tbuckley/cabot-search huggingface dataset:
Abstract 6320: Benfotiamine and fursultiamine prevent glioblastoma cells growth, invasion and migration
Authors: Breauna Keane, Swathi Senthil, Kota V. Ramana
Journal: Cancer Research (2025)

Abstract Glioblastoma is the most common malignant and aggressive brain tumor in adults. Recent advances in surgical techniques and adjuvant therapies have modestly improved the overall survival rate. Thus, there is a need for novel therapeutic approaches and preventive strategies to control glioblastoma. Lipophilic derivatives of vitamin B1 have been used for many health conditions due to their substantial antioxidant and anti-inflammatory properties. However, their chemopreventive effects in glioblastoma are not known. This study investigated the chemopreventive potential of benfotiamine and fursultiamine using glioblastoma cells. Human glioblastoma (U-87) cell lines grown in Eagle’s Minimum Essential Media (EMEM) were treated with various concentrations of benfotiamine and fursultiamine. Cell viability was determined by MTT assay in a time- and dose-dependent manner. Apoptotic cell death was determined by Annexin-V staining and live-dead cell assay kits. The expression of various pro-apoptotic and anti-apoptotic factors and other inflammatory factors, including Bad, Bax, Bcl-2, cIAP-1, cIAP-2, and procaspase 3, was determined using a human apoptosis antibody array. Our results suggest that benfotiamine and fursultiamine prevent the growth of U-87 cells in a dose- and time-dependent manner. Further, they prevented the invasion and migration of glioblastoma cells. They also elevated the caspase-3 activation and reduced the mitochondrial reactive oxygen species. These compounds also regulate the expression of various pro- and anti-apoptotic factors. These findings suggest vitamin B1 derivatives could prevent glioblastoma tumor growth by upregulating the caspase-3-mediated apoptotic signaling pathways. Next, we plan to inject glioblastoma cells into the athymic nude mice xenograft model and examine the growth of glioblastoma cells in the absence and presence of vitamin B1 derivatives. Citation Format: Breauna Keane, Swathi Senthil, Kota V. Ramana. Benfotiamine and fursultiamine prevent glioblastoma cells growth, invasion and migration [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 XX.
Abstract 3319: Evaluating and targeting DNA repair defects in pediatric high grade glioma
Authors: Evan Savage, Ke Xu, Miaomiao Li, Jason Myers, Evadnie Rampersaud, Rebekah DeVries, Kamran Mohammad Zahid, Krista Millican, Yawei Hui, Ti-Cheng Chang, Gang Wu, Anang Shelat, Christopher Tinkle
Journal: Cancer Research (2025)

Abstract Homologous recombination deficiency (HRD) has been extensively studied in breast cancer and ovarian cancer given its correlation with sensitivity to Poly (ADP-ribose) polymerases (PARP) inhibitors. In these cancers, HRD is most frequently caused by biallelic inactivation of BRCA1/2 and these tumors often exhibit ‘genomic scars’ (Nik-Zainal, 2016; Telli, 2016; Davies, 2017). Our group profiled a cohort of 255 pediatric high-grade glioma (pHGG) patient samples for DNA damage response (DDR) gene variants and genomic scars. We found no evidence of BRCA1/2 loss in any sample, but we did detect evidence for HRD-associated genomic scars in 30% of our samples. Interestingly, we also detected biallelic loss of ATM, which is reported to be synthetically lethal with ATR inhibition (Marwan, 2016). Given these findings, our group set out to answer the following questions: 1) Does the presence of BRCA deficiency or HRD-related genomic scars predict sensitivity to PARP inhibition in pHGG tumors? 2) Do the ATM mutations we found impair ATM pathway activation and confer radiosensitivity, and do they induce synthetic lethality with ATR inhibition? Overall, this work underscores the importance of looking beyond simple mutation status to identify robust biomarkers of drug response in pHGG tumors. Citation Format: Evan Savage, Ke Xu, Miaomiao Li, Jason Myers, Evadnie Rampersaud, Rebekah DeVries, Kamran Mohammad Zahid, Krista Millican, Yawei Hui, Ti-Cheng Chang, Gang Wu, Anang Shelat, Christopher Tinkle. Evaluating and targeting DNA repair defects in pediatric high grade glioma [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 3319.
Abstract 1762: Preclinical and clinical studies of PEP07, a novel brain penetrating oral Chk1 inhibitor, on AML and MCL treatments
Authors: Hui-Ling Chen, Chieh-Fang Cheng, Feng-Yu Lee, Cheng-Hao Liu, Hong-Ren Wang
Journal: Cancer Research (2025)

Abstract PEP07 is an orally available and brain penetrating selective Chk1 inhibitor. Chk1 is involved in the DNA damage response and cell cycle regulation and helps maintain the integrity of the genome during cell division, especially in response to DNA damage or replication stress. Acute myeloid leukemia (AML) is characterized by an impaired DNA damage response (DDR) pathway and elevated Chk1 expression, which correlates with poor patient outcomes. Likewise, mantle cell lymphoma (MCL), a rare and aggressive form of Non-Hodgkin lymphoma, features a chromosomal translocation that leads to cyclin D1 overexpression. Since Chk1 regulates cdk1/cyclin activity, Chk1 inhibitors have been proposed as a novel therapeutic approach in this cancer. In addition to in vitro inhibitory effect on multiple hematology cancer cell lines, PEP07 has been demonstrated as monotherapy to show tumor growth inhibition and tumor regression in the AML and MCL xenograft models, respectively. It also showed enhanced tumor growth inhibition in the cytarabine-resistant AML xenograft model when combined with cytarabine. PEP07 is currently being evaluated in clinical studies for both hematologic and solid cancers. PEP07-101 (NCT05659732), a Phase 1b, open-label, multi-center PK/PD and dose-escalating study, employs an accelerated titration design combined with a traditional 3+3 approach. This study is ongoing in multiple countries and evaluates oral PEP07 as monotherapy for AML and MCL. With its ability to penetrate the blood-brain barrier (BBB), PEP07 is also being considered for investigating treatment options for brain cancer in clinical settings. Citation Format: Hui-Ling Chen, Chieh-Fang Cheng, Feng-Yu Lee, Cheng-Hao Liu, Hong-Ren Wang. Preclinical and clinical studies of PEP07, a novel brain penetrating oral Chk1 inhibitor, on AML and MCL treatments [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 1762.
Abstract 2879: A novel therapeutic approach to treat patients with Type I interferon autoantibodies
Authors: Eduardo Garcia-Reino, Nicholas Gao, Thanuka Udumulla, Elie Sosa, Nana Ayoluwa, Pargol Mashati, Andrew Patera, Jean-Laurant Casanova, Prem Premsrirut
Journal: Cancer Research (2025)

Abstract Type I interferons (IFNs) are a group of nonredundant pleiotropic cytokines that play an important role in eliciting antiviral responses and have also been shown to have antineoplastic effects. Deficits in this signaling pathway have been shown to increase susceptibility to viral infection and decrease immune surveillance to block tumorigenesis. Prior studies demonstrate that inhibition of the type I IFN pathway markedly compromises the anti-neoplastic effects of chemotherapies, such as anthracycline-based drugs like doxorubicin, and dramatically decreases the number of tumor-free mice in experimental settings. Recent large-scale clinical studies revealed that circulating anti-type I interferon autoantibodies capable of neutralizing type I IFN signaling contributed to disease severity in patients infected by SARS-CoV-2 and may be responsible for nearly 20% of COVID-19 deaths. These IFN autoantibodies were directly capable of hindering innate antiviral responses, thus allowing viral replication to occur more robustly and spread to distal tissues. Additional studies revealed that these type I IFN autoantibodies are quite prevalent in the aging population, found at high levels in nearly 1 in 15 over the age of 65 and confer a 100-fold risk of severe life-threatening viral illness. Despite their high prevalence and ability to block IFN signaling, no study to date has examined the role of type I IFN autoantibodies in cancer progression and tumor response. Here, we investigate whether neutralizing type I IFN autoantibodies can block critical innate immune signaling pathways that result in a higher conversion of pre-malignant cells to malignant tumors. We hypothesize that carriers of type I IFN autoantibodies may respond poorly to primary anticancer therapies, including standard chemotherapy regimens and immunotherapies. Furthermore, using a first-in-class therapeutic decoy, we test whether blockade of type I IFN autoantibodies can provide a synergistic benefit when combined with standard anticancer agents. Citation Format: Eduardo Garcia-Reino, Nicholas Gao, Thanuka Udumulla, Elie Sosa, Nana Ayoluwa, Pargol Mashati, Andrew Patera, Jean-Laurant Casanova, Prem Premsrirut. A novel therapeutic approach to treat patients with Type I interferon autoantibodies [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 2879.
Abstract 2872: DXC018: A novel HER2 dual-payload bispecific ADC with promising potential for gastrointestinal cancers and other solid tumors
Authors: Huihui Guo, Yong Du, Yuanyuan Huang, Juan Wang, Qingliang Yang, Junxiang Jia, Jun Zheng, Hangbo Ye, Fang Du, Meng Dai, Hui Xia, Xiaoxiao Chen, Xingyan Jiang, Ziyu Zhao, Wei Liu, Robert Yongxin Zhao
Journal: Cancer Research (2025)

Abstract HER2 (human epidermal growth factor receptor 2) is a transmembrane tyrosine kinase receptor critical for cell growth and differentiation. As a pivotal therapeutic target, HER2 has been extensively investigated in ADC drug development, resulting in numerous innovative designs along with approval in recent years. Among these, dual-payload ADCs, particularly those utilizing small molecules with distinct mechanisms of action, represent a promising yet still evolving area of research. DXC018 is a novel HER2-targeting bispecific antibody-drug conjugate (ADC) featuring dual epitope binding and dual payload delivery. The bispecific feature of DXC018 to bind HER2 domains II and IV with high affinity, enables its target specificity and therapeutic efficacy. Its payload, comprising an antimetabolite inhibitor and a topoisomerase I inhibitor, effectively induces DNA damage and cytotoxic effects. Pharmacokinetic studies in mice revealed favorable properties, with overlapping pharmacokinetic profiles for the ADC and total antibody, indicating excellent linker stability. Toxicological evaluations confirmed its tolerability at doses up to 300 mg/kg. In xenograft models of human cancer cells, including NCI-N87, JIMT-1, and CFPAC-1 cells, DXC018 exhibited superior or comparable antitumor activity to Dxd conjugate at equivalent doses. These findings suggest that DXC018, by leveraging dual HER2 binding and the complementary mechanisms of the antimetabolite and the topoisomerase I inhibition, offers significant therapeutic potential for the treatment of gastrointestinal malignancies and the other solid tumors. This innovative dual-action design establishes DXC018 as a promising next-generation ADC to address unmet needs in gastrointestinal cancers. Citation Format: Huihui Guo, Yong Du, Yuanyuan Huang, Juan Wang, Qingliang Yang, Junxiang Jia, Jun Zheng, Hangbo Ye, Fang Du, Meng Dai, Hui Xia, Xiaoxiao Chen, Xingyan Jiang, Ziyu Zhao, Wei Liu, Robert Yongxin Zhao. DXC018: A novel HER2 dual-payload bispecific ADC with promising potential for gastrointestinal cancers and other solid tumors [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 2872.
Abstract 6258: Inter- and intra-tumoral heterogeneity of TNBC determined by spatial gene transcriptomics
Authors: Fengyuan Huang, Deepa Bedi, Clayton Yates
Journal: Cancer Research (2025)

Triple-negative breast cancer (TNBC), one of the most aggressive subtypes of breast cancer, is associated with poor prognosis and limited treatment options, particularly when diagnosed at later stages. The extensive inter- and intra-tumoral heterogeneity observed in TNBC further complicates its clinical management. Understanding the molecular difference within this TNBC is crucial for elucidating its biological characteristics and clinical behaviors, as well as for developing personalized therapeutic approaches. In this study, we employ digital spatial profiling (DSP) technology to quantitatively analyze transcript and protein abundance across spatially distinct regions of TNBC, including primary tumor cores, surrounding stroma regions, and metastatic sites. The analysis reveal marked spatial heterogeneity in gene expression profiles, cellular composition, and the immune microenvironment across these regions. Additionally, we identify distinct TNBC subtypes based on unique gene expression patterns. In primary tumor, Basal-like 1 (BL1) emerged as one of the predominant subtypes and was associated with an increased present of memory B cells. We also identified a subgroup resembling unclassified (UNS) subtypes, characterized by low macrophage levels. Moreover, tumor tissues exhibited multiple TNBC subtypes within a single tumor site. This intricate subtyping within the tumor mass underscores the challenges associated with developing effective treatment for TNBC. Our findings demonstrate the power of DSP technology in elucidating the spatial dynamics of TNBC at the molecular level. The identified molecular signatures and subtypes hold potential for improving diagnostic accuracy, enabling targeted drug development, and guiding personalized treatment approaches. Ultimately, this work underscores the utility of spatial transcriptomics for addressing the challenges posed by TNBC heterogeneity and advancing precision medicine for this aggressive cancer subtype. Citation Format: Fengyuan Huang, Deepa Bedi, Clayton Yates. Inter- and intra-tumoral heterogeneity of TNBC determined by spatial gene transcriptomics [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 6258.
Abstract 3023: Preclinical study of TR-412, a novel and highly selective CLK inhibitor for acute myeloid leukemia
Authors: Wentao Zhang, He Tian, Mengyang Yan, Qian Shao
Journal: Cancer Research (2025)

Abstract Alternative splicing (AS) is a major mechanism for diversifying mRNA transcripts and regulating protein expression. Most tumors exhibit widespread splicing abnormalities relative to peritumoral healthy tissues, including frequent retention of normally excised introns, inappropriate expression of isoforms normally restricted to other cell types or developmental stages, and splicing errors that disable tumor suppressors or promote oncogene expression. The CDC2-like kinases (CLKs) and dual-specificity tyrosine-regulated kinases (DYRKs) are thought to govern the efficiency and specificity of AS by directly phosphorylating serine/arginine-rich splicing factors (SRSFs) and thereby influencing pre-mRNA splice junction selection. TR-412 is a novel inhibitor of CLK2/3 and DYRK1A/B, which was evaluated its anti-leukemic activities both in vitro and in vivo. TR-412 showed strong inhibitory effects in an exon-skipping luciferase reporter assay, achieving an IC50 of 120 nM. Furthermore, it significantly suppressed the proliferation of hematological malignancies, with a median IC50 of 350 nM. To understand the mechanism of anti-cancer cell growth, the effect of TR-412 on AS and protein expression of key tumor related biomarkers were examined. The experimental results showed that TR-412 effectively inhibited pSRSF (IC50 &amp;lt;100 nM in AML cells). In addition, RNA-seq analysis revealed that TR-412 induced global splicing changes, which typically resulted in exon exclusion (exon skipping) of cassette exon. To further investigate the effect of TR-412 on tumor growth in vivo, we established multiple AML-derived subcutaneous xenograft models (CDX), which were treated with varying doses of TR-412. In particular, complete tumor regression was achieved in the MV4-11 tumor model. Overall, the preclinical findings strongly support that this novel CLK inhibitor TR-412 is worthy of further exploration in hematologic malignancies. Citation Format: Wentao Zhang, He Tian, Mengyang Yan, Qian Shao. Preclinical study of TR-412, a novel and highly selective CLK inhibitor for acute myeloid leukemia [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 3023.
Abstract 2727: Histone deacetylase (HDAC1) and IKAROS are critical regulators of histone methylation and epigenomic landscape in T-cell acute lymphoblastic leukemia
Authors: Jiaxing Tan, Yali Ding, Bing He, Daniel Bogush, Joseph Schramm, Chingakham Singh, Diwakar Tukaramrao, Charyguly Annageldiyev, Avinash Kudva, Dhimant Desai, Arati Sharma, Sinisa Dovat
Journal: Cancer Research (2025)

Abstract Objective: To dissect the role of IKAROS-HDAC1 complexes in global regulation of gene expression and chromatin landscape in T-ALL. Methods: We studied IKAROS and HDAC1 role in epigenomic regulation of gene expression in primary human T-ALL, IKZF1-null human T-ALL, Ikzf1-null mouse T-ALL cells and following IKZF1-re-introduction into IKZF1-null human and mouse T-ALL cells. We used ATAC-seq and ChIP-seq of IKAROS, HDAC1, Enhancer of zeste homolog 2 (EZH2), along with CUT&amp;Tag of histone modification markers, coupled with RNA-seq to study dynamic effect of IKAROS in IKZF1- null T-ALL and at several time points following IKZF1 re-introduction. Results: Deletion of IKZF1 results in severely reduced HDAC1 DNA occupancy and reduced H3K27me3 enrichment. Re-introduction of IKZF1 results in the increased HDAC1 recruitment to promoters, EZH2 re-distribution, and de novo formation of H3K27me3 facultative heterochromatin. This was associated with cessation of cellular proliferation and induction of T- cell differentiation. The newly-formed heterochromatin was often located at promoters of known oncogenes and the genes that promote cell cycle progression. In contrast, IKAROS binding to DNA, without concomitant HDAC1 recruitment results in increased H3K27 histone acetylation with de novo formation of active enhancers, characterized with H3K4me1+/H3K27ac+ and super- enhancers, with a broad enrichment of histone H3K27 acetylation across the large genomic areas. Pathway enrichment analysis showed that newly-formed active enhancers positively regulate genes that are involved in cell cycle suppression and T cell differentiation. Conclusion: Our results demonstrated that IKAROS and HDAC1 are the key regulators of histone acetylation and epigenomic landscape in T-ALL. HDAC1 recruitment by IKAROS is critical for formation of facultative heterochromatin, while IKAROS DNA binding without HDAC1 promotes of histone H3K27 acetylation. Results provide novel insight into mechanisms of regulation of histone acetylation, gene expression and tumor suppression in T-ALL. Citation Format: Jiaxing Tan, Yali Ding, Bing He, Daniel Bogush, Joseph Schramm, Chingakham Singh, Diwakar Tukaramrao, Charyguly Annageldiyev, Avinash Kudva, Dhimant Desai, Arati Sharma, Sinisa Dovat. Histone deacetylase (HDAC1) and IKAROS are critical regulators of histone methylation and epigenomic landscape in T-cell acute lymphoblastic leukemia [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 2727.
Abstract 6210: The predictive performance of risk prediction models in determining lung cancer incidence in Western and Asian countries: A systematic review and meta-analysis
Authors: Yah Ru Juang, Lina Ang, Wei Jie Seow
Journal: Cancer Research (2025)

Abstract Introduction: Numerous prediction models have been developed to identify high-risk individuals for lung cancer screening, aimed at improving early detection and survival rates. However, there has been no comprehensive review and meta-analysis of model performance across different sociocultural contexts. Therefore, this review aims to systematically examine the performance of lung cancer risk prediction models in Western and Asian populations. Methods: PubMed and EMBASE were searched from inception to January 2023. Studies published in English and proposed a validated model on human populations with well-defined predictive performances were included. Two reviewers independently screened titles and abstracts and the Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to appraise study quality. A random-effects meta-analysis was performed and a 95% confidence interval (CI) for model performance was provided. Between-study heterogeneity was adjusted for using the Hartung-Knapp-Sidik-Honkman test. Results: Fifty-four studies were included, with 42 from Western and 12 from Asian countries. Most Western studies were designed for ever-smokers (19/42; 45.2%) and the general population (17/42; 40.5%), and only two Asian studies developed models exclusively for never-smokers. Across both Western and Asian prediction models, the three most consistently included risk factors are age, sex, and family cancer history. In 45.2% (19/42) of Western and 50.0% (6/12) of Asian studies, models incorporated both traditional risk factors and biomarkers; 14.8% (8/54) directly compared their biomarker-based models with those incorporating only traditional risk factors, demonstrating better discrimination. Machine-learning algorithms were applied in eight Western models and two Asian models. External validation of PLCOM2012 (AUC=0.748; 95% CI: 0.719-0.777) outperformed prediction models such as Bach (AUC=0.710; 95% CI: 0.674-0.745) and Spitz models (AUC=0.698; 95% CI: 0.640-0.755). Conclusion: Despite showing promising results, the majority of Asian risk models in our study lack external validation. Our review also reveals a significant gap in prediction models for never-smokers. Future research should externally validate existing Asian models or incorporate relevant Asian risk factors in widely-used Western models (PLCOM2012) to account for their unique risk profiles and lung cancer progression patterns. Citation Format: Yah Ru Juang, Lina Ang, Wei Jie Seow. The predictive performance of risk prediction models in determining lung cancer incidence in Western and Asian countries: A systematic review and meta-analysis [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 6210.