC cells. PYR enhanced chemo-radiosensitivity by acting as a molecular glue specifically in NRF2Mut ESCC cells, supporting PYR as a novel therapy for NRF2Mut ESCC. Citation Format: Zhaohui Xiong, Chorlada Paiboonrungruang, Boopathi Subramaniyan, Candice Bui-Linh, Yahui Li, Huan Li, Francis Spitz, Xiaoxin Chen. Pyrimethamine inhibits NRF2Mut in esophageal squamous cell carcinoma as a molecular glue [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 392.