tbuckley/cabot-search huggingface dataset:
Abstract 6872: Repurposing the DNA labeling agent EdU for glioblastoma treatment
Authors: Humeyra Kaanoglu, Adebimpe Adefolaju, Casey Fraley, Mariah Shobande, Rajaneekar Dasari, Breanna Mann, Noah Bell, Stephen T. Keir, Shawn Hingtgen, Aziz Sancar, Andrew B. Satterlee
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is the most common and aggressive type of malignant central nervous system tumors, with over 300, 000 new cases diagnosed globally each year. Despite intensive efforts to improve survival with different treatment regimens, GBM is still deemed largely incurable. We previously found that 5-ethynyl-2’-deoxyuridine (EdU), which is commonly used in laboratories to study DNA replication, is recognized by mammalian cells as DNA damage, removed from the genome by nucleotide excision repair, and causes death of proliferating cells. Here, we evaluate the therapeutic potential of EdU for treatment of GBM, as EdU has been shown to cross the blood-brain barrier and incorporate into proliferating GBM cells but not into post-mitotic neurons. We tested the efficacy of EdU against several different model systems, including not only GBM cell lines in in vitro cell culture and in vivo orthotopic mouse models of GBM, but also living, uncultured GBM patient tumor tissues grown within our Organotypic Brain Slice Culture (OBSC) ex vivo platform. In all three model systems, EdU was effective in killing GBM cells. When compared to the standard of care drug Temozolomide (TMZ) in in vitro GBM cell survival assays, EdU displayed ED50 values orders of magnitude lower than TMZ in all five GBM tumor cell lines tested. Against two in vivo orthotopic brain tumor models, EdU significantly extended survival relative to controls. Using our OBSC ex vivo platform, we were able to quantify the capability of EdU to potently kill rapidly dividing cells within heterogeneous GBM patient tumor tissues without harming the healthy OBSC-associated brain tissue. EdU efficacy against a panel of patient GBMs largely correlated with the clinical Ki-67 status of each tumor, save for one tumor that remained unresponsive to treatment with both EdU and TMZ. Overall, these data suggest that (1) EdU has potential to be repurposed as an anticancer therapeutic and is especially adept at killing rapidly proliferating cells with low off-target toxicity; (2) the OBSC platform can measure nuanced differences in efficacy of experimental therapeutics on heterogeneous patient tumor tissues; and (3) OBSCs can continue to help identify potential responders and non-responders to EdU treatment via functional precision testing of patient tumors ex vivo. [HK and AA contributed equally to this work.] Citation Format: Humeyra Kaanoglu, Adebimpe Adefolaju, Casey Fraley, Mariah Shobande, Rajaneekar Dasari, Breanna Mann, Noah Bell, Stephen T. Keir, Shawn Hingtgen, Aziz Sancar, Andrew B. Satterlee. Repurposing the DNA labeling agent EdU for glioblastoma treatment [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 6872.
Abstract 4109: Accelerated aging in breast cancer survivors: the role of therapy-induced epigenetic modifications
Authors: Nikita Nikita, Zhengyang Sun, Swapnil Sharma, Amy Shaver, Victoria Seewaldt, Ana Maria Lopez, Grace Lu Yao
Journal: Cancer Research (2025)

Abstract Breast cancer affects over 300, 000 individuals annually in the United States, with survival rates improving due to advances in chemotherapy, radiation, hormonal, and targeted therapies. However, these treatments may inadvertently accelerate biological aging through epigenetic modifications, including DNA methylation, histone alterations, and changes in non-coding RNAs. This review explores how breast cancer therapies impact aging-related epigenetic pathways. Chemotherapy induces cellular senescence by altering DNA methylation patterns and histone modifications, potentially leading to the early onset of age-related diseases. Targeted therapies also affect epigenetic regulation, influencing gene expression related to cell cycle control, apoptosis, and DNA repair. Non-coding RNAs, such as microRNAs and long non-coding RNAs, are essential gene expression regulators affected by cancer treatments. They play significant roles in cellular senescence and therapeutic resistance, adding complexity to the aging phenotype observed in survivors. Clinical manifestations like cardiovascular dysfunction, endocrine disorders, and systemic inflammation are linked to therapy-induced epigenetic changes and in turn accelerated aging. Emerging epigenetic therapies targeting DNA methylation and histone modifications offer potential strategies to mitigate treatment-induced aging effects. DNA methyltransferase inhibitors and histone deacetylase inhibitors show promise in reactivating silenced genes and enhancing therapy sensitivity. Non-pharmacological approaches, including exercise, dietary modifications rich in bioactive compounds, and gut microbiota modulation, may also counteract therapy-exacerbated aging processes. In conclusion, existing evidence shows that cancer therapies are associated with decreased cardiorespiratory fitness, increased risk of cardiomyopathy, osteoporosis, and metabolic dysregulation, contributing to accelerated biological aging via diverse epigenetic mechanisms. Recognizing these changes is crucial for developing interventions that survivor’s health and quality of life. Further research is needed to fully understand therapy-induced epigenetic alterations and their long-term impacts, facilitating personalized survivorship care that addresses this population’s aging complexities. Citation Format: Nikita Nikita, Zhengyang Sun, Swapnil Sharma, Amy Shaver, Victoria Seewaldt, Ana Maria Lopez, Grace Lu Yao. Accelerated aging in breast cancer survivors: the role of therapy-induced epigenetic modifications [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 4109.
Abstract 7026: Nanobody-PROTACs: Method development towards using single-domain antibodies to target undruggable proteins for degradation
Authors: Caroline Cope, Cristina Tufarelli, Robert Britton
Journal: Cancer Research (2025)

Abstract Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that can bring an E3 ligase (e.g. VHL) into the vicinity of a protein of interest (POI). The E3 ligase poly-ubiquitinates the POI, marking it for degradation via a proteasome. Uniquely, PROTACs have the ability to bind to any chosen amino acid region, meaning there is tailored targeting of the POI, followed by subsequent degradation. This means that PROTACs have the potential to degrade targets previously considered ‘undruggable’, such as the oncogene, KRAS, which is historically difficult to therapeutically target due to lack of deep binding pockets. Typically, PROTACs utilize small molecules to target the POI, however, our work aims to uncover the potential of nanobodies to replace these small molecules. The gold standard for protein targeting remains monoclonal antibodies, however, nanobodies possess the same antigen binding site specificity, whilst possessing a tertiary structure only a tenth of the size. Our work focuses on identifying whether the nanobody-PROTAC has the potential for cellular entry, and thus degradation of its POI. For proof of concept, we utilized an anti-GFP nanobody tagged with AZdye647, synthesized using the Michael addition reaction, followed by SDS-PAGE analysis to assess successful conjugation. This conjugate was then used to treat fixed and live cells expressing enhanced green fluorescent protein (EGFP), followed by fluorescent microscopy to confirm cellular entry and POI targeting. Initial SDS-PAGE analysis revealed the successful conjugation of the AZDye647 to the nanobody. Specific binding within fixed cells was confirmed using fluorescent microscopy, as co-localization of EGFP and the AZdye647-tagged anti-GFP nanobody was revealed. Our data also confirmed that liposomal encapsulation of the AZdye647-tagged anti-GFP nanobody yielded efficient delivery into live EGFP expressing cells. Together, this data provides confirmation that a nanobody-PROTAC would be capable of passing through the cellular membrane, maintaining its integrity and degrading its POI. Further understanding of whether the replacement of AZDye647 with an E3 ligase ligand could result in the degradation of ‘undruggable’ oncogenes such as KRAS, in vitro, will confirm whether this is a viable therapeutic approach to patients with KRAS-mutant cancers. Citation Format: Caroline Cope, Cristina Tufarelli, Robert Britton. Nanobody-PROTACs: Method development towards using single-domain antibodies to target undruggable proteins for degradation [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 7026.
Abstract 4665: Real-world data of resected early-stage non-small cell lung cancer (NSCLC) harboring copy number variations
Authors: Jun Wang, Ning Gao, Ding Zhang
Journal: Cancer Research (2025)

Abstract Introduction: Copy number variations (CNVs) in several genetic regions are associated with cancer susceptibility and poor clinical outcomes. Currently, the role of CNVs in Non-Small Cell Lung Cancer (NSCLC) is relatively vague. This study investigates the CNVs profile in early-stage NSCLC. Methods: We retrospectively analyzed the next-generation sequencing (NGS) data of tumor tissue specimens from NSCLC patients over the past 3 years in our center. All samples were obtained by surgical resection, and clinical characteristics were collected for further analysis. Results: A total of 102 early-stage NSCLC performed NGS in our study, the mean age was 60.5 years, with 51% female. Genomic analysis revealed that 85.3% (87/102) patients had driver gene mutations, predominantly EGFR mutations (72/102) and ALK fusions (6/102). CNVs were observed in 29 NSCLC patients, including 22 with EGFR mutations, 1 with ALK fusion, 1 with BRAF V600E, and 5 without driver gene mutations. Among patients with CNVs, 9p21 (CDKN2A/CDKN2B) copy number losses were most frequent (24.1%, 7/29), followed by EGFR copy number gains (20.7%, 6/29), MYC copy number gains (13.8%, 4/29), and GATA1 copy number losses (13.8%, 4/29). There was no significant difference in age (median: 63 vs 61 years, P=0.504, Mann-Whitney U test) and sex (male: 66% vs 34%, P=0.221, chi-square test) between patients with and without CNVs. A significant trend of increased CNVs was observed in smokers compared to non-smokers (CNVs: 45.5% vs. 23.8%, P=0.046, chi-square test). Patients with small tumors accompanied by lymph node metastasis showed a significantly higher incidence of driver gene fusions than those without lymph node metastasis (T1-2N1-2 vs. T1-2N0 = 50.0% vs. 7.7%, P&amp;lt;0.001, chi-square test). However, no significant difference in CNVs incidence was found between these groups. The prognostic value of CNVs requires further validation through follow-up. Conclusions: Our study reveals a high prevalence of copy number losses of 9p21 (CDKN2A/CDKN2B) exists in early-stage non-small cell lung cancer. And we find that NSCLC patients with a history of smoking are more likely to have copy number variations. Citation Format: Jun Wang, Ning Gao, Ding Zhang. Real-world data of resected early-stage non-small cell lung cancer (NSCLC) harboring copy number variations [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 4665.
Abstract 6874: Bkt300, a novel small molecule targeting the protein regulator of cytokinesis 1 pathway in hepatocellular carcinoma
Authors: Amnon Peled, Lika Gamaev, Hanna Wald, Rakefet Rosenfeld, Orly Eizenberg, Arnon Aharon, Michal Abraham
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality worldwide, largely due to its high recurrence rate and chemoresistance. The microtubule-associated protein regulator of cytokinesis 1 (PRC1) has been implicated in HCC progression, associated with poor prognosis, enhanced cancer proliferation, stemness, metastasis, and chemoresistance. PRC1 functions as an oncogenic driver, particularly in HCC cases with elevated expression, where it promotes Wnt signaling and the expression of genes linked to early recurrence. BKT300, a novel targeted anti-cancer agent, was found to inhibit PRC1, offering a potential treatment option for advanced, difficult-to-treat cancers that express high levels of PRC1, such as HCC. This study investigated the effects of BKT300 on HCC cell migration and survival pathways. BKT300 selectively inhibited HCC cell migration, induced G2/M cell cycle arrest, and triggered mitotic catastrophe and apoptosis through the caspase 3 pathway. BKT300 targeted PRC1 by arresting it in a phosphorylated state at T481, concurrently downregulating CDC25C and upregulating p21. siRNA-mediated suppression of PRC1 in HCC cells prevented the activity of BKT300, indicating that BKT300’s efficacy is dependent on PRC1 expression. Direct binding of BKT300 to PRC1 was further confirmed through multiple assays. In vivo studies in two HCC mouse models demonstrated significant tumor growth inhibition and tumor regression, underscoring the therapeutic promise of BKT300 for HCC. Overall, BKT300 presents a novel approach to tackling HCC by directly targeting PRC1, potentially improving outcomes in HCC cases with high PRC1 expression and resistance to conventional therapies. Citation Format: Amnon Peled, Lika Gamaev, Hanna Wald, Rakefet Rosenfeld, Orly Eizenberg, Arnon Aharon, Michal Abraham. Bkt300, a novel small molecule targeting the protein regulator of cytokinesis 1 pathway in hepatocellular carcinoma [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 6874.
Abstract 7033: Unraveling <i>Kiaa1549</i>-<i>Braf</i> driven brain tumors: From modeling to therapy
Authors: Ylenia Cendon Florez, Ram Kannan, Matthias A. Karrajannis, Darlene Dela Cruz, Udi Segal, Danilo Maddalo, Scott Foster, Robert Benezra, Andrea Ventura
Journal: Cancer Research (2025)

Abstract The KIAA1549-BRAF (KB) fusion is a prevalent genetic event in two distinct central nervous system tumors: pilocytic astrocytomas (PAs) and diffuse leptomeningeal glioneuronal tumors (DLGNTs). This chromosomal rearrangement, consisting of a 2 Mbp tandem duplication at 7q34, results in the formation of a fusion protein absent in normal cells. The KB fusion protein has been described to dimerize the BRAF kinase in a RAS-independent manner, leading to a constitutive activation of the MAPK pathway and promoting tumorigenesis. Despite its significance, the lack of pre-clinical models limits our understanding of how KB promotes DLGNTs and PAs development, so effective therapeutic strategies remain elusive. To address this, we aimed to model the KB fusion at its endogenous chromosomal location. Overcoming the challenges of modeling chromosomal rearrangements, we used the CRISPR-Cas9 gene-editing technique to model the fusion event ex vivo and in vivo in the mouse brain, leveraging p53- or Arf-deleted backgrounds. These models allow us to investigate the molecular mechanisms by which KB promotes tumor initiation and progression and test the therapeutic potential of Belvarafenib, a class II BRAF inhibitor that targets BRAF dimers. Our results demonstrate that CRISPR-mediated engineering of KB in p53- or Arf-deficient backgrounds, both ex vivo and in vivo, generates CNS tumors resembling human DLGNTs in their histology and growth patterns. Furthermore, targeting the robust MAPK pathway activation in these KB-driven tumor models with Belvarafenib significantly reduced ERK phosphorylation and tumor growth, and significantly increased the survival of treated mice. These findings demonstrate that KB promotes tumor initiation and progression, and highlight the therapeutic potential of Belvarafenib targeting this oncogenic event. Thus, our KB-DLGNTs model emerges as a valuable tool to evaluate the efficacy of novel pre-clinical BRAF inhibitors. Citation Format: Ylenia Cendon Florez, Ram Kannan, Matthias A. Karrajannis, Darlene Dela Cruz, Udi Segal, Danilo Maddalo, Scott Foster, Robert Benezra, Andrea Ventura. Unraveling Kiaa1549-Braf driven brain tumors: From modeling to therapy [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 7033.
Abstract 4793: BCG033: a first-in-class PTK7×TROP2 bispecific ADC demonstrating potent and broad efficacy in various preclinical models
Authors: Lillian Ma, Na Zhang, Chengzhang Shang, Yi Yang
Journal: Cancer Research (2025)

Abstract TROP2 is frequently overexpressed in a number of epithelial cancers, and therapeutics targeting TROP2 has demonstrated clinical efficacy in multiple indications, including triple-negative breast cancer (TNBC), HR+/HER2- breast cancer, and non-small cell lung cancer (NSCLC). However, its broad expression in normal tissues raises the risk of on-target and off-tumor toxicity, potentially limiting the therapeutic effectiveness. PTK7 has emerged as an alternative target, exhibiting high prevalence and overexpression in a variety of tumors, such as TNBC, NSCLC, ovarian, oesophageal and colorectal cancers. BCG033 is a bispecific antibody-drug conjugate (ADC) that targets both PTK7 and TROP2, enhancing the therapeutic efficacy while reducing the off-target effects. Developed using Biocytogen’s fully human common light chain RenLite® mice, BCG033 is conjugated with BLD1102--a novel linker/payload containing a DNA Topoisomerase I inhibitor paired with a highly hydrophilic, protease-cleavable linker, achieving an optimal drug-to-antibody ratio (DAR) of 8. Structurally, the backbone of BCG033 consists of a bivalent antibody with two monovalent components that separately target PTK7 and TROP2, which are engineered to minimize internalization and improve tumor selectivity. BCG033 backbone antibody demonstrates strong binding activity under varying PTK7 and TROP2 expression levels in tumors, and exhibits promising developability under stress force degradation. In proof of concept studies, BCG033 AB-vcMMAE showed synergistic effect and enhanced activity compared to the parental ADCs in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of TNBC, even with low PTK7 expression. When conjugated with Biocytogen’s linker/payload BLD1102, BCG033 demonstrated superior efficacy across varying PTK7 and TROP2 expression levels in PDX models and consistently outperformed benchmark ADCs in multiple tumor models, including NSCLC, TNBC, gastric cancer, and colorectal cancer. In summary, BCG033 demonstrates promising potential for delivering potent and broad anti-tumor activity across a range of solid tumors, offering broad clinical application opportunities. Citation Format: Lillian Ma, Na Zhang, Chengzhang Shang, Yi Yang. BCG033: a first-in-class PTK7×TROP2 bispecific ADC demonstrating potent and broad efficacy in various preclinical 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 4793.
Abstract 4791: Immunosuppressive myeloid cells can be modulated with NRP2-targeting antibody ATYR2810 leading to enhanced anti-tumor immunity
Authors: Christoph Burkart, Clara Polizzi, John Hyunkuk Choi, Max Pastenes, Alison Barber, Michael Lim, Leslie Nangle
Journal: Cancer Research (2025)

Abstract Introduction: A major obstacle for many cancer immunotherapies is intrinsic or acquired resistance to treatment. Myeloid-derived immune cell populations such as myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) are promoting an immunosuppressive tumor environment. This limits the effectiveness of current cancer immunotherapies. When activated, myeloid lineage immune cells express high levels of Neuropilin2 (NRP2), a single pass transmembrane protein. NRP2 forms heterodimeric complexes with other membrane receptors such as VEGF receptors, plexins and integrins. In experimental models of immune disease, NRP2 has demonstrated anti-inflammatory effects. However, the role of NRP2 on immune cells in the context of tumor biology is largely unknown. Results: NRP2 expression is upregulated on myeloid cells in an experimental model of acute lung injury and can be detected on myeloid cells in syngeneic tumor models. In experimental models of immune diseases like atopic dermatitis and collagen-induced arthritis, NRP2-deficient mice show a stronger immune response and worse pathology. Blocking NRP2 with a monoclonal antibody (ATYR2810) in a syngeneic, orthotopic mouse model of glioblastoma (GBM), resulted in anti-tumoral polarization of myeloid cells and a significant increase in overall survival. Additionally, in syngeneic tumor models with a large immunosuppressive myeloid population, ATYR2810 treatment improved the effectiveness of checkpoint inhibition via anti-PD-1. Conclusions: Here we demonstrate that NRP2 is a negative regulator of the inflammatory response and is highly expressed on immunosuppressive myeloid cells in the tumor environment. Blocking NRP2 with ATYR2810 was effective as a single therapy and when combined with checkpoint inhibition in syngeneic tumor models with a high prevalence of MDSCs. This suggests that modulating NRP2 offers a new approach to targeting and reversing the immunosuppressive function of myeloid cells in the tumor microenvironment. Citation Format: Christoph Burkart, Clara Polizzi, John Hyunkuk Choi, Max Pastenes, Alison Barber, Michael Lim, Leslie Nangle. Immunosuppressive myeloid cells can be modulated with NRP2-targeting antibody ATYR2810 leading to enhanced anti-tumor immunity [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 4791.