tbuckley/cabot-search huggingface dataset:
Abstract 4100: Aberrant translation regulated by METTL1/WDR4-mediated Val-AAC tRNA N7-methylguanosine modification promotes gastric carcinogenesis
Authors: Yuan Li, Silei Sui, Rui Su, Ajay Goel
Journal: Cancer Research (2025)

Background: Dysregulated epigenetic modifications in RNA are closely associated with the onset and progression of human tumors. Among cellular RNA modifications, transfer RNAs (tRNAs) are the most frequently modified type; however, the role of tRNA modifications in cancer remains largely unexplored. The RNA methyltransferase METTL1, which catalyzes N7-methylguanosine (m7G) modification of tRNAs, is often amplified and overexpressed in cancers and correlates with poor patient survival. In this study, we aimed to investigate the function and underlying mechanisms of m7G modification in tRNAs driving the development and progression of gastric cancer (GC). Methods: We conducted a series of mechanistic studies to investigate the physiological functions of tRNA m7G modifications in GC tumorigenesis. Using tRNA modification and expression profiling, mRNA translation profiling, and rescue assays, we identified the molecular mechanisms underlying m7G modification in GC. Additionally, we analyzed the expression levels of the tRNA m7G methyltransferase complex components, methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in human GC samples. Results: METTL1/WDR4 promoted GC progression and metastasis in cell-based and xenograft mouse models. Mechanistically, the loss of METTL1 reduced tRNA m7G levels, particularly in Val-AAC tRNAs, leading to decreased translation of mRNAs enriched with m7G tRNA codons and impairing the synthesis of a subset of oncogenic transcripts. Moreover, the tRNA m7G methyltransferase complex components METTL1 and WDR4 were found to be upregulated in GC and correlated with poor patient prognosis. Conclusion: The tRNA m7G methyltransferase METTL1 was identified as a key driver of GC development and malignancy by regulating global mRNA translation through tRNA modifications. Our findings highlight METTL1 as a promising therapeutic target for GC patients. Citation Format: Yuan Li, Silei Sui, Rui Su, Ajay Goel. Aberrant translation regulated by METTL1/WDR4-mediated Val-AAC tRNA N7-methylguanosine modification promotes gastric carcinogenesis [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 4100.
Abstract 4217: Effect of HDAC3 targeting on endometrial cancer progression and therapeutic potential
Authors: Keun Cheon Kim, Dunston Krystina, Hall Amanda, Hunter I Mark, Tae Hoon Kim, None jaewook Jeong
Journal: Cancer Research (2025)

Abstract Endometrial cancer (EC) exerts a considerable burden on women’s health worldwide. Epigenetic dysregulation is often reported in the development and progression of various cancers. A negative regulator of PI3K signaling and frequently found to be mutated in human EC is PTEN whereas HDAC3 is critical in cell survival, proliferation, differentiation, and cancer development. HDAC inhibitors are being explored as an epigenetic treatment option, but their effects in EC are not well characterized. Pgrcre/+Hdac3f/fPtenf/f (Hdac3d/dPtend/d) mice were generated and histopathologic analysis was performed to examine the effect of Hdac3 ablation on EC with Pten deficiency. Hdac3d/dPtend/d mice revealed remarkably delayed tumorigenesis of EC compared to Ptend/dmice. To evaluate the effect of HDAC3 inhibitor (RGFP966), 6-week-old Ptend/d(Stage l EC) mice were treated with vehicle (sunflower oil) or RGFP966 (10mg/kg) twice per week for 5 weeks by intraperitoneal injection. The effect of EC progression wasexamined by immunohistochemistry using proliferation and apoptosis markers. In RGFP966-treated Ptend/dmice, uterine/body weight ratio (average 22.56±2.99) was significantly (p&amp;lt; 0.05) decreased compared to vehicle-treated Ptend/d mice (66.78 ± 10.11). Immunohistochemistry revealed a significant reduction of proliferation marker and a significant increase of apoptosis marker in RGFP966 treatment compared to vehicle. Furthermore, the level of pAKT and pERK1/2 was substantially reduced in RGFP966 treatment group. These results demonstrate that HDAC3 targeting impedes the pathogenesis of EC and RGFP966 delays EC progression. Citation Format: Keun Cheon Kim, Dunston Krystina, Hall Amanda, Hunter I Mark, Tae Hoon Kim, jaewook Jeong. Effect of HDAC3 targeting on endometrial cancer progression and therapeutic potential [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 4217.
Abstract 3167: Longer and brighter live cell bioluminescence prosubstrates
Authors: Chao Gao, Brock Binkowski, Hui Wang, Wenhui Zhou
Journal: Cancer Research (2025)

Abstract Bioluminescence prosubstrates are chemically protected bioluminescence substrates which, upon introduction to cells, can gradually and slowly release free substrate for generating luminescent signals in cellular assays. Prosubstrates can generate steady signals that last for several hours or days, enabling live-cell, kineticassays. Noticeable examples of bioluminescence prosubstrates include Nano-Glo Endurazine and Vivazine Live Cell Substrates. Although these prosubstrates have been serving the scientific community for years, they still have drawbacks, including reduced brightness, sensitivity, and signal duration. Herein, we describe a new generation of live cell bioluminescence prosubstrates that can overcome the drawbacks of current prosubstrates. Citation Format: Chao Gao, Brock Binkowski, Hui Wang, Wenhui Zhou. Longer and brighter live cell bioluminescence prosubstrates [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 3167.
Abstract 2806: The putative role of the lncRNA (<i>SOCS3 DT</i>) as a potential biomarker for ovarian cancer diagnosis and progression
Authors: Yahya Tamimi, Safa Al-Battashi, Shika Hanif Malgundkar, Sidika Sevde Yenigun, Hamad Al Riyami, Mohammed Al Toubi, Moza AL Kalbani, Aikou Okamoto, Ikram Burney
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OC) is a major global health challenge due to its high rates of cancer-related morbidity and mortality. The majority of OC cases are diagnosed at advanced stages, leading to poor survival outcomes. Thus, the identification of effective screening methods for early detection is crucial. The emergence of long non-coding RNAs (lncRNAs) as key regulators of gene expression has opened new avenues for investigating cancer biology. Previous in-silico analyses have indicated elevated expression levels of the lncRNA SOCS3-DT in OC, suggesting its potential as a biomarker. However, the exact functional role of SOCS3-DT in OC remains elusive. In this study, we conducted bioinformatic analysis using R software to identify differentially expressed lncRNAs in recurrent OC samples compared to primary ovarian tumor samples. Our analysis revealed increased expression of SOCS3-DT in recurrent OC samples compared to primary samples. To validate these findings, we utilized qRT-PCR to monitor SOCS3-DT expression in OC cell lines and human tissue samples. The qRT-PCR analysis revealed the overexpression of SOCS3-DT in the high-grade OC cell line OVSAHO, with a gradual increase in expression across early and late stages of OC tissue samples compared to healthy individuals. This suggests its potential as a promising marker for OC detection.Moreover, we suppressed SOCS3-DT expression in OVSAHO cells and assessed its impact on proliferation, colony formation, and wound healing. Additionally, to assess the effect of SOCS3-DT knockdown on crucial markers associated with cancer pathways, we conducted qRT-PCR and western blotting. Compared to the negative control, silencing SOCS3-DT in OVSAHO cells resulted in reduced cell proliferation and colony formation abilities, decreased expression of apoptotic markers (CASPASE-3, BCL-2), downregulation of autophagy markers (ATG5 and BECLIN), and mesenchymal markers (VIMENTIN and CDH2). In conclusion, this study provides new insights into identifying an effective early detection biomarker (SOCS3-DT) implicated in the early stages of the disease. This biomarker shows promise as a novel therapeutic target, presenting new approaches for the effective treatment of OC. Citation Format:Yahya Tamimi, Safa Al-Battashi, Shika Hanif Malgundkar, Sidika Sevde Yenigun, Hamad Al Riyami, Mohammed Al Toubi, Moza AL Kalbani, Aikou Okamoto, Ikram Burney. The putative role of the lncRNA (SOCS3 DT) as a potential biomarker for ovarian cancer diagnosis and 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 2806.
Abstract 4524: The independent prognostic nomogram models for primary and recurrent retroperitoneal liposarcoma: A population-based cohort study
Authors: Huan Deng, Zhenhau Lu, Binrui Wang, Yisheng Pan
Journal: Cancer Research (2025)

Abstract Purpose: The aim of this study was to establish independent prognostic models for primary and recurrent retroperitoneal liposarcoma (RLS). Experimental design: A total of 2429 patients confirmed to have RLS were extracted from the Surveillance, Epidemiology and End Results (SEER) database. The 245 patients collected from the same period at First Medical Center, Chinese People Liberation Army General Hospital (CPLAGH), were used for external validations. Nomogram were built on the basis of clinical practicability, univariate and multivariate Cox analyses. Results: The simplified predictive models for primary RLS was mainly based on tumor size (median size, 162 mm [range, 90-230], P &amp;lt; 0.001) and pathological subtypes (WDL vs DDL, hazard ratio[HR]=2.11; 95% confidence interval [CI]=1.71-2.61; P &amp;lt; 0.001), which can be acquired in the outpatient clinics. However, TNM stage (Stage 1 vs Stage 2, HR=2.18; 95% CI=1.49-3.20; P &amp;lt; 0.001) as an extremely important postoperative indicator was enrolled in the model for recurrent RLS. The area under the time-dependent receiver operating characteristic curve (time-dependent AUC) and concordance index (C-index) of models almost approach 0.75 in the training and validation cohorts. These results indicated favourable discrimination of the models. The calibration curves of the model illustrated good consistency between the predicted and observed survival probabilities in both the training and two validation cohorts. Furthermore, decision curve analysis (DCA) revealed that the nomogram models were clinically useful and had considerable practicability. Conclusion: Efficient and independent models for primary and recurrent RLS will providing clinical guidance for both prognostication and individualized therapeutic decision-making. Citation Format: Huan Deng, Zhenhau Lu, Binrui Wang, Yisheng Pan. v [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 4524.
Abstract 4103: MLL4/COMPASS dysfunction in cancer and treatment
Authors: Zibo Zhao, Sarah Gold, Yuki Aoi, Khyati A. Meghani, Luke St John, Rukkia Liaqat, Carolyn Moloney, Yanni Yu, Jun Qian, Issam Ben-Sahra, Rintaro Hashizume, Devalingam Mahalingam, Joshua Meeks, Ali Shilatifard
Journal: Cancer Research (2025)

Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. We investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 (KMT2C) and MLL4 (KMT2D). We performed a CRISPR dropout screen that revealed a targetable metabolic dependency arising from epigenetic factor deficiency, identifying potential therapies for cancers with epigenetic alterations secondary to MLL3/4-COMPASS dysfunction. We identified strong evidence that there is an internal balance between promoter and enhancer usage dictated by MLL1- versus MLL4-COMPASS, and this equilibrium is subject to disruption during cancer. Using an autochthonous carcinogen model of bladder cancer, we demonstrate that truncated, cytoplasmic MLL4 predicts response to targeted metabolic inhibition therapy for bladder cancer and could be developed as a biomarker for KMT2D-mutated cancers. We also highlight the broader potential for prognosis, patient stratification and treatment decision-making based on KMT2D mutation status in MLL4 truncation-relevant diseases, including human cancers and Kabuki Syndrome. Due to the high prevalence of loss-of-function mutations affecting MLL4 or its COMPASS partner UTX (KDM6A) in bladder cancer, we hypothesized that KMT2D mutation status may predict responsiveness to purine-targeting therapy, including methotrexate and pemetrexed. Our study found that KMT2D mutant bladder cancer cells were selectively dependent on TYMS and showed heightened sensitivity to pemetrexed, a drug that inhibits TYMS, DHFR, and GART. This suggests that targeting multiple enzymes within the one-carbon metabolism and de novo purine synthesis pathway could be promising for the treatment of MLL4/UTX-COMPASS mutant bladder cancer. Based on our previous and current findings, a clinical trial using pemetrexed in MLL4/UTX-COMPASS mutant solid tumors is being launched at Northwestern Medicine. Citation Format: Zibo Zhao, Sarah Gold, Yuki Aoi, Khyati A. Meghani, Luke St John, Rukkia Liaqat, Carolyn Moloney, Yanni Yu, Jun Qian, Issam Ben-Sahra, Rintaro Hashizume, Devalingam Mahalingam, Joshua Meeks, Ali Shilatifard. MLL4/COMPASS dysfunction in cancer and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4103.
Abstract 2530: Multispectral imaging system for intraoperative molecular imaging with two near-infrared fluorescent probes
Authors: Brianna Hajek, Zhongmin Zhu, Viktor Gruev
Journal: Cancer Research (2025)

Abstract Image-guided surgery using near-infrared (NIR) fluorescent probes offers surgeons real-time guidance to locate tumors and sentinel lymph nodes. The past decade has seen a proliferation in NIR fluorophore development, with options for targeting different tumor markers and tissue types. Using multiple fluorophores could improve tumor detection sensitivity and specificity, allow simultaneous tumor imaging and lymph node mapping, or distinguish tumors from vital anatomical structures. Current imaging systems, however, are limited to detecting a single NIR probe. This has motivated the development of a novel multispectral camera, capable of simultaneously imaging multiple NIR fluorophores with similar emission spectra that are excited with a single excitation source. The camera features a unique spectral filter array, with filters to capture both visible light and nine overlapping spectral bands in the NIR, monolithically integrated with three vertically stacked photodiodes. The result is a compact instrument that can produce overlaid visible and NIR images without co-registration error, while sampling the NIR spectrum in a nuanced manner to distinguish similar NIR fluorophores. The pixelated filters are arranged in a 2x2 “super-pixel” pattern, comprising a visible filter and three NIR filters with several passbands. The NIR filters produce nine spectral features, which are used to classify fluorescent spectra using machine learning. Initial experiments were performed to demonstrate the camera’s ability to differentiate two NIR fluorophores in vials. Combinations of indocyanine green (ICG), pafolacianine, and JAS239 in 10% FBS solutions were mixed with a range of volumetric ratios. The fluorophore concentrations were chosen to have similar overall fluorescence intensity, indistinguishable by a traditional NIR camera. Gradient boosting classifiers were trained to predict the dye or combination of dyes that produced the fluorescence at each pixel in an image. Pure ICG and pafolacianine were classified with 97% accuracy and their mixtures with 77% accuracy. ICG and JAS239 were discriminated with 99% accuracy, and mixtures of these two dyes with 81% accuracy. The results demonstrate that our single-chip multispectral imager captures sufficient information to distinguish two NIR fluorescent probes, a task unachievable by current instruments. Future steps will test the discrimination capabilities in more complex samples, moving closer to clinical applications. Citation Format: Brianna Hajek, Zhongmin Zhu, Viktor Gruev. Multispectral imaging system for intraoperative molecular imaging with two near-infrared fluorescent probes [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 2530.
Abstract 1739: Identification of a potent and selective KAT6A/6B inhibitor: HW321005 exhibits strong antitumor activity in KAT6A-high ER+/HER2− breast cancer
Authors: Xin Zhao, Qun Li, Qian Wu, Zexin Tong, Yang Zang, Tiejun Bing, Lifei Liu, Xuejun Zhang
Journal: Cancer Research (2025)

KAT6A and its paralog KAT6B are histone lysine acetyltransferases (HATs) that regulate gene transcription via the acetylation of histones. Dysregulation of KAT6 leads to lineage-specific gene expression changes in cancer. Overexpression of KAT6 is associated with poorer clinical outcomes in ER+/HER2− breast cancers. Dysregulation of KAT6 activity, including gene amplification, overexpression, fusion, and mutation, is observed in various cancers, including breast cancer. We have developed potent and selective small molecule inhibitors targeting KAT6A/6B. Our proprietary compound, HW321005, inhibits KAT6A/6B with single-digit nanomolar IC50 values, demonstrating high selectivity over other KAT family members. The efficacy of HW321005 was evaluated in multiple cancer cell lines, including ZR-751 (IC50 = 1.7 nM). Treatment with HW321005 led to a marked downregulation of KAT6A-mediated histone acetylation and estrogen receptor signaling in KAT6A-high ER+ breast cancer models. Consistent with in vitro findings, HW321005 showed significant anti-tumor efficacy and a robust pharmacodynamic response (H3K23Ac, acetylation marker; ERα, estrogen receptor signaling marker) in ZR-751 xenograft model in a dose-dependent manner. HW321005 demonstrates substantial biological potency and high selectivity, with favorable drug-like properties, including desirable in vitro ADME characteristics, excellent in vivo exposure, clearance, and good oral bioavailability across multiple preclinical species. These findings highlight the potential of HW321005 as a novel and highly effective KAT6A/6B inhibitor for the treatment of KAT6A-high ER+ breast cancer. IND-enabling studies for HW321005 are planned for early 2025. Citation Format: Xin Zhao, Qun Li, Qian Wu, Zexin Tong, Yang Zang, Tiejun Bing, Lifei Liu, Xuejun Zhang. Identification of a potent and selective KAT6A/6B inhibitor: HW321005 exhibits strong antitumor activity in KAT6A-high ER+/HER2− 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 1739.
Abstract 5919: Performance of the Oncuria-detect bladder cancer test for evaluating patients presenting with hematuria: results from a real-world clinical setting
Authors: Ian Pagano, Zhen Zhang, Sergei Tikhonenkov, Florence Le Calvez-Kelm, Steve Goodison, Toru Sakatani, Kaoru Murakami, Takashi Kobayashi, Howard Kim, Riko Lee, Sunao Tanaka, Charles J. Rosser, Hideki Furuya
Journal: Cancer Research (2025)

Abstract Background and Objective: Bladder cancer is the 9th most diagnosed cancer worldwide with high incidences reported in Europe and the United States. Here, we evaluated the real-world performance of a commercially available multiplex immunoassay Oncuria-Detect that detects bladder cancer by simultaneously measuring a panel of 10 biomarker proteins in naturally voided urine samples. Methods: We tested prospectively collected urine samples from a real-world cohort of 1, 002 patients presenting to five USA centers, one European center and one Japanese center with hematuria. Assay results were collated with patient clinical data and a cancer diagnosis was defined by biopsy and pathology. The prevalence of bladder cancer in the cohort was 15.9%. Results: In a training set (n=684), the Oncuria-Detect assay correctly identified bladder cancer in 94/109 cases, representing a sensitivity of 91.8%, specificity of 71.6% (AUC 0.885; 95% CI 0.843 - 0.927) and with improved performance for high-grade bladder cancer and muscle-invasive bladder cancer (sensitivity 93.6% and 92.1%, respectively). In a test cohort of n =339 the AUC for detecting bladder cancer was 0.850 (95% CI 0.779-0.920). Conclusions and Implications: The multiplex Oncuria-Detect assay identified bladder cancer with high sensitivity and NPV, for low-grade and high-grade tumors alike. Oncuria-Detect’s high NPV could effectively rule out 66% of patients from requiring subsequent cystoscopy. Citation Format: Ian Pagano, Zhen Zhang, Sergei Tikhonenkov, Florence Le Calvez-Kelm, Steve Goodison, Toru Sakatani, Kaoru Murakami, Takashi Kobayashi, Howard Kim, Riko Lee, Sunao Tanaka, Charles J. Rosser, Hideki Furuya. Performance of the Oncuria-detect bladder cancer test for evaluating patients presenting with hematuria: results from a real-world clinical setting [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 5919.