tbuckley/cabot-search huggingface dataset:
Abstract 1019: HRD status and biallelic loss of BRCA1/2 in breast cancer patients with germline BRCA1/2 mutation assessed by whole genome sequencing
Authors: Ji Soo Park, Jeongsoo Won, Tae Yong Kweon, Sangwoo Kim, Hyung Seok Park
Journal: Cancer Research (2025)

Background: Beyond the properties of hereditary cancers with BRCA1 and BRCA2 mutations, the concept of BRCAness is used to predict hypersensitivity to PARP inhibitors by synthetic lethality. In addition to detecting deleterious mutation in homologous recombination (HR) - related genes and genomic instability score (GIS), the application of a mutational signature has been tried using whole genome sequencing (WGS). Although a BRCA-associated cancer arose in the heterozygous carrier with germline likely pathogenic/ likely pathogenic variant (PGVs) in BRCA1/2 (gBRCA1/2 mutant) had generally been considered as be in HRD status, some BRCA-associated cancer with gBRCA1/2 mutation were classified into homologous recombination proficient (HRP) status by HRD assays. In this study, we tried to investigate the discordance in aspects of assay tools and bi-allelicity. Methods: We collected WGS data from prospectively enrolled clinical database (N=18) and public database (TCGA, N=37) of gBRCA1/2 mutant breast cancer patients. We compared the HRD status analyzed using HRDetect, CHORD, and HRD score (calculated by GIS) method, and investigated the association with biallelic or monoallelic alteration. Results: Of all the 55 WGS data from the clinical and public database, 39 (71 %), 39 (71 %), 44 (80 %) were predicted to be HRD by HRD score, CHORD, and HRDetect, respectively. HRDetect showed 94.9 % positive percent agreement (PPA) and 56.3 % negative percent agreement (NPA) to CHORD, and HRDscore showed 86.4 % PPA and 90.9 % NPA to HRDetect. Most biallelic losses of BRCA1/2 were identified in the tumor with germline mutation and LOH of wild type allele (40 of 43, 93.0%). For the HRD assay using HRDetect, 43 tumors with biallelic loss in BRCA1/2 showed significant correlation with HRD compared to those with monoallelic loss in BRCA1/2 (p value &amp;lt; 0.0001). Conclusions: Even among the gBRCA1/2 mutant breast cancers, HRD status showed some discordance according to the prediction tools and biallelic loss in BRCA1/2 genes. Clinical utility of HRD tumors with biallelic loss in BRCA1/2 need to be further investigated. Citation Format: Ji Soo Park, Jeongsoo Won, Tae Yong Kweon, Sangwoo Kim, Hyung Seok Park. HRD status and biallelic loss of BRCA1/2 in breast cancer patients with germline BRCA1/2 mutation assessed by whole genome sequencing [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 1019.
Abstract 512: Inhibition of ATR enhances the anticancer activity of ciclopirox in triple-negative breast cancer
Authors: Bing Cheng, Chinedum Okafor, Jehan Abdulsattar, Bolin Liu, Shile Huang
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) is a deadly and difficult-to-treat cancer, partly due to drug resistance, which links to enhanced DNA damage response (DDR). Our previous studies have shown that ciclopirox olamine (CPX), an off-patent fungicide, inhibits cell proliferation and induces apoptosis of various tumor cells in vitro and in vivo. Mechanistically, this is partly associated with inhibition of the mTOR signaling in tumor cells. Meanwhile, CPX can induce DDR by activating the ATR-Chk1 pathway. AZD6738 (ATR inhibitor) is currently under clinical trials for treatment of solid tumors including TNBC. This study aimed at investigating whether AZD6738 can enhance the anticancer activity of CPX in TNBC. We found that AZD6738 potentiated CPX-induced inhibition of cell proliferation and induction of apoptosis in TNBC cells. CPX treatment decreased the levels of cyclins, CDKs and phospho-Rb and increased the levels of cleaved caspase-3 and γH2AX in TNBC cells, which could be strengthened by addition of AZD6738. In addition, we observed that the combined treatment with CPX/AZD6738 did not exhibit significant toxicity in nude mice, but inhibited tumor growth more potently than the single treatment with CPX or AZD6738 in MDA-MB-231 xenografts. The results indicate that inhibition of ATR with AZD6738 can potentiate the anticancer activity of CPX in TNBC cells in vitro and in vivo. Our finding suggests that combination of CPX and AZD6738 may represent a novel therapeutic approach for TNBC. Citation Format: Bing Cheng, Chinedum Okafor, Jehan Abdulsattar, Bolin Liu, Shile Huang. Inhibition of ATR enhances the anticancer activity of ciclopirox in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 512.
Abstract 525: From unbiased genetic screen to therapy: Combination of 5-ALA and artesunate for the treatment of primary glioblastoma multiforme
Authors: Michael Orthofer, Marianna Rozsova, Ferdinand Baumgartner, Barabara Kiesel, Georg Widhalm, Moritz Horn, Josef M. Penninger
Journal: Cancer Research (2025)

The natural compound Artemisinin and its derivative Artesunate are widely used anti-malarial drugs. Due to their cytotoxic activity, they have also been investigated as anti-cancer agents, while their precise mechanism of action and key host cell targets have remained largely elusive. Using an innovative forward genetic screening approach, we identified porphyrin biosynthesis as the critical pathway governing Artemisinin’s cytotoxicity. Genetic or pharmacological modulation of porphyrin production, e.g. by supplementation of the porphyrin precursor 5-aminolevulinic acid (5-ALA), defines Artesunate’s cytotoxicity in multiple eukaryotic cells, including human cancer cells. 5-ALA, a clinically approved photodynamic porphyrin enhancer, is used as a surgical fluorescence marker, which specifically labels tumorigenic brain areas due to differential uptake and metabolism. Combining Artesunate with 5-ALA therefore provides an additional level of selectivity towards malignant tissue. We translated the screening results into clinically relevant model systems of brain tumor development: glioblastoma models in engineered cerebral organoids, patient-derived brain tumor spheroids, and orthotopic xenograft models using freshly isolated patient cells. The 5-ALA-Artesunate combination showed a strong and selective antineoplastic activity in all three model systems. At AACR 2025 we will present a comprehensive preclinical data-package, including a new delivery system with animal pharmacokinetics and efficacy data, paving the way for the clinical application of this promising therapeutic approach. Citation Format: Michael Orthofer, Marianna Rozsova, Ferdinand Baumgartner, Barabara Kiesel, Georg Widhalm, Moritz Horn, Josef M. Penninger. From unbiased genetic screen to therapy: Combination of 5-ALA and artesunate for the treatment of primary glioblastoma multiforme [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 525.
Abstract 531: Treatment of pancreatic adenocarcinoma with omeprazole
Authors: Karl N. Thomas, Rohit Singh, William E. Grizzle, Lacey R. McNally
Journal: Cancer Research (2025)

Abstract Background: Pancreatic adenocarcinoma (PADC) is associated with poor clinical outcomes that show resistance to apoptosis. Therefore, we explored an off-label use of Omeprazole to discover its effect on PADC. Our goal was to expose underlying cellular processes, namely autophagy, which are differentially regulated by Omeprazole to aid in treatment design and improve patient outcomes. Methods: Freshly cultured S2VP10 and Panc1 cells were given 50uM and 500uM Omeprazole treatment for 4-hours. Neutral Red (NR), Acridine Orange (AO), and LysoTracker stains were used to assess viability and lysosomal activity. Immunocytochemistry (ICC) in S2VP10 and Suit2 Cells was used to examine the activity of proton-sensing ion channels ASIC1 and ASIC3 following 50uM Omeprazole treatment. For AO, LysoTracker, and ICC experiments, analysis of fluorescence was performed using Nikon NIS Elements to trace relevant regions and normalize to region area. Significance was determined using Kruskal-Wallis tests followed by pairwise Wilcoxon pos hoc tests. Differences were considered statistically significant at p&amp;lt;0.05. Results: Following Omeprazole treatment, mean NR fluorescence decreased by 54.5% and 6.0% respectively for 500uM treatment of S2VP10 and Panc1 cells. AO staining of S2VP10 cells after 4-hour 500uM treatment showed a 58.2% increase in red fluorescence indicative of autophagosomes and lysosomes. This finding is supported by qualitative analysis of LysoTracker staining. Significantly increased ASIC1 and ASIC3 staining was observed for the 4-hour treatment groups compared to controls in S2VP10 and Suit2 cells lines. Discussion: Our results show that Omeprazole, a proton pump inhibitor, has a significant effect on the proton compartmentalization within pancreatic cancer. Treatment of PDAC remains challenging due to its enhanced autophagy expression and low extracellular pH which enables cell survival despite nutrient deprivation. We have shown that use of proton inhibitors like Omeprazole disrupt autophagy and cytoprotective mechanisms. Exploiting this, may help to reduce chemoresistance in PDAC. Citation Format: Karl N. Thomas, Rohit Singh, William E. Grizzle, Lacey R. McNally. Treatment of pancreatic adenocarcinoma with omeprazole [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 531.
Abstract 472: A simple, rapid, and robust bioluminescent assay for detecting anti-AAV neutralizing antibodies in serum samples
Authors: Morten Seirup, Trish Hoang, Jeff Nelson, Brock Binkowski, Marjeta Urh
Journal: Cancer Research (2025)

Abstract Adeno-associated viruses (AAVs) are widely used as vectors in gene therapy, including for the delivery of therapeutic genes in cancer treatments. In the context of cancer therapeutics, AAVs can be engineered to deliver tumor-suppressing genes or immune-modulating factors directly to cancer cells, enhancing the efficacy of immunotherapy and oncolytic strategies. However, these treatments can be compromised by pre-existing neutralizing antibodies (NAbs) in human serum. To address the need for a sensitive and efficient screening method, we present a novel cell-based transduction inhibition (TI) assay using NanoLuc luciferase, an engineered enzyme known for its high brightness and stability. This assay enables rapid and sensitive detection of NAb activity, utilizing low multiplicities of infection (MOI: 100-10, 000) and incubation times as short as 4 hours. Our workflow employs a straightforward add-mix-read format with a luminescent detection reagent, facilitating luminescence measurements with high reproducibility and minimal hands-on time. The assay's ability to tolerate high serum concentrations, allowing dilutions as low as 1:3, significantly enhances sensitivity for detecting neutralizing activity. Comparative analysis with firefly luciferase demonstrated that NanoLuc produces over 700-fold brighter signals, providing superior detection at lower MOIs. We validated the assay using HEK293 cells, achieving consistent intra-assay variability (%CV &amp;lt;18%) and precise neutralizing dose (ND50) determinations in a 3-fold dilution series of 60 human serum samples. Single-dilution screening highlighted the impact of serum dilution on hit rates, while robust 4-parameter logistic (4PL) curve fitting enabled reliable ND50 determinations for 28 of the tested samples. The assay’s simplicity, high sensitivity, and rapid turnaround make it an invaluable tool for the preclinical and clinical evaluation of NAbs against AAV serotypes, thereby supporting patient eligibility assessments and therapeutic development. These findings underscore the NanoLuc-based assay as a transformative solution for advancing AAV-based gene therapy, particularly in the realm of cancer therapeutics, where precise and rapid NAb screening is crucial for successful treatment outcomes. Citation Format: Morten Seirup, Trish Hoang, Jeff Nelson, Brock Binkowski, Marjeta Urh. A simple, rapid, and robust bioluminescent assay for detecting anti-AAV neutralizing antibodies in serum samples [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 472.
Abstract 478: Engineering viruses for the next generation targeted cancer therapy
Authors: Ikeda Trashi, Jeremiah Gassensmith
Journal: Cancer Research (2025)

Abstract The development of targeted therapies, including monoclonal antibodies, CAR-T cells, nanobodies, and combination treatments, has significantly advanced cancer management, particularly for HER2-positive tumors. Despite these advancements, challenges such as instability, high toxicity, immune responses, rapid clearance, drug resistance, and exorbitant manufacturing costs persist. A major contributor to these costs is the reliance on mammalian cell systems for production. Additionally, minimizing off-target effects remains a critical concern for targeted therapies.In this study, we engineered virus-like particles (VLPs) to selectively target HER2-positive tumors with minimal off-target effects. These VLPs were further designed to carry genetically expressed RNA interference (RNAi) systems for in situ gene silencing. Cryo-electron microscopy (Cryo-EM) was employed to characterize the functionalization of the VLP exterior and verify the packaging of the RNAi cargo. This novel single-cell approach combines targeted tumor homing with siRNA delivery, enabling simultaneous tumor targeting and silencing of the PDL1 gene. The multivalent nature of VLPs allows for the incorporation of multiple peptides, enhancing tumor affinity and specificity. With a size of approximately 35 nm, VLPs exhibit favorable pharmacokinetics, including reduced clearance and effective tumor homing. A key advantage of our approach is the ability to express VLPs in Escherichia coli systems, significantly reducing production costs compared to traditional mammalian cell-based systems, making the therapy more accessible.Our findings demonstrate that intravenously administered HER2-targeting VLPs achieve high specificity and affinity for HER2-positive tumors. Once localized, the VLPs penetrate deeply into tumor tissue, delivering RNAi cargo to silence PDL1 expression. Light sheet microscopy will be used to visualize tumor architecture in three dimensions to further investigate tumor penetration, offering a more comprehensive view than traditional cryosections. By inhibiting tumor growth and recruiting immune cells, this approach offers a dual mechanism of action: direct tumor suppression and enhanced immune-mediated clearance. Furthermore, VLPs provide unique advantages such as efficient cell penetration, scalable production, and robust cargo delivery, positioning them as a promising platform for cost-effective and effective cancer therapies. Citation Format: Ikeda Trashi, Jeremiah Gassensmith. Engineering viruses for the next generation targeted cancer 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 478.
Abstract 470: Appropriateness of long-term culture of patient-derived tumor organoid for colorectal cancer modeling through genetic and phenotypic profiling
Authors: Jaemin Cho, Eun Ah Jung, Hyowon Hong, Sang Joon Byun, Sung Wook Bae, Inchul Seo, Jumgsook Ha, Hyewon Lee, Shin Kim
Journal: Cancer Research (2025)

Abstract Background and Objective: Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, requiring effective disease models to study its progression and develop novel therapeutics. This study aimed to establish a long-term patient-derived tumor organoid (PDO) model and evaluate its suitability for colorectal cancer modeling through comprehensive genetic, morphological, and molecular analyses. Methods: PDOs were cultured for 1, 3, and 6 months to mimic the progression of CRC. Chromosomal instability was assessed using karyotyping, and morphological changes were evaluated through hematoxylin and eosin (H&amp;E) staining and bright-field imaging. Immunofluorescence staining was performed for the colorectal stem cell marker LGR5 and the epithelial differentiation marker CDX2, which is specifically expressed in the small intestine and colon epithelium and plays a key role in epithelial growth and differentiation. Temporal changes in genetic instability, structural characteristics, and marker expression were analyzed to validate the model. Results: Karyotyping revealed a progressive increase in chromosomal instability across the 1-, 3-, and 6-month PDOs, consistent with CRC-associated genetic alterations. Morphological analysis using H&amp;E staining and bright-field imaging demonstrated gradual structural changes, with the 6-month PDOs displaying histological features characteristic of CRC. Immunofluorescence staining showed a decline in LGR5 expression over time, reflecting reduced stemness in advanced stages, while CDX2 expression was maintained across all time points, indicating its critical role in epithelial differentiation during cancer progression. Conclusion: The long-term PDO-based model successfully recapitulates the genetic, morphological, and molecular hallmarks of colorectal cancer progression. This model captures key transitions, including chromosomal instability, structural alterations, and dynamic marker expression, while retaining essential epithelial markers like CDX2. These findings underscore the potential of PDOs as a robust in vitro platform for studying colorectal cancer development and progression and advancing therapeutic research. Citation Format: Jaemin Cho, Eun Ah Jung, Hyowon Hong, Sang Joon Byun, Sung Wook Bae, Inchul Seo, Jumgsook Ha, Hyewon Lee, Shin Kim. Appropriateness of long-term culture of patient-derived tumor organoid for colorectal cancer modeling through genetic and phenotypic profiling [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 470.
Abstract 352: Preclinical development of MHB042C: A next-generation anti-c-Met ADC conjugating VHH-Fc fusion protein with a novel topoisomerase I inhibitor
Authors: Bo Liu, Liyuan Zhu, Yile Chen, Xiang Meng, Ao Li, Li Liu, Zhili Yao, Yan Wang, Xialian Weng, Xuefeng Zhu, Yang Liu, Shiyu Zhou, Junwei Shi, Guoqing Cao
Journal: Cancer Research (2025)

Abstract c-MET, a receptor tyrosine kinase encoded by the MET proto-oncogene, is widely expressed in various solid tumors. Antibody-drug conjugates (ADC) targeting c-Met have shown promising clinical activity in patients with high c-MET expression, yet the therapeutic benefit remains limited for those with moderate or low expression levels. Here, we present the development and preclinical characterization of MHB042C, a next-generation anti-c-Met ADC. Unlike conventional monoclonal antibody (mAb), MHB042C utilizes a humanized VHH targeting c-Met, fused with human IgG1 Fc to deliver the cytotoxic payload. The smaller VHH-Fc fusion protein offers higher potential for tumor tissue penetration compared to traditional mAb. This unique configuration streamlines the conjugation process, achieving a uniform drug-to-antibody ratio (DAR) of 4. Additionally, Fc function was silenced to minimize nonspecific ADC uptake. The payload, SuperTopoiTM, a novel DNA topoisomerase I inhibitor, was 3 to 5 times more potent than DXd. The linker was designed to enhance hydrophilicity and to resist the retro-Michael reaction, thereby improving plasma stability. In preclinical assays, MHB042C demonstrated stronger cellular binding than competitor antibodies, reaching an internalization rate of approximately 60% in Hs746t cells within one hour. MHB042C exhibited potent cytotoxicity across c-Met-positive cancer cell lines and showed marked antitumor activity in an EBC-1 Squamous NSCLC xenograft model. GLP study in monkeys revealed a favorable safety profile with no off-target toxicities. The highest non-severely toxic dose (HNSTD) was determined to be 15 mg/kg Q3W, the maximum dose tested. In conclusion, MHB042C demonstrated potent antitumor activity both in vitro and in vivo, along with a favorable safety profile, supporting advancement to clinical development. Citation Format: Bo Liu, Liyuan Zhu, Yile Chen, Xiang Meng, Ao Li, Li Liu, Zhili Yao, Yan Wang, Xialian Weng, Xuefeng Zhu, Yang Liu, Shiyu Zhou, Junwei Shi, Guoqing Cao. Preclinical development of MHB042C: A next-generation anti-c-Met ADC conjugating VHH-Fc fusion protein with a novel topoisomerase I inhibitor [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 352.