tbuckley/cabot-search huggingface dataset:
Abstract 2238: NOX2 plays a key role in M2 polarization of macrophages associated with cancer-associated fibroblast in tumor microenvironment
Authors: Hye ji Jang, Jihyun Um, Eun Sil Lee, Sung Hwan Moon, Soo Jin Lee
Journal: Cancer Research (2025)

The tumor microenvironment (TME) is a dynamic ecosystem surrounding a tumor. The TME consists of various components such as cancer cells, stromal tissue, immune cells and the extracellular matrix (ECM). In particular, the interaction between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) is a key regulator of immunosuppression in the TME, subsequently contributing to tumor progression, resistance and metastasis. CAFs stimulate TAMs to differentiate into a M2-like macrophage phenotype, supporting immune evasion and tumor growth. It has been found that reactive oxygen species (ROS) produced by NADPH oxidase (NOX) enzymes are involved in process. ROS have been reported to stimulate CAF activity and TAM differentiation, but the role of NOX in the interaction between CAF and TAM has not yet been elucidated. Herein, we aimed to investigate the role of NOX2 in M2 polarization of macrophages, especially CAF-mediated TAM differentiation, and evaluate the therapeutic potential of targeting NOX2 in the TME. In this study, we utilized THP-1 monocytic cell lines and human pancreatic CAFs (pCAFs) to examine the functional significance of NOX2. NOX2 was predominantly expressed in THP-1 cells compared to other NOX isozymes when polarized into M2-like macrophages and knockdown of NOX2 effectively inhibited M2-like polarization of THP-1-derived macrophages. In addition, knockdown of NOX2 significantly reduced the secretion of M-CSF by pCAFs. These findings suggest that NOX2 plays a crucial role in CAF-mediated M2 differentiation of macrophages. Based on these findings, we confirmed the effects of NOX2 inhibition using com-19, a selective NOX inhibiting molecule. Com-19 modulated M2 polarization of macrophages and downregulated NOX2 mRNA levels in the cells. Moreover, com-19 also significantly reduced ROS production and the secretion of cytokines/chemokines in macrophages under M-CSF-induced conditions. Importantly, the results also demonstrated that com-19 inhibited pCAF-induced M2-like polarization of THP-1. Taken together, we confirmed that CAFs and TAMs interact closely and NOX2 inhibition could be a potential therapeutic target for CAF- and TAM-mediated immunosuppression, especially for M2-polarization of macrophages in the TME. Furthermore, com-19 can provide a novel approach to overcome immunosuppressive barriers by interrupting their interaction in the TME, offering the potential for more effective combination therapies in cancer treatment. Citation Format: Hye ji Jang, Jihyun Um, Eun Sil Lee, Sung Hwan Moon, Soo Jin Lee. NOX2 plays a key role in M2 polarization of macrophages associated with cancer-associated fibroblast in tumor 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 2238.
Abstract 697: The role of salivary exosomal cargo as diagnostic biomarker for oral squamous cell carcinoma among South African population
Authors: Dada Oluwaseyi Temilola, Manogari Chetty
Journal: Cancer Research (2025)

Abstract Introduction: Globally, oral cancer remains a non-communicable debilitating disease of major public health concerns in Africa and other low- and middle-income countries (LMICs). South Africa has the highest incidence and prevalence of oral cancer in Africa. More than 90% of all oral cancer are oral squamous cell carcinoma (OSCC). Factors such as the aggressive nature of the disease among Africans, late diagnosis, and access to and limited healthcare resources have contributed to the growing burden of OSCC in Africa and other LMICs. Exosomes play a major intercellular communication role due to their ability to transmit their cargo of proteins, nuclei acids, and lipids from one cell to another. Aim: The study is focused at investigating the role of salivary exosome cargo as diagnostic biomarkers for OSCC in a South African population. Methodology: Saliva samples were collected from 10 OSCC patients and 5 healthy individuals that consent to be part of the study. Exosomes were isolated from all saliva samples. Characterization of exosomes size and concentration was done using NanoSight NS300. Exosomes samples were also characterized using transmission electron microscope. Results: Salivary exosomes from OSCC patients were found to significantly have higher concentration and size than those from healthy individuals. There are no significant differences in size and concentration of exosomes between male and female OSCC patients. ROC analysis showed a maximal sensitivity (100%) and specificity (80%) (AUC of 0.98) at cut-off of 1.99e+9 particles/ml. Conclusion: Our study showed the potential uses of salivary exosomes morphological characteristic as diagnostic biomarker tool for OSCC. Citation Format: Dada Oluwaseyi Temilola, Manogari Chetty. The role of salivary exosomal cargo as diagnostic biomarker for oral squamous cell carcinoma among South African population [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 697.
Abstract 1587: A novel dual-payload HER3-directed antibody-drug conjugate, shows potent antitumor efficacy in HER3-low <i>in vivo</i> tumor models
Authors: Yonghao Zhao, Pengfei Ren, Menglong Guan, Jiao Tang, Lu Qi, Xinzou Fan, Shijun Yin, Gang Lei, Xiao Ke
Journal: Cancer Research (2025)

Abstract HER3 (Receptor tyrosine-protein kinase erbB-3) is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers. Elevated HER3 expression is associated with poor patient outcomes and therapeutic resistance. Several HER3-ADCs have been developed for cancer therapy. To date, patritumab deruxtecan (U3-1402) is the only HER3-targeting therapy that has demonstrated clinical efficacy in both non-small cell lung cancer. But patritumab deruxtecan is ineffective in more challenging tumor type including low HER3 expression tumors.This study presents preclinical evaluation of a novel dual-payload HER3-targeting ADC, KHN922, composed of a humanised IgG1 antibody (patritumab) directed against HER3 which is conjugated to a topoisomerase I inhibitor (TopoIi) and an RNA polymerase II inhibitor (RNA POL IIi). KHN922 achieves an average drug-to-antibody ratio (DAR) of about 7.5 (3.9+3.6) using cystein and glycosite antibody coupling technologies with an appropriate DAR, high SEC purity, homogeneous particle size distribution, and favorable thermal stability.The dual mechanism of KHN922 enables the simultaneous inhibition of RNA synthesis and the induction of DNA double-strand breaks, resulting in a potent and synergistic anti-tumor effect both in vitro and in vivo xenograft mouse models in comparison to other TopoIi-TROP2-targeting ADCs. In low and ultra-low HER3 expression CDX models, the KHN922 demonstrated superior tumor suppression effects compared to single-TopoIi ADCs, patritumab deruxtecan and patritumab exatecan.Furthermore, KHN922 still showed strong activity to DXd-ADC treatment resistance CDX models. The non-GLP toxicity study in cynomolgus monkeys provided evidence of the favorable safety profile of KHN922, the highest non-severely toxic dose (HNSTD) is 50 mg/kg/dose. In summary, KHN922, an ADC with dual toxins and unique mechanisms of action, displayed superior anti-tumor effects, the ability to overcome treatment-resistance and tumour recurrences, and an acceptable safety profile in preclinical studies. These findings support the potential of KHN922 as a promising advanced therapeutic candidate for HER3 tumors. Citation Format: Yonghao Zhao, Pengfei Ren, Menglong Guan, Jiao Tang, Lu Qi, Xinzou Fan, Shijun Yin, Gang Lei, Xiao Ke. A novel dual-payload HER3-directed antibody-drug conjugate, shows potent antitumor efficacy in HER3-low in vivo tumor models [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 1587.
Abstract 2693: BA3361, a tumor selective, conditionally active biologic (CAB) anti-nectin4-ADC with a novel NextGen linker system enhances therapeutic efficacy in pancreatic cancer
Authors: Jing Wang, Jian Chen, Gerhard Frey, Haizhen Liu, Cathy Chang, William J. Boyle, Jay M. Short
Journal: Cancer Research (2025)

Abstract Antibody drug conjugates (ADCs) are a unique therapeutic combination of the tumor-targeting monoclonal antibody, high-potency cytotoxic drug, and a chemical linker. Together, these components enable the tumor-specific delivery of the highly potent cytotoxin. However, treatment efficacy is often limited by on-target/off-tumor toxicity due to antigen expression in healthy tissue and by unwanted payload release outside the tumor caused by linker cleavage via circulating proteases. In this study, we present BA3361, a NextGen ADC featuring a conditionally active biologics (CAB) anti-Nectin4-ADC, optimized with novel CAB and linker technologies. BA3361 demonstrates pH-selective enhanced target binding in the tumor microenvironment conditions, improved serum stability, increased solubility, and tumor-specific payload release. These advancements effectively address critical clinical challenges by reducing off-tumor, on-target and off-target toxicities. In vivo efficacy data showed complete tumor regression in several patient derived cancer models. Notably, compared to an Enfortumab vedotin analogue, superior efficacy was observed in patient-derived pancreatic xenograft models, and the in vivo potency was tightly correlated with target expression. Furthermore, we discovered that intracellular glycosidase activity is high in pancreatic tumor tissue, independent of target expression, indicating efficient tumor selective linker cleavage. In conclusion, our NextGen Nectin4-CAB-ADC BA3361 demonstrates comparable or superior activity in lung, breast, and urothelial patient derived cancer models compared to Enfortumab vedotin and outperforms it in pancreatic PDX models. In addition, the conditional binding in the TME should help to reduce side effects of nonCAB ADCs and potentially widen the therapeutic index. Citation Format: Jing Wang, Jian Chen, Gerhard Frey, Haizhen Liu, Cathy Chang, William J. Boyle, Jay M. Short. BA3361, a tumor selective, conditionally active biologic (CAB) anti-nectin4-ADC with a novel NextGen linker system enhances therapeutic efficacy in pancreatic 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 2693.
Abstract 1482: Discovery of HW221043, a potent and orally bioavailable KIF18A inhibitor for treating chromosomal instability in cancer
Authors: Qun Li, Yang Zang, Xin Zhao, Qian Wu, Tiejun Bing, Lifei Liu, Xuejun Zhang
Journal: Cancer Research (2025)

Abstract Background: KIF18A, a molecular motor protein, is crucial for regulating microtubule length, essential for maintaining proper cell function and division. Chromosomal instability (CIN) significantly contributes to cancer progression and is targeted by emerging therapies such as PARP inhibitors, which exploit synthetic lethality in cancer cells. CIN resulting from whole genome duplication (WGD) is associated with poor outcomes and metastatic disease, with cancers demonstrating sensitivity to spindle assembly checkpoint disruption. This makes KIF18A a promising target in this drug class. Methods and Results: We have discovered HW221043, a highly potent and orally bioavailable small molecule inhibitor of KIF18A. Biochemical assays revealed that HW221043 potently inhibits the ATPase activity of KIF18A (IC50, 6 nM) without affecting other kinesin family members, even at the highest tested concentration of 10 μM. In cell-based assays, HW221043 markedly inhibited the viability of CIN-positive tumor cell lines at nanomolar concentrations, with no effect on CIN-negative cells even at 10 μM. The compound demonstrated excellent pharmacokinetic (PK) profiles in mice, rats, dogs, and monkeys. In two cell-derived xenograft (CDX) models (OVCAR3 and BT549), oral administration of HW221043 dose-dependently inhibited tumor growth, with nearly complete inhibition observed at 15 mg/kg once daily. Higher doses led to tumor regression. All in vitro and in vivo PK and safety tests yielded favorable results, supporting the preclinical development of HW221043. Conclusion: These findings provide pharmacological proof-of-concept for the synthetic lethal effect of HW221043 and support KIF18A inhibition as a novel therapeutic strategy in oncology. HW221043 is currently in the Investigational New Drug (IND) enabling stage of development. Citation Format: Qun Li, yang zang, xin zhao, qian wu, tiejun bing, lifei liu, xuejun zhang. Discovery of HW221043, a potent and orally bioavailable KIF18A inhibitor for treating chromosomal instability in 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 1482.
Abstract 2248: Inhibiting NNMT in cancer-associated fibroblasts reduces immunosuppression
Authors: Janna Heide, Agnes J. Bilecz, Maria F. Allega, Samarjit Patnaik, Gordon M. Stott, Matthew D. Hall, Andras Piffko, Ernst Lengyel
Journal: Cancer Research (2025)

Cancer-associated fibroblasts (CAFs) are critical in supporting cancer progression, yet effective CAF-targeted therapies are lacking. Through spatial transcriptomics and single-cell RNA sequencing, we identified nicotinamide N-methyltransferase (NNMT) upregulation and the resulting histone hypomethylation as a global regulator across various CAF subtypes. NNMT-expressing CAFs activate the complement system and recruit myeloid-derived suppressor cells (MDSCs), driving an immunosuppressive tumor microenvironment. Using high-throughput screening, we developed a potent NNMT inhibitor (NNMTi) that significantly reduces tumor burden in murine cancer models by decreasing MDSC infiltration and enhancing CD8+ T cell activation, thereby restoring the efficacy of immune checkpoint inhibitors. These findings establish NNMT as a key regulator of the CAF landscape and present a novel therapeutic strategy for reprogramming the tumor microenvironment. Citation Format: Janna Heide, Agnes J. Bilecz, Maria F. Allega, Samarjit Patnaik, Gordon M. Stott, Matthew D. Hall, Andras Piffko, Ernst Lengyel. Inhibiting NNMT in cancer-associated fibroblasts reduces immunosuppression [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 2248.
Abstract 2985: UHRF1 drives small cell lung cancer progression and immune evasion via epigenetic regulation
Authors: Yijun Gu, Claudia Benavente
Journal: Cancer Research (2025)

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer, with a five-year survival rate of less than 8%. This poor prognosis stems primarily from rapid tumor growth, early metastasis, and an immunologically “cold” tumor microenvironment. A hallmark of SCLC is the near-universal inactivation of the RB transcriptional corepressor 1 (RB1), yet therapeutic advancements have been hindered by the lack of targetable oncogenic mutations. Our research has identified ubiquitin-like containing PHD and RING Finger domains 1 (UHRF1) as a direct downstream target of the RB pathway and a key protein overexpressed in RB-deficient cancers, including SCLC. Elevated UHRF1 expression correlates with poor survival outcomes in SCLC patients, but its specific role in disease progression remains poorly understood. We hypothesized that UHRF1 overexpression is critical for SCLC tumor progression. To test this hypothesis, we employed CRISPR-Cas9 and shRNA to disrupt UHRF1 expression in human SCLC cell lines. We assessed changes in tumor cell proliferation, clonogenicity, migration, and invasion in vitro, alongside primary tumor growth, metastasis, and survival in vivo. Additionally, we developed genetically engineered mouse models of SCLC to explore Uhrf1’s role of in tumor development, particularly its interaction with the immune microenvironment. Our findings reveal that UHRF1 overexpression drives a more aggressive tumor phenotype by promoting SCLC proliferation, angiogenesis, and maintaining an immune “cold” environment. Loss of UHRF1 in both human and mouse models led to significantly improved survival outcomes. These results underscore UHRF1’s critical role in SCLC progression and highlight its potential as therapeutic target. To elucidate the molecular mechanisms behind UHRF1’s oncogenic roles, we performed transcriptomic analysis using bulk RNA-seq, further validated by RT-qPCR. Upon UHRF1 KO, we observed significant gene expression changes, including downregulation of ST6GALNAC5 and upregulation of MAGEA4, RERG, and TGFBI. Pathway analysis suggests that UHRF1 modulates these downstream targets epigenetically, potentially through DNA methylation. In conclusion, our study identifies UHRF1 as an oncogenic driver in SCLC, facilitating tumor growth, metastasis, and immune evasion via epigenetic regulation. These findings provide a foundation for developing targeted therapies aimed at UHRF1 or its key downstream effectors to improve outcomes for SCLC patients. Citation Format: Yijun Gu, Claudia Benavente. UHRF1 drives small cell lung cancer progression and immune evasion via epigenetic regulation [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 2985.
Abstract 2455: AI-based robust testicular cancer triaging, a promise for an efficient and cost-effective diagnostic/predictive modality
Authors: Siddhesh Thakur, Ujjwal Baid, Andres Martin Acosta, Muhammad T. Idrees, Michael Feldman, Spyridon Bakas
Journal: Cancer Research (2025)

Testicular cancer is one of the most common malignancies in males aged 20-44, with its two major subtypes being Seminoma and Non-Seminomatous Germ Cell Tumors (NSGCT). Accurate classification is essential for patient management and treatment, after initial histologic diagnosis on radical orchiectomy specimens or biopsies of metastases. Histopathological diagnosis, though effective, is time-consuming, costly, and subject to inter-observer variability. Digital pathology combined with artificial intelligence (AI) promises to improve diagnostic consistency and efficiency while benefitting settings without expertise in these tumors. We seek rapid and robust triaging of these subtypes through a foundation model interrogating H&amp;E-stained tissue sections and an attention-based Multiple Instance Learning (abMIL) approach providing interpretable predictions highlighting decision-driving regions. Retrospective multi-institutional data from 144 patients (254 slides) were used to develop our AI model. 118 patients (202 slides) were used for model training, 14 (30 slides) for validation, and 14 (22 slides) as an independent hold-out set. The UNI foundation model was pre-trained on diverse datasets and fine-tuned using abMIL, identifying discriminative features from the training data without requiring pixel-level annotations. Independent hold-out set evaluation revealed Area Under the Curve=96%, Accuracy=94.54%, Specificity=92%, and importantly, Sensitivity=100%. Specifically, all predicted NSGCT are correctly identified as NSGCT, and all Seminomas are always detected. In other words, no Seminoma case is overlooked, while 8% of the actual NSGCT may be misclassified as Seminoma. A sensitivity of 100% supports our model as a triaging tool, enabling faster decision-making for high-risk patients. Our proposed abMIL approach leveraging the foundation model UNI, provides a perfectly sensitive and scalable solution for clinical triaging between Seminoma and NSGCT testicular tumors in digitized tissue sections, ensuring subtype detection and supporting pathologists in improving diagnostic accuracy and efficiency. Furthermore, the model’s focus on highlighting AI decision-driving regions of the tissue section, renders it well-suited for large-scale clinical data, where it can make further data-driven contributions in extending our current disease knowledge. Citation Format: Siddhesh Thakur, Ujjwal Baid, Andres Martin Acosta, Muhammad T. Idrees, Michael Feldman, Spyridon Bakas. AI-based robust testicular cancer triaging, a promise for an efficient and cost-effective diagnostic/predictive modality [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 2455.
Abstract 243: FLT4, a novel regulator of renal cell carcinoma progression
Authors: Djazia Haferssas, Nathalie Henley, Jonatan Barrera Chimal, Casimiro Gerarduzzi
Journal: Cancer Research (2025)

Abstract Background: Clear Cell Renal Cell Carcinoma (ccRCC) is one of the ten most frequently diagnosed malignancies worldwide and constitutes 2-3% of all adult cancers. Disruption of p53 function, a critical tumor suppressor, plays a pivotal role in cancer development and resistance to chemotherapy. While p53 gene mutations are rare in ccRCC, these tumors often resist DNA-damage- based therapies, suggesting alternative mechanisms suppressing wild-type p53 in ccRCC. Therefore, reactivating this pathway represents a potential therapeutic strategy. p53 is tightly regulated by MDM2 and MDMX which are frequently elevated in ccRCC patients. However, the molecular mechanisms underlying MDM2/MDMX-mediated p53 regulation in ccRCC remain unclear. Our study identified the Receptor Tyrosine Kinase FLT4 as a novel regulator of MDM2/MDMX and p53 activity. Notably, both FLT4 and its ligand, VEGFC, are overexpressed in ccRCC patients. Hypothesis: We propose that FLT4 activation increases the stability of the MDM2/MDMX complex, resulting in p53 inactivation and promoting ccRCC tumorigenesis. Methods: 1) We analyzed Bulk and single cell RNAseq data of ccRCC patients from the Cancer Genome Atlas (TCGA) to assess the expression of FLT4 and VEGFC. 2) The ccRCC cell lines ACHN and Caki-2 were used for in vitro experiments, including VEGFC treatment for functional assays (proliferation, migration, and survival) and MDM2/MDMX/p53 protein analysis. 3) ACHN and Caki-2 cells were transduced with Luciferase and FLT4 and injected into immunodeficient NOD/SCID mice to study tumor development and metastasis using In vivo Imaging System (IVIS). Results: FLT4 and VEGFC are overexpressed in ccRCC patients and correlate with cancer progression and poor survival. In addition, FLT4 activation promotes proliferation and migration both in vitro and in vivo and reduces the chemosensitivity of ccRCC cells mainly through the modulation of p53 levels. Mechanistically, FLT4 activation decreases p53 stability and activity by increasing MDM2/MDMX levels through post-translational modifications. Conclusion: Aberrant FLT4 signaling drives ccRCC progression by suppressing p53 through the upregulation of its negative regulators MDM2 and MDMX. These findings highlight FLT4 as a potential target for restoring p53 activity and improving ccRCC outcomes. Citation Format: Djazia Haferssas, Nathalie Henley, Jonatan Barrera Chimal, Casimiro Gerarduzzi. FLT4, a novel regulator of renal cell carcinoma 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 243.