tbuckley/cabot-search huggingface dataset:
Abstract 2740: Mechanisms of phase-separation driven chromatin looping in acute myeloid leukemia
Authors: Tooba Rashid, Zachary Drum, Doris Cruz Alonso, Gelila Petros, Yoseli Quiroga, Douglas Phanstiel
Journal: Cancer Research (2025)

Abstract New therapies are desperately needed for NUP98-fusion-driven Acute Myeloid Leukemia (AML) patients as they exhibit a poor prognosis on existing therapies, with a 5-year overall survival rate of ∼30%. We and others have shown that one fusion, NUP98-HOXA9 drives leukemogenesis through the formation of liquid-liquid phase separated (LLPS) condensates. Specifically, NUP98-HOXA9 binds DNA and pulls bound regions into the nuclear condensates, forming 3D chromatin loops that activate oncogenes' transcription. Mutation of the phenylalanine-glycine (FG) repeats responsible for NUP98-HOXA9 phase separation abolishes the formation of these condensates and inhibits malignant transformation. These findings suggest a new class of chromatin loops, that form via a mechanism distinct from loop extrusion and drive oncogene expression. We set out to characterize the necessary components for the formation and maintenance of these aberrant loops. Using an Auxin Inducible Degron (AID) system in HCT116 cells, we rapidly degraded loop extrusion proteins, CTCF and RAD21, followed by in situ Hi-C to observe impact on loop formation. We observe approximately 8, 000 canonical loops, which are bound by CTCF and lost upon auxin treatment. Additionally, we identify approximately 60 phase-separation driven loops, bound by NUP98-HOXA9 which do not require CTCF. We additionally explore the role of ATP, BRD4, and p300 as requirements for the formation of these loops. Future work includes further characterization of loop maintenance and screening for compounds to disrupt condensate formation with the goal of using a deeper understanding of phase-separation driven loops to create new promising therapeutic avenues for NUP98-fusion-driven AMLs. Citation Format: Tooba Rashid, Zachary Drum, Doris Cruz Alonso, Gelila Petros, Yoseli Quiroga, Douglas Phanstiel. Mechanisms of phase-separation driven chromatin looping in 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 2740.
Abstract 4662: Tracking gene expression in the tumor microenvironment throughout breast cancer progression
Authors: Ola Sayed Ahmed, heba Morsy, Heba Ateya, Morkoss Medhat, Abdel Rahman Zekri
Journal: Cancer Research (2025)

Abstract Background Genetic profiling of the tumor microenvironment involves looking at a lot of genes to figure out what roles they play in the progression of cancer and in how well treatments work. The tumor microenvironment is responsible for tumor genesis, metastasis, and resistance to standard therapy. Characterizing the tumor microenvironment through gene expression, such as ABCB1, FOXA, SFRP1, EGF, and XPB1, can provide valuable insights into the mechanisms driving cancer behavior. By understanding the interactions between these genes and their surrounding environment, researchers can develop more targeted and effective therapeutic strategies that enhance patient outcomes. This study design indicates the systematic procedure of genetic profiling, including patient enrollment and data analysis, with the objective of enhancing our comprehension of the tumor microenvironment in the specific context of Egyptian patients. Materials and Participants This study involved 60 patients, evaluating the expression levels of specific genes and identifying patterns linked to disease characteristics. RT2 Profiler PCR Arrays PASH-131Z were used to determine the gene expression of 84 genes for tumor cells and surrounding normal cells in each individual. Results: The FOXA1 gene is up-regulated significantly (p = 0.03). It is involved in the laminal classification of breast cancer and the control of transcription for genes related to estrogen hormone and estrogen receptor activity. On the other hand, genes like ABCB1, ATM, BRCA1, CCNA1, CCND2, CDK2, CDKN1A, EGF, EGFR, GATA3, IGF1R, IL6, TP53, and HPRT1 show significant down-regulation (p &amp;lt;0.02). These genes are involved in DNA damage and repair, cell cycle regulation, and apoptosis. Conclusion: FOXA1 and XBP1 are more important for luminal A breast cancer as a connect with hormone receptor signaling. On the other hand, SFRP and ABCB1 are more important for triple-negative breast cancer because they affect Wnt pathway activation and treatment resistance, respectively. These genes underscore the unique biological pathways present in breast cancer subtypes and demonstrate the problems and potential in their therapeutic targeting. Citation Format: Ola Sayed Ahmed, heba Morsy, Heba Ateya, Morkoss Medhat, Abdel Rahman Zekri. Tracking gene expression in the tumor microenvironment throughout breast cancer 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 4662.
Abstract 1544: Fatty acid oxidation inhibition with anti-cancer agents abrogated tumor growth in a melanoma cancer model
Authors: Jeong Hwan Park, Wonyoung Choi, Woojin Ham, Woosol Hong, Chae-Young Kim, Ho Lee, Soo-Youl Kim
Journal: Cancer Research (2025)

Abstract Purpose: We found that chemotherapy on melanoma induced fatty acid oxidation (FAO). Therefore, we propose that FAO inhibition may suppress tumor growth synergistically with anti-cancer therapeutics. Experimental Design: To block FAO, CAC (carnitine-acylcarnitine carrier, gene: SLC25A20) in the mitochondria inner membrane and ACAA1 (acetyl-CoA acyltransferase1, gene: ACAA1) in the peroxisome were targeted for inhibition. KN510 and KN713 were identified through drug screening for their inhibitory effects on CAC, and ACAA1, respectively. Using allograft and xenograft models with mouse and human melanoma cancer cells, we investigated the anti-cancer effects of KN510713 in combination with standard chemotherapy. Results: Anti-cancer drug treatment such as dabrafenib and dacarbazine induced fatty acid catabolism as well as mitochondrial oxidative phosphorylation for ATP production which is the core metabolic pathway for FAO. Increase of ATP production correlated with mTOR activation. Anti-cancer drug treatment combined with KN510713 induced cell death significantly concomitantly with mTOR inactivation in vitro. Melanoma cancer models of allograft and xenograft showed significant suppression of tumor growth by KN510713 treatment with anti-cancer agents such as dabrafenib or dacarbazine. Conclusion: FAO inhibition abrogated tumor growth by ATP depletion in melanoma. The changes in molecular signaling upon FAO inhibition revealed that ATP levels are a key regulator of all signaling. Thus, combinations of systemic anti-cancer agents with FAO inhibitors have shown excellent anti-cancer activity in mice. Even if signal transduction is induced by various growth receptors, ATP down-regulation through FAO inhibition may provide a novel therapeutic effect. Funding source: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT to SK (NRF-2019M3A9G1104345) and by a grant from the National Cancer Center of Korea to WC (NCC 2410891-1). Citation Format: Jeong Hwan Park, Wonyoung Choi, Woojin Ham, Woosol Hong, Chae-Young Kim, Ho Lee, Soo-Youl Kim. Fatty acid oxidation inhibition with anti-cancer agents abrogated tumor growth in a melanoma cancer model [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 1544.
Abstract 4227: Chromatin remodeling enhances the anti-cancer effects of estrogen therapy in ER+ breast cancer
Authors: Anneka L. Johnson, Alexa Warren, Nicole Traphagen, Alyssa Roberts, Patricia Muskus, Barbara Karakyriakou, Eugene Demidenko, Fred W. Kolling, Owen Wilkins, Kimberly Birmingham, Brock Christensen, Todd W. Miller
Journal: Cancer Research (2025)

Abstract Resistance to endocrine therapies in estrogen receptor alpha (ER)-positive breast cancer can be driven by ER amplification or overexpression. We hypothesized that the anti-cancer effects of the estrogen 17b-estradiol (E2) could be enhanced through combination with chromatin remodeling agents. We evaluated the effects of E2 and the histone deacetylase inhibitor (HDACi) entinostat in long-term estrogen-deprived (LTED) ER+ breast cancer cells, cells engineered to overexpress exogenous ER, and mice bearing endocrine-resistant patient-derived xenografts (PDX). Assayed endpoints included apoptosis, growth, DNA damage (gamma H2AX), histone post-translational modification, ER-inducible transcripts and proteins, cell cycle and replication status, chromatin accessibility by ATAC-seq, and transcriptomic changes. HDAC inhibition with entinostat increased histone H3 acetylation (H3K27ac) in cell lines and PDX models. Combination treatment with E2 and entinostat induced higher levels of apoptosis compared to single-agent treatments in LTED cells. In ER-overexpressing cells, single-agent E2 or entinostat inhibited growth that was increased with combination treatment. Entinostat and E2 each induced DNA damage and ER target gene expression. Pre-treatment with entinostat halted cell cycling while addition of E2 stalled cells in S-phase. ATAC-seq showed entinostat increases chromatin accessibility in regions containing ER target genes. In mice, entinostat slowed tumor growth rate, while single-agent E2 and the combination of E2/entinostat induced complete tumor regression. The drug combination synergized to promote more rapid tumor regression than E2 alone, and the combination delayed time to tumor recurrence compared to single-agent E2. We conclude that combination therapy with chromatin remodeling agents and E2 synergistically inhibits ER+ breast cancer cell growth and induces tumor regression in mice. Efficacy is a result of increased DNA damage, elevated chromatin accessibility, treatment-induced ER activation, cell cycle stalling, and subsequent cell death. The novel combination of an HDACi and E2 has the potential to be an effective therapy for patients with endocrine-resistant ER+ breast cancer. Citation Format: Anneka L. Johnson, Alexa Warren, Nicole Traphagen, Alyssa Roberts, Patricia Muskus, Barbara Karakyriakou, Eugene Demidenko, Fred W. Kolling, Owen Wilkins, Kimberly Birmingham, Brock Christensen, Todd W. Miller. Chromatin remodeling enhances the anti-cancer effects of estrogen therapy in ER+ 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 4227.
Abstract 5566: Comprehensive protein and genomic analysis demonstrate IGF2BP2 promotes cell proliferation via NF-kB signaling pathway in endometrial cancer
Authors: Hiroki Kurahashi, Yuko Watanabe, Kosuke Hiramatsu, Tatsuo Masuda, Mamoru Kakuda, Satoshi Nakagawa, Tadashi Iwamiya, Shinya Matsuzaki, Yutaka Ueda
Journal: Cancer Research (2025)

Introduction: Endometrial cancer (EC) is the most common gynecological cancer. While multidisciplinary therapy including surgery and chemotherapy improves the prognosis, that of refractory cases remains poor. In this study, we aimed to investigate the new treatment target and predictive marker for treatment of refractory EC using comprehensive protein analysis and TCGA genomic data. Materials and Methods: We performed iTRAQ-based comprehensive protein analysis using EC tissue samples before treatment, and compared protein expression data of refractory and responsive cases. To evaluate the function of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) which is highly expressed in refractory EC, we generated IGF2BP2 knockdown (KD) EC cells using siRNA and shRNA and evaluated cell proliferation after IGF2BP2 KD in vitro and in vivo. Moreover, we investigated signaling pathway regulated by IGF2BP2 using protein dataset. Finally, we measured IGF2BP2 cfDNA in the case of EC before and after treatment. Results: iTRAQ-based comprehensive protein analysis identified 2,299 proteins, and IGF2BP2 had the highest expression in refractory EC. High expression of IGF2BP2 in refractory EC was validated by immunohistochemistry. TCGA data analysis revealed the significant correlation between elevated IGF2BP2 mRNA levels and poor prognosis of EC (p &amp;lt; 0.01). Furthermore, we demonstrated that IGF2BP2 KD in EC cell lines significantly suppressed cell proliferation in vitro and tumor growth in vivo (p &amp;lt; 0.01, respectively). Moreover, analysis of protein datasets (Cell. 2020) of EC showed that high expression of IGF2BP2 was associated with activation of NF-kB pathway, and IGF2BP2 KD inactivated NF-kB in vitro. Finally, we demonstrated that IGF2BP2 cfDNA was decreased after complete surgery for EC. Conclusion: IGF2BP2 is highly expressed in refractory EC and contributes to cell proliferation via NF-kB pathway and poor prognosis. Citation Format: Hiroki Kurahashi, Yuko Watanabe, Kosuke Hiramatsu, Tatsuo Masuda, Mamoru Kakuda, Satoshi Nakagawa, Tadashi Iwamiya, Shinya Matsuzaki, Yutaka Ueda. Comprehensive protein and genomic analysis demonstrate IGF2BP2 promotes cell proliferation via NF-kB signaling pathway in endometrial 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 5566.
Abstract 2736: Mutation of histone H2A at glutamate 121 is frequently observed in cancer patient samples and promotes cancer-associated cellular properties
Authors: Richard L. Bennett, Jixiu Shan, Anthony J. Lamberto, Rishika Cherukuru, Kimberly Espinoza Pereira, Pierre Priam, Jonathan D. Licht
Journal: Cancer Research (2025)

Background: Histones are essential proteins that facilitate DNA compaction into nucleosomes and chromatin fibers. Their dynamics are crucial for various cellular processes, including regulation of gene expression, cellular differentiation, maintenance of cell identity, DNA replication and DNA repair. By surveying the cBioPortal of Cancer genomics we previously found that approximately 11% of cancer patients had alterations of histone H2A genes, primarily missense mutations of unknown significance. The most commonly mutated H2A residue was a glutamate at amino acid position 121. Prior work by others has demonstrated that mutation of H2A at E121 caused decreased ACF-dependent nucleosome sliding in vitro and impaired yeast growth. Objective: To determine the effect of the histone H2A glutamate to lysine mutation at amino acid 121 (H2A-E121K) on gene expression and cell growth properties relevant to cancer. Methods: We expressed HA-tagged wild type or mutant histone H2A-E121K at near physiological levels in the lung epithelial cell line BEAS-2B using a "minigene" construct which drove expression from a native H2A promoter and 3’ UTR regulatory region. Using live cell imaging we determined the effect of H2A-E121K on cell proliferation, apoptosis and migration in normal serum free media or growth factor deprived conditions. We measured the rate of serum-induced EMT signatures by immunoblotting for proteins such as claudin and cadherins. We investigated how expression of H2A-E121K may alter chromatin accessibility and gene expression by ATAC-seq and RNA-seq. Results: Expression of H2A-E121K promoted both proliferation and survival of lung epithelial cell line BEAS-2B when cultured in normal media or under growth factor deprived conditions. The H2A-E121K mutant promoted colony formation. Cells expressing H2A-E121K had altered chromatin accessibility and gene expression compared to cells expressing WT H2A. Conclusions: Expression of the histone H2A-E121K mutation promotes cancer-associated cellular properties in lung epithelial cells. Citation Format: Richard L. Bennett, Jixiu Shan, Anthony J. Lamberto, Rishika Cherukuru, Kimberly Espinoza Pereira, Pierre Priam, Jonathan D. Licht. Mutation of histone H2A at glutamate 121 is frequently observed in cancer patient samples and promotes cancer-associated cellular properties [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 2736.
Abstract 1415: FraAP, a peptide antagonist against the activator protein 1 transcription factor complex, demonstrates cancer cell cytotoxicity and reduced invasion in vitro and tumor regression in vivo in HNSCC models
Authors: Karen Mendelson, Zachary F. Mattes, Siok Leong, Ricardo Ramirez, Mark Koester, Claudio Scuoppo, Julia Diehl, Erin Gallagher, Binh Lee, Franco Abbate, Lila Ghamsari, Gene Merutka, Barry J. Kappel, Abi Vainstein-Haras, Jim A. Rotolo
Journal: Cancer Research (2025)

Abstract The AP-1 transcription factor complex, comprised of Fra1 and Jun heterodimers, plays a pivotal role in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). This complex significantly contributes to tumor progression and metastasis with its expression positively correlating with poor prognosis. As dimerization of components of the AP-1 complex is required for DNA binding and subsequent transcriptional activity, we designed a peptide (Fra1 antagonizing peptide, FraAP) targeting the basic leucine zipper motif of AP-1 to antagonize AP-1 complex formation and prevent associated activity. Bio-layer interferometry (BLI) and DNA ELISA assays demonstrate target binding and selectivity of FraAP towards AP-1 family members, co-immunoprecipitation experiments reveal that FraAP blocks protein-protein interactions between cJun and Fra1, and reporter assays confirm inhibition of AP-1 transcriptional activity in vitro. Transcriptomic analysis reveals that FraAP suppresses AP-1-driven pathways required for cell cycle progression, proliferation, and invasion and promotes apoptosis. RNAseq data was confirmed by qPCR analysis of relevant target genes. Corresponding functional in vitro assays reveal that FraAP exhibits an inhibitory effect on invasion in Boyden chamber assays and induces a phenotypic mesenchymal to epithelial transition characterized by decreased mesenchymal marker N-cadherin and increased epithelial marker E-cadherin. Annexin V characterization of FraAP treated cells by flow cytometry confirms that FraAP induces dose-dependent apoptosis. Further, in a HNSCC subcutaneous xenograft model, administration of FraAP results in significant tumor growth inhibition, demonstrating the anti-cancer potential of targeting the AP-1 complex. In summary, these data support FraAP as a potent peptide antagonist of the AP-1 transcription factor family that warrants further development as a potential therapeutic option for AP-1 driven tumors. Citation Format: Karen Mendelson, Zachary F. Mattes, Siok Leong, Ricardo Ramirez, Mark Koester, Claudio Scuoppo, Julia Diehl, Erin Gallagher, Binh Lee, Franco Abbate, Lila Ghamsari, Gene Merutka, Barry J. Kappel, Abi Vainstein-Haras, Jim A. Rotolo. FraAP, a peptide antagonist against the activator protein 1 transcription factor complex, demonstrates cancer cell cytotoxicity and reduced invasion in vitro and tumor regression in vivo in HNSCC 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 1415.
Abstract 2403: Efficient detection of whole genome duplication: a targeted sequencing approach
Authors: Hua Bao, Haimeng Tang, Rui Liu, Ningyou Li, Min Wu, Xunbiao Liu, Zhili Chang, Xue Wu
Journal: Cancer Research (2025)

Objective: Whole Genome Duplication (WGD) involves the replication of an organism's entire genome and is linked to increased evolutionary complexity and cancer progression. In tumors, WGD contributes to heterogeneity and therapy resistance, making its identification crucial for targeting genomic instabilities and informing treatment strategies. Current methods for detecting WGD are often expensive and time-consuming, highlighting the need for a cost-effective and efficient detection panel to improve therapeutic strategies, patient outcomes, and resource allocation in clinical settings. Methods: We retrospectively analyzed 4,941 tissue samples from patients spanning 14 different cancer types, including ovarian, uterine, breast, pancreatic, prostate, cervical, liver, lung, colorectal, and gastric cancers. Using a targeted sequencing panel (GENESEEQ GENAVISTA) focused on 437 cancer-related genes, we performed comprehensive mutational profiling (∼1,000X). WGD was determined by analyzing read depth, allele frequency, and employing variant calling algorithms to detect gene duplications and genomic rearrangements. Additionally, a prospective cohort of 33 cancer patients was evaluated to compare the performance of our panel with whole exome sequencing (WES, ∼200X) and whole genome sequencing (WGS, ∼30X). Results: Our analysis revealed varying prevalence of WGD across cancer types, with significant rates observed in ovarian (50.93%) and breast cancers (52.32%). Pelvic cancer (60.61%) and melanoma (60.00%) also showed high WGD-positive rates. Conversely, endometrial cancer exhibited a notably lower rate of 19.41%. Pancreatic and prostate cancers showed moderate WGD frequencies of 27.46% and 21.51%, respectively, while liver and bile duct cancers had an incidence of 41.30%. In the prospective cohort, our panel demonstrated higher sensitivity compared to WES (100% vs. 84.62%) but slightly lower specificity (90% vs. 95%). The overall concordance with the gold standard WGS was 93.9%, surpassing that of WES (90.9%). Conclusion: Our study highlights the significant variability of WGD across cancer types, with a notably high prevalence in ovarian and breast cancers. This underscores the potential of WGD as a biomarker for therapeutic targeting. Our targeted sequencing panel offers an efficient and cost-effective detection method, demonstrating substantial clinical potential for informing personalized treatment strategies and improving patient outcomes. Citation Format: Hua Bao, Haimeng Tang, Rui Liu, Ningyou Li, Min Wu, Xunbiao Liu, Zhili Chang, Xue Wu. Efficient detection of whole genome duplication: a targeted sequencing approach [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 2403.