tbuckley/cabot-search huggingface dataset:
Abstract 6661: Effect of berberine on cholesterol regulation in pancreatic ductal adenocarcinoma via heat shock factor 1
Authors: Ahmad Hegazi, Rejina Shrestha, Shruti Ghai, Kuo-Hui Su
Journal: Cancer Research (2025)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by poor prognosis and elevated metabolic activity, including dysregulated lipid metabolism that supports aggressive growth. Cholesterol homeostasis, involving synthesis, uptake, and efflux, is pivotal for tumor progression. The pro-oncogenic transcription factor heat shock factor 1 (HSF1) has been reported to sustain the increasing metabolic demands of cancer cells by directly inhibiting AMP-activated protein kinase (AMPK), leading to an enhanced de novo cholesterol synthesis process and lipogenic phenotype in human melanoma cells. Berberine, a natural alkaloid with anti-cancer properties, has demonstrated efficacy in modulating cholesterol metabolism. However, its role in cholesterol regulation through HSF1 in PDAC remains poorly understood. Objectives: To investigate the role of berberine in modulating cholesterol homeostasis in PDAC through the regulation of HSF1. Methods: Multiple human pancreatic epithelial cells and cancer cell lines were treated with berberine to evaluate its effects on cholesterol regulation. Immunoblotting was used to assess changes in key proteins associated with cholesterol metabolism, focusing on determining berberine's impact on cholesterol efflux pathways. Results: Berberine treatment significantly reduced total HSF1 levels, phosphorylation at Serine326, and downstream target HSP72 in a dose-dependent manner. Berberine treatment also increased AMPK phosphorylation at Thr172 and decreased cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1). However, the expression of another cholesterol efflux transporter, ABCG2, remained unaffected by berberine treatment. Conclusion: This study reveals a novel mechanism by which berberine exerts an anti-cancer effect in PDAC by modulating cholesterol regulation through HSF1. Citation Format: Ahmad Hegazi, Rejina Shrestha, Shruti Ghai, Kuo-Hui Su. Effect of berberine on cholesterol regulation in pancreatic ductal adenocarcinoma via heat shock factor 1 [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 6661.
Abstract 7445: Deep learning prioritizes cancer mutations that alter protein nucleocytoplasmic shuttling to drive tumorigenesis
Authors: Ze-Xian Liu, Kai Yu, Yongqiang Zheng, Jin-Fei Lin
Journal: Cancer Research (2025)

Abstract Genetic variants can affect protein function by driving aberrant subcellular localization. However, due to limitations in existing computational tools, comprehensive analysis of how mutations promote tumor progression by influencing nuclear localization is currently lacking. Here, for the first time, we systematically characterized potential shuttling-attacking mutations (SAMs) across cancers. The deep learning model Predicting Shuttling-Attacking Mutations (pSAM) was the leading tool constructed for the ab initio decoding of protein sequence determinants essential for subcellular shuttling, including classical nuclear localization signals and unconventional sequences such as fragments embedded in DNA/RNA-binding domains. Leveraging cancer mutations across 11 cancer types, we found that SAMs constitute about 6.7% of the mutations and enrich functional genetic variations and critical genes in cancer; for example, SAMs in transcription factors prevent them from entering the nucleus and subsequently cause abnormal expression of downstream targets. We experimentally validated a dozen SAMs, among which R14M in PTEN, P255L in CHFR, R674C in NFE2L1 and R144C in KAT8 were identified to disrupt the nuclear localization through interfering their interactions with importins. Further studies confirmed that the altered nucleocytoplasmic shuttling triggered by SAMs in PTEN and CHFR rewired the downstream signaling pathways and eliminated their function of suppressing cancer progression. Thus, this study greatly contributes to the understanding of the molecular details of nucleocytoplasmic shuttling and reveals the variants mediating aberrant protein subcellular localization and dysfunction in cancers and diseases. Citation Format: Ze-Xian Liu, Kai Yu, Yongqiang Zheng, Jin-Fei Lin. Deep learning prioritizes cancer mutations that alter protein nucleocytoplasmic shuttling to drive tumorigenesis [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 7445.
Abstract 6673: Alternate mechanism of translation initiation in TNBC metabolism
Authors: Emilia F. Carlo, Erna Mitaishvili, Columba de la Parra
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype of breast cancer. Metastasis is considered one of the primary causes of mortality in cancer patients. TNBC has been shown to exhibit advanced cancer hallmarks, such as metabolic reprogramming and selective mRNA translation, which contribute to metastatic progression. Previous studies show that TNBC utilizes an alternate cap-dependent translation mechanism mediated by Death Associated Protein 5 (DAP5). Our studies indicate this alternate translation plays an essential role in metabolic reprogramming. Analysis from genome-wide translatome studies, qRT-PCR, Western blot analyses, as well as metabolomic assays on the TNBC cell line (MDA-MB-231) with non-silencing controls (shNsi) and DAP5-silenced (shDAP5) samples indicate that this alternate translation plays a significant role in the metabolic reprogramming. DAP5 silencing reduces the translation of several glucose metabolism-related mRNAs, independent of their steady-state abundance, and reduces proteins associated with glycolytic metabolism. Targeted metabolomics shows that DAP5 silencing alters metabolites critical in breast cancer energy metabolism. Our findings also suggest that DAP5-dependent translation may selectively regulate metabolic mRNAs under stress conditions when canonical mTORC1/eIF4E cap-dependent translation is attenuated. This alternative translation initiation mechanism suggests this metabolic switch is necessary for malignant progression and metastasis in TNBC cells. These results provide new insights into the molecular mechanisms underlying metabolic reprogramming in metastatic breast cancer and may offer novel therapeutic targets for TNBC treatment. Citation Format: Emilia F. Carlo, Erna Mitaishvili, Columba de la Parra. Alternate mechanism of translation initiation in TNBC metabolism [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 6673.
Abstract 6444: PP2A activation targets PAI-1/CCL2 to suppress therapy-induced senescence in neuroblastoma
Authors: Nazia Nazam, Maryam Ghufran, Morgan L. Brown, Sorina Shirley, Jerry E. Stewart, Michael Ohlmeyer, Taylor Schanel, Elizabeth A. Beierle
Journal: Cancer Research (2025)

Abstract Background: Neuroblastoma (NBL) is the most common extracranial childhood solid tumor, and it is responsible for 15% of pediatric cancer deaths. Refractory and relapsed disease are exceedingly difficult to treat and the survival for these children is less than 50%. One hypothesis to explain this poor therapeutic response and tendency for disease recurrence is therapy-induced senescence (TIS) which is a temporary state of growth arrest following treatment. Protein phosphatase 2A (PP2A), a known tumor suppressor, is downregulated in NBL. Preliminary studies indicate that PP2A reactivation reduces TIS in NBL, therefore, we investigated the effects of a novel PP2A activator as a senotherapeutic in NBL. Methods: We employed the human NBL cell line, SK-N-AS. Topotecan, a common NBL chemotherapeutic, known and confirmed to induce senescence, and ATUX-1215, a novel small molecule PP2A activator were utilized. NBL cells were treated with topotecan and ATUX-1215 alone, as well as in combination. TIS was detected by senescence associated SA-β-galactosidase (SA-β-gal) assay. Colony forming assay detected cell proliferation while immunoblotting identified senescence associated proteins including γ-H2AX, plasminogen activator inhibitor-1 (PAI-1) and C-C motif chemokine ligand 2 (CCL2). R2 Genomics Analysis and Visualization Platform was used for mRNA expression data from human neuroblastoma samples to evaluate the association of PAI-1 and CCL2 gene expression with relapse free survival. Results: PP2A activator reduced SA-β-gal staining and protein expression of γ-H2AX, two markers of senescence, that were induced by topotecan treatment. Further, activation of PP2A in combination with topotecan significantly reduced colony forming potential in NBL cells. Immunoblotting demonstrated the reduction of two mediators and markers of senescence-associated secretory phenotype, PAI-1 and CCL2 with PP2A activation. Clinically, neuroblastoma patients with low PAI-1 as well as CCL2 expression have significantly higher (p=0.054, p=3.74e-03, respectively) relapse free survival. Conclusions: PP2A activator, ATUX-1215, holds potential as novel senotherapeutic adjunct by targeting PAI-1 and CCL2. Further investigations into the mechanisms responsible for these findings will be required with goals to advance this therapy to the clinical arena to prevent disease relapse. Citation Format: Nazia Nazam, Maryam Ghufran, Morgan L. Brown, Sorina Shirley, Jerry E. Stewart, Michael Ohlmeyer, Taylor Schanel, Elizabeth A. Beierle. PP2A activation targets PAI-1/CCL2 to suppress therapy-induced senescence in neuroblastoma [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 6444.
Abstract 2717: Dual inhibition of PRC2 complex subunits EZH1/2 enhances DNA hypomethylation therapy in colorectal cancer
Authors: Ashley K. Wiseman, Ali A. Chomiak, Rochelle Tiedemann, Yanqing Liu, Scott Rothbart
Journal: Cancer Research (2025)

Abstract Aberrant DNA methylation patterning is an epigenetic hallmark of human cancers. DNA methyltransferase inhibitors (DNMTi) act by reversing these aberrant DNA methylation patterns and are clinically approved to treat hematologic cancers. However, there is limited evidence for clinical efficacy in solid tumors. Our prior work showed that compensatory transcriptional silencing through the Polycomb Repressive Complex 2 (PRC2) emerges following DNMTi to maintain epigenetic silencing of critical tumor suppressor gene networks. This provides mechanistic rationale for combining DNMTi with inhibitors of EZH2 (EZH2i), the most well studied lysine methyltransferase (KMT) subunit of PRC2 that catalyzes all three orders of lysine 27 methylation on histone H3 (H3K27me1/2/3). EZH1 is an interchangeable KMT subunit of the PRC2 complex whose role in cancer is less well studied. A small molecule screen of PRC2 inhibitors revealed that compounds targeting both EZH1 and EZH2 were more effective in combination with DNMTi than those that were selective for EZH2. Integrative proteomics and epigenomics analyses revealed a mechanism in which H3K27me1, supported by EZH1, blocks the activity of the lysine acetyltransferases p300/CBP towards the H3K27 substrate, which is critical for transcriptional activation downstream of DNMTi and EZH1/2i treatment. Collectively, these studies are defining the division of labor between the two KMT subunits of PRC2 in colon cancer cells, uncovering mechanisms of crosstalk between DNA methylation, histone methylation, and histone acetylation, and revealing therapeutic vulnerabilities that we propose are targetable with dual EZH1/2 inhibitors in combination regimens to enhance the clinical efficacy of DNMTi therapy. Citation Format: Ashley K. Wiseman, Ali A. Chomiak, Rochelle Tiedemann, Yanqing Liu, Scott Rothbart. Dual inhibition of PRC2 complex subunits EZH1/2 enhances DNA hypomethylation therapy in colorectal 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 2717.
Abstract 6986: Discovery of trihydroxyflavone from botanical sources targeting the epigenomic driver NSD3 in lung squamous cell carcinoma
Authors: Betty Yangari, Kelsey Zou, Kala Mignone, Huisheng Xie, Jianliang Zhang
Journal: Cancer Research (2025)

Abstract Lung squamous cell carcinoma (LSCC) represents a highly aggressive subtype of non-small cell lung cancer, accounting for approximately 30% of all lung cancer cases. Despite its significant prevalence, effective targeted therapies for LSCC remain elusive, contributing to poor clinical outcomes. Recent molecular research has identified NSD3 as a critical oncogenic driver, with gene amplification observed in 60% of LSCC cases. NSD3 catalyzes the di-methylation of histone H3K36, leading to the epigenetic upregulation of key oncogenes such as MYC, CDK1, and CCNB1. Furthermore, the hyperactive NSD3-T1232A mutation has been implicated in accelerating tumor progression. This study aimed to develop and characterize novel small-molecule inhibitors targeting both wild-type NSD3 and the hyperactive NSD3-T1232A mutant in LSCC. Using AI-assisted molecular docking, kaempferol, an anticancer compound derived from medicinal plants, emerged as a promising lead. Comprehensive in silico drug design, cellular cytotoxic screening, surface plasmon resonance (SPR) assays, NSD3 chemiluminescent assays, and immunoblotting were employed to identify potent NSD3 inhibitors among kaempferol derivatives. Trihydroxyflavone (THF), one such derivative, demonstrated top DiffDock Confidence and SMANA Affinity scores, indicating a strong potential for NSD3 binding. SPR analysis confirmed the physical interaction between THF and NSD3, yielding favorable binding kinetics with a dissociation constant (KD) of 6.9 µM. Additionally, THF inhibited NSD3-catalyzed histone H3K36 methylation and disrupted critical oncogenic pathways involved in chromatin remodeling, cell cycle control, and mTOR signaling. Cell viability assays revealed that THF significantly reduced the proliferation of LSCC cell lines with NSD3 amplification or gain-of-function mutations, achieving an IC50 of 2.3 µM. In conclusion, our findings demonstrate the therapeutic potential of THF as a targeted inhibitor for NSD3-driven LSCC, laying the groundwork for future preclinical studies aimed at developing selective NSD3 inhibitors to improve outcomes for LSCC patients. Citation Format: Betty Yangari, Kelsey Zou, Kala Mignone, Huisheng Xie, Jianliang Zhang. Discovery of trihydroxyflavone from botanical sources targeting the epigenomic driver NSD3 in lung squamous cell 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 6986.
Abstract 6981: Discovery and optimization of purine-based CDK11 inhibitors for the treatment of Ewing’s sarcoma
Authors: Nada Elkholy, Pompom Ghosh, Hannah Walker-Mimms, Luxin Sun, Dylan Grassie, Ernst Schonbrunn, Derek Duckett, Andrii Monastyrskyi
Journal: Cancer Research (2025)

Abstract RNA splicing, the process of intron removal from pre-mRNA, is a fundamental step in gene expression regulation mediated by the spliceosome. In Ewing’s sarcoma, driven by the EWS-FLI1 fusion transcription factor, splicing is essential for generating in-frame fusion transcripts. Cyclin-dependent kinase 11 (CDK11) has been identified as a bona fide kinase responsible for phosphorylating SF3B1, a core component of the U2 snRNP. Both CDK11 and SF3B1 are crucial for EWS-FLI1 pre-mRNA maturation, with inhibition of either impairing splicing and disrupting downstream oncogenic target expression, revealing key therapeutic vulnerabilities in Ewing’s sarcoma. These vulnerabilities offer novel therapeutic strategies to target EWS-FLI1-driven malignancy. We have employed structure-based drug design to develop a novel series of purine-based CDK11 inhibitors. Subsequently, machine learning-based quantitative structure activity relationship (QSAR) modeling was employed to optimize the dataset by identifying key structural features correlated with CDK11 activity, enabling a more focused refinement of the inhibitor series. Differential scanning fluorimetry confirmed preferential binding of one series of stereoisomers, indicating a potential for enhanced selectivity across the kinome. Furthermore, radiometric kinase assays further validated the inhibition of CDK11 functional activity. Biochemical and cell-based assays, including NanoBRET target engagement and CellTiter-Glo viability assays were performed to triage compounds. These efforts aim to identify potent and selective CDK11 inhibitors, ultimately advancing our understanding of CDK11's role in Ewing’s sarcoma and its therapeutic potential. Citation Format: Nada Elkholy, Pompom Ghosh, Hannah Walker-Mimms, Luxin Sun, Dylan Grassie, Ernst Schonbrunn, Derek Duckett, Andrii Monastyrskyi. Discovery and optimization of purine-based CDK11 inhibitors for the treatment of Ewing’s sarcoma [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 6981.
Abstract 6997: Impact of KRASG12C oxidation state on non-small-cell lung cancer response to targeted therapeutics
Authors: Yismeilin R. Feliz Mosquea, Maria Luiza Carneiro Buchele, Derek Parsonage, Jingyun Lee, Surbhi Mundra, Sharon L. Campbell, Leslie B. Poole, Cristina M. Furdui
Journal: Cancer Research (2025)

Abstract RAS proteins are critical signaling nodes that regulate cellular growth, with activating mutations in KRAS found in approximately 25% of human cancers. These mutations lead to chronic KRAS activation and sustained oncogenic signaling. Among &amp;gt;130 cancer-associated point mutations in KRAS, 99% cluster at hotspots (G12, G13, and Q61), with G12C mutations predominant in non-small cell lung cancer (NSCLC, ∼80%). The G12C mutation introduces a reactive cysteine, enabling covalent drug discovery strategies. Therapeutics such as AMG510 (Sotorasib) target KRASG12C by locking it in an inactive state; however, resistance arises in ∼60% of treated patients. To address this challenge, we aim to investigate how oxidation of KRAS and at Cys12 inKRASG12C influences its ability to bind covalent inhibitors, potentially offering insights into resistance mechanisms and novel therapeutic strategies. To explore the effects of oxidative modifications on KRASG12C function, we have started by engineering a recombinant KRASG12C protein that lacks other cysteines (denoted KRASG12C-CL) and introduced a Trp substitution (Y137W) to enable fluorescent kinetic analyses (KRASG12C-CLW; CL stands for cysteine-light). Recombinant protein samples were exposed to oxidants (H2O2) in the presence or absence of GDP, subsequently desalted using Bio-Spin Chromatography columns, and then analyzed by mass spectrometry to quantify the kinetics of oxidation to sulfinic acid state (-SO2H) under these conditions. Further fluorescent kinetic assays of reduced and oxidized KRASG12C with AMG510 and other KRAS inhibitors showed complex profiles distinguishing inhibitor binding to the reduced and oxidized KRASG12C. Additionally, we conducted targeted analyses of endogenous KRASG12C oxidation in Calu-1 non-small cell lung cancer cells. Calu-1 cells treated with 1 mM H2O2for 5 minutes demonstrated rapid oxidation of KRASG12C. Data will be presented showing the impact of KRASG12C oxidation on the therapeutic efficacy of clinical and experimental inhibitors. These approaches aim to better evaluate the impact of KRASG12C oxidation state on inhibitor engagement and therapeutic outcomes, addressing mechanisms of resistance and optimizing treatment strategies. Citation Format: Yismeilin R. Feliz Mosquea, Maria Luiza Carneiro Buchele, Derek Parsonage, Jingyun Lee, Surbhi Mundra, Sharon L. Campbell, Leslie B. Poole, Cristina M. Furdui. Impact of KRASG12C oxidation state on non-small-cell lung cancer response to targeted therapeutics [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 6997.
Abstract 6993: Development of synthetic lethal compounds targeting RB1-SUCLA2 deletion in advanced prostate cancer
Authors: Susumu Kohno, Chiaki Takahashi
Journal: Cancer Research (2025)

Abstract The deletion of the tumor suppressor gene RB1 frequently occurs upon metastatic and/or castration-resistant conversion in prostate cancer. This extensive chromosomal loss associated with RB1 deletion also results in the loss of additional neighboring genes. Inhibition of gene products that compensate for these defective deletions can induce tumor-specific synthetic lethality. Our previous research demonstrated that SUCLA2 is collaterally deleted with RB1 often in advanced prostate cancer and that 5-Isopropyl-2-methyl-1, 4-benzoquinone (TQ) selectively kills SUCLA2-deficient tumors. In this study, we explored the target of TQ and the mechanism of action. To determine the binding targets of TQ, we synthesized a biotinylated alkyl TQ enabling target identification via mass spectrometry analysis. Four mitochondrial enzymes were identified (W, X, Y, and Z). Enzymatic assays revealed that only enzyme X was inhibited by TQ in a dose-dependent manner. Enzyme X composes qn enzymatic complex consisting of six alpha and six beta subunits, which TQ dissociated. Notably, TQ irreversibly depleted 2-oxoglutarate and glycine in SUCLA2 knockout (KO) cells, while TQ did not affect these metabolites in SUCLA2-reconstituted cells. Adding cell-permeable 2-oxoglutarate prevented TQ-induced apoptosis in SUCLA2 KO cells, suggesting that TQ induces apoptosis by depleting tricarboxylic acid (TCA) cycle intermediates, likely through the inhibition of enzyme X. We are currently developing new TQ derivatives to improve IC50 and pharmacokinetics. This research opens avenues for novel therapeutic strategies targeting metabolic pathways through this distinctive mechanism. Citation Format: Susumu Kohno, Chiaki Takahashi. Development of synthetic lethal compounds targeting RB1-SUCLA2 deletion in advanced prostate 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 6993.