tbuckley/cabot-search huggingface dataset:
Abstract 6723: Targeting RAS in angiosarcoma
Authors: Donghee Lee, Eslenur Nipa, Erin B. Dickerson, Jong Hyuk Kim
Journal: Cancer Research (2025)

Abstract Angiosarcomas are aggressive, rare soft tissue sarcomas that form in the lining of blood vessels. Although recurrent mutations in oncogenic drivers, including VEGFR/TIE2 (KDR, FLT4, PTPRB, and PLCG1), RAS-MAPK (KRAS, HRAS, NRAS, and NF1), and PI3K (PIK3CA and PTEN) have been identified in angiosarcomas, attempts to target these pathways using selective or multi-kinase inhibitors have generally failed to produce meaningful clinical responses. RAS proteins act as critical molecular switches that regulate cell signaling, and oncogenic mutations in RAS or VEGFR/TIE2 proteins are strongly implicated in the development of angiosarcoma. However, the mechanisms that govern these mutant pathways and the challenge of developing effective therapeutic interventions have remained elusive. A promising advancement for targeting RAS mutant tumors has been the development of the tri-complex RAS(ON) multi-selective inhibitor, RMC-7977, which simultaneously targets wild-type and mutant KRAS, NRAS, and HRAS in their active, GTP-bound state, offering a potential treatment for angiosarcoma. In this study, we identified HRAS Q61R and NRAS Q61L mutations in KU-CAS3 and KU-CAS5 angiosarcoma cell lines using Nanopore sequencing. Additionally, we detected FLT4 amplification and an NF1 frameshift deletion in HAMON cells, as well as a PTPRB deletion in ISO-HAS-B cells. Our results show that RMC-7977 and MEK1/2 inhibitor mirdametinib exhibit strong potency against angiosarcoma cell lines harboring mutations in RAS and VEGFR/TIE2 pathways. Notably, RMC-7977 showed significantly greater anti-proliferation effects in RAS wild-type and PTEN frameshift deletion AS5 angiosarcoma cells compared to midrametinib or VEGFR inhibitors. Furthermore, long-term treatment with RMC-7977 inhibited the colony-forming capacity of angiosarcoma cells. These findings suggest that RMC-7977 effectively inhibits the proliferation and survival of angiosarcoma cells. Our ongoing work involves studies to evaluate the in vivo effects of RMC-7977 on the the growth of angiosarcomas xenografts containing RAS mutations. We will also investigate the molecular mechanisms underlying oncogenic signaling to elucidate RAS dependency and strengthen the rationale for using RAS inhibitors to treat angiosarcoma. This approach aims to demonstrate that targeting RAS through RAS(ON) multi-selective inhibitors is effective, highlighting the urgent need for clinical trials to advance treatment options for angiosarcoma patients. Citation Format: Donghee Lee, Eslenur Nipa, Erin B. Dickerson, Jong Hyuk Kim. Targeting RAS in angiosarcoma [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 6723.
Abstract 6721: NUAK2: The key player in ovarian cancer progression - Unraveling the impact of expression and nuclear localization
Authors: Cong Xu, O.G.W Wong, Annie.N.Y Cheung
Journal: Cancer Research (2025)

Abstract Background: NUAK2 is a kinase related to the catalytic α-subunits of the AMP-activated protein kinase (AMPK) complexes. Although NUAK2 is amplified in several human cancers, its role in cancer is poorly understood. By immunohistochemical study, we demonstrated that elevated nuclear expressed NUAK2 is associated with poor ovarian cancer patient survival and more aggressive cancer cell behaviour. Exploring the implications of NUAK2 in ovarian cancer could offer valuable perspectives on disease development and patient prognosis. Aim: To delineate the impact of NUAK2 nuclear localization on cellular mechanisms crucial for tumor proliferation, and metastasis. Methods: Lentiviral expression vectors harbouring wild type NUAK2 (NUAK2-WT) and NUAK2 NLS mutant (NUAK2-375AAAA378) were used to transduce KF and OVCA420, two ovarian cancer cell lines expressing low level of endogenous NUAK2. Cytoplasmic localization of NUAK2-375AAAA378 was confirmed by immunoblotting and immunofluorescence microscopy. The impact on cell growth was evaluated by CCK8 assay and colony formation assay. The ability of the transduced cells in migration and invasion was compared with wound healing assay and transwell assay. Results: Mutating the NLS excluded NUAK2 from the nucleus. Cells expressing NUAK2-375AAAA378 proliferated significantly slower and migrated significantly slower than cells expressing NUAK2-WT. Conclusion: The study's outcomes indicated nuclear localization is crucial for NUAK2’s oncogenic functions in enhancing the proliferation and migration capabilities of ovarian cancer cells. These results underscore the crucial role of NUAK2 in ovarian cancer progression. Citation Format: Cong Xu, O.G.W Wong, Annie.N.Y Cheung. NUAK2: The key player in ovarian cancer progression - Unraveling the impact of expression and nuclear localization [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 6721.
Abstract 6682: Circulating Epstein-Barr virus microRNAs associated with Hodgkin lymphoma prognosis
Authors: Soo Mi Lee, Cristina S. Bogsan, Jason T. Howard, Abigail G. Wandoff, Meng-Xuan Wu, Estelle Verburgh, Maxine van der Schyff, Frank J. Slack, Yujing J. Heng, Katherine Antel
Journal: Cancer Research (2025)

Abstract Background: Epstein-Barr virus (EBV) infection is an established causal factor for Hodgkin lymphoma (HL). MicroRNAs (miRNAs) are master regulators of gene expression and are ideal biomarkers. We profiled the circulating expression of 42 EBV miRNAs in HL patients to determine if EBV miRNA(s) can be a noninvasive biomarker for EBV+ HL or disease severity. Method: Plasma was obtained from 11 patients with HL in a tuberculosis and HIV-endemic setting in Cape Town, South Africa. EBV infection in HL tumor cells were confirmed using a clinical PCR assay. The expression of 42 miRNAs were measuring using a qPCR-based Mirxes ID3EALTM EBV miRNA panel. Wilcoxon test or Fisher’s test were used to compare data between two groups. Spearman’s rho was used for correlation analysis. Fold changes were calculated using the 2^-ΔΔCT method. Results: EBV+ HL patients were significantly older (p=0.04; Table 1). No miRNA was associated with EBV or prognostic factors at FDR&amp;lt;0.05. Of interest, miR-BART20-3p expression was 33% lower in EBV+ patients compared to EBV- patients (p=0.052) and did not correlate with age (rho=0.39, p=0.23). MiR-BART17-3p was inversely correlated with stage (rho=-0.61, p=0.047). MiR-BART2-5p correlated with International Prognostic Score (IPS; rho=0.72, p=0.01). miR-BART14-3p was inversely correlated with Eastern Cooperative Oncology Group (ECOG) score (rho=-0.60, p=0.049). MiR-BART11-5p and miR-BART14-5p were higher in patients that reported B-symptoms (11.2-fold p=0.01 and 2.5-fold p=0.02, respectively). In contrast, MiR-BART14-3p and miR-BART17-3p were 33% and 41% lower in patients with B-symptoms (both p=0.03). No miRNA was associated with HIV. Conclusion: Circulating EBV miRNAs were associated with HL disease severity but not EBV status. Further investigations into these candidate miRNAs will increase our understanding of HL disease progression as well as explore the potential of these miRNAs as therapeutics or therapeutic targets. Table 1. Citation Format: Soo Mi Lee, Cristina S. Bogsan, Jason T. Howard, Abigail G. Wandoff, Meng-Xuan Wu, Estelle Verburgh, Maxine van der Schyff, Frank J. Slack, Yujing J. Heng, Katherine Antel. Circulating Epstein-Barr virus microRNAs associated with Hodgkin lymphoma prognosis [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 6682.
Abstract 6724: The role of human leukocyte antigen F adjacent transcript 10 in the tumorigenesis of nasopharyngeal carcinoma
Authors: Yusi Liang, Ngar Woon Kam, Zhuoyou YU, Ho Fun LEE
Journal: Cancer Research (2025)

Abstract Nasopharyngeal carcinoma (NPC) is a highly aggressive malignancy prevalent in Southern China and Southeast Asia related to Epstein-Barr virus (EBV) infection and genetic variations at the Human Leukocyte Antigen (HLA) locus. Human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10) is a ubiquitin-like protein modifier that can modulate its substrates by (1) mediating degradation via the 26S proteasome or (2) altering function through Fat10ylation. Previously studies have found FAT10 overexpression in various cancers, including gliomas and hepatocellular carcinoma, promoting tumorigenesis by altering cell proliferation, metastasis, and angiogenesis. Nevertheless, the precise role of FAT10 in NPC remains ambiguous. NPC public cohort GSE150430 showed high expression of FAT10 in NPC malignant cells. We also found overexpression of FAT10 in both NPC cell lines and patient-derived xenografts (PDXs) by real-time polymerase chain reaction (RT-PCR) and western blot at mRNA and protein level respectively. FAT10 overexpression in both NPC cell line C666-1 and immortalized normal nasopharyngeal cell line NP460 by lentiviral transduction increased proliferation proved by XTT assay, colony formation assay, and ki67 staining assay. Transwell migration and wound healing assay were performed in FAT10 overexpression cancer cell line and normal cell line to show the enhancement of migration ability. ROS production was also increased in these FAT10 overexpression cell lines by using the CellROX Green reagent. However, the western blot result showed that stemness ability cannot be changed in NP460. To conclude, our findings indicated that FAT10 may play a significant role in the tumorigenesis of NPC. Its underlying mechanism will be further explored. Citation Format: Yusi Liang, Ngar Woon Kam, Zhuoyou YU, Ho Fun LEE. The role of human leukocyte antigen F adjacent transcript 10 in the tumorigenesis of nasopharyngeal 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 6724.
Abstract 7370: Evaluations of lifestyle factors with biliary tract cancer risk in cohort studies including 742,906 Asian adults
Authors: Valerie Gunchick, Wei Zheng
Journal: Cancer Research (2025)

Abstract Biliary tract cancer (BTC) is a rare, aggressive malignancy and incidence has globally increased 76% from 1990 to 2017. BTC incidence is higher in Asia than Europe and North America, yet studies evaluating BTC risk in Asian populations are limited. Herein we evaluate tobacco smoking, alcohol consumption, BMI, physical activity, and dietary factors with BTC risk. We evaluated 742, 906 adults enrolled in 14 cohort studies as part of the Asia Cohort Consortium. Represented countries include China, Japan, Korea, Bangladesh, India, and Iran. Participants completed baseline surveys which collected demographics, lifestyle characteristics, and medical histories, and were followed to identify cancer diagnoses. Participants were removed due to data only on cancer death, a baseline history of cancer or stroke, among other reasons. Cox regression was used to estimate hazard ratios and 95% confidence intervals describing risk of first primary incident BTC in pooled cohort data. Models were adjusted for age, sex, education, cohort study, diabetes, and BMI, where applicable. Some evaluations were stratified by sex due to differing smoking and drinking behaviors. The analyzed cohort includes 451, 053 participants with a median age of 54 years, follow-up time of 15.0 years, and 1, 300 incident BTC cases. More men than women reported ever smoking or drinking (76.9% vs 7.0%, 63.3% vs 8.0%, respectively). Alcohol consumption was positively associated with BTC risk in men [HR (95% CI) comparing &amp;gt;=60 to 0 grams/day was 1.48 (0.99-2.20), p-trend=0.02]. In both sexes, duration of smoking was positively associated with BTC risk [comparing &amp;gt;40 to 0 years: 1.40 (0.81-2.43), p-trend=0.008] as was high BMI [comparing ≥27.5 to 18.5-22.9: 1.36 (1.11-1.66), p-trend=0.002]. Physical activity was not associated with BTC risk [comparing moderate to minimal activity: 1.00 (0.77-1.28), p-trend=0.76]. Given that our study suggests that obesity, alcohol, and smoking may play an important role in the etiology of BTC, mitigating these conditions could combat the rising incidence of this fatal malignancy. Future plans include dietary evaluations, study-specific estimates combined with meta-analysis, and sensitivity analysis studying BTC death. Citation Format: Valerie Gunchick, Wei Zheng. Evaluations of lifestyle factors with biliary tract cancer risk in cohort studies including 742, 906 Asian adults [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 7370.
Abstract 6968: Targeting overexpressed NEK2 kinase in esophageal adenocarcinoma
Authors: Lei Chen, Heng Lu, Farah Ballout, Wael El-Rifai, Oliver Gene McDonald, Dunfa Peng
Journal: Cancer Research (2025)

Abstract The incidence of esophageal adenocarcinoma (EAC) has rising rapidly during the past four decades in the US and Western countries, becoming the dominant type of esophageal cancer and a significant clinical challenge. However, the prognosis of EAC patients is still poor with 5-year overall survival rate about 20%. There is an urgent need to identify novel therapeutic targets associated with EAC biology. NEK2 is a serine/threonine protein kinase of NEK (NIMA related kinase) family which has 11 members, NEK1-NEK11. NEK2 is frequently overexpressed in human cancers, associated with tumor progression and drug resistance. We detected the overexpression of NEK2 in both mRNA and protein levels in EAC cell lines and primary EAC tissues using qRT-PCR, western blotting, immunohistochemistry. Functionally, we demonstrated that overexpression of NEK2 in EAC cells promoted tumor cell growth. Targeting NEK2 using specific siRNAs and a recent NEK2 specific inhibitor NBI-961 in EAC cells significantly inhibited EAC tumor growth in vitro and in vivo in a xenograft mouse model. RNA-seq analyses indicate that NEK2 inhibition using NBI-961 impaired important signaling pathways such as EMT, IL6-JAK -STAT3, mTOR1 and DNA repair, and enhanced interferon alpha response pathway in EAC cells. Our data suggests that targeting frequently overexpressed NEK2 in EAC is a promising approach. Citation Format: Lei Chen, Heng Lu, Farah Ballout, Wael El-Rifai, Oliver Gene McDonald, Dunfa Peng. Targeting overexpressed NEK2 kinase in esophageal adenocarcinoma [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 6968.
Abstract 4669: Prognostic value of postoperative circulating tumor DNA in patients with resectable hepatocellular carcinoma
Authors: Van-Anh Nguyen Hoang, Dao Nguyen Vinh, Giang Hoang Vu, Duy Sinh Nguyen, Hoa Giang, Hoai-Nghia Nguyen, Lan N. Tu
Journal: Cancer Research (2025)

Abstract Background: Hepatocellular carcinoma (HCC) is endemic in Asia, particularly Vietnam due to the prevalence of hepatitis B virus infection. Liver resection is the first-line treatment but prognosis remains poor with a high relapse rate. Current methods including imaging and serum tumor biomarkers have suboptimal accuracy to monitor tumor burden and predict relapse. Method: In this prospective study, sixty HCC patients who were eligible for curative-intent liver resection were recruited. Genomic DNA isolated from primary tumor tissues and paired white blood cells were subjected to targeted sequencing of 95 cancer-related genes to profile tumor-derived mutations. Top-ranked mutations specific to each individual were then used to track the presence of circulating tumor DNA (ctDNA) in serial plasma samples. Results: The most frequently mutated genes in our cohort were TP53 (42.4%), TERT promoter (39.0%), CTNNB1 (23.7%), and AXIN1 (22.0%). TP53 R249S was the major hotspot found in 8.5% of the patients. Mutations in TERT promoter were significantly more prevalent in hepatitis C- than hepatitis B- infected patients, while CTNNB1 was not mutated in those with no virus infection. On average, 4 mutations were selected to track ctDNA in plasm samples. Pre-operative detection rate of ctDNA was 96.6%, higher than AFP (57.6%). Post-operative ctDNA positivity, both at the landmark time point and during surveillance, was the strongest independent predictor of disease-free survival (HR: 17.9, 95% CI: 5.9 - 54.1, p&amp;lt;0.001). ctDNA detection could predict clinical relapse with sensitivity and specificity of 82.8% and 96.0% respectively, and the lead time of up to 7.3 months. This outperformed all serum tumor biomarkers: AFP, AFP-L3, and PIVKA-II. Conclusion: Our simplified and cost-effective assay enabled longitudinal ctDNA monitoring for early relapse detection and predict disease-free survival in HCC patients. This study also provided the first mutation spectrum of Vietnamese HCC that could be helpful to uncover the multifactorial etiology of the disease. Citation Format: Van-Anh Nguyen Hoang, Dao Nguyen Vinh, Giang Hoang Vu, Duy Sinh Nguyen, Hoa Giang, Hoai-Nghia Nguyen, Lan N. Tu. Prognostic value of postoperative circulating tumor DNA in patients with resectable hepatocellular 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 4669.
Abstract 4685: Targeting fatty acid oxidation improves radiation sensitivity in glioblastoma
Authors: Tingting Huang, Kenneth Austin, Todd W. Miller, Kelli B. Pointer
Journal: Cancer Research (2025)

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival of less than two years. A significant barrier to effective treatment is GBM's resistance to standard therapies, including radiation. This resistance is partially attributed to glioblastoma cancer stem cells (GSCs), a subpopulation with self-renewal capacity and the ability to regenerate all tumor components. Alterations in metabolic pathways, including fatty acid metabolism, are critical to GSC-mediated resistance. While fatty acid metabolism is known to be upregulated in GBM, its specific role in radiation-resistant GSCs remains poorly understood. Here, we investigated the impact of fatty acid metabolism inhibition on GSC radiation sensitivity. Methods: Two human GBM cell lines were treated for 72 hours with perhexiline, a carnitine acyltransferase 1a/b inhibitor, or vehicle control. The IC25 was determined using the SRB assay and validated with cell counts. Cells were subsequently treated with the IC25 concentration of perhexiline and irradiated with a single dose of either 0 Gy or 8 Gy. Sphere formation assays and immunoblotting for stemness markers were performed. All experiments were conducted in triplicate for statistical rigor. Results: The IC25 for perhexiline was determined to be 3 μM. Sphere formation assays using 3μM perhexiline combined with radiation revealed a significant reduction in both sphere number (p &amp;lt; 0.0001) and sphere size (350 μm vs. 125 μm). Immunoblotting demonstrated a decrease in stemness markers CD44 and nestin following drug treatment compared to vehicle control. Conclusion: These findings suggest that perhexiline, an FDA-approved drug, enhances radiation sensitivity in GBM by targeting GSCs. The observed reduction in sphere formation and stemness marker expression highlights its potential as a GSC-directed therapy. Further studies are warranted to explore the therapeutic potential of perhexiline in overcoming radiation resistance and improving outcomes for GBM patients. Citation Format: Tingting Huang, Kenneth Austin, Todd W. Miller, Kelli B. Pointer. Targeting fatty acid oxidation improves radiation sensitivity in glioblastoma [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 4685.
Abstract 6688: Differential serum mirnas in obese and diabetic African American colon adenoma patients
Authors: Hassan Brim, Adeyinka O. Laiyemo, Hassan Ashktorab
Journal: Cancer Research (2025)

Abstract Background: Metabolic syndrome, characterized by obesity, diabetes, and other metabolic disturbances, is associated with an increased risk of colon cancer. There is a critical need for assays that can detect biomarkers to enable risk stratification, early diagnosis, and prevention of colon adenomas and colorectal cancer. Serum miRNAs are emerging as promising biomarkers for this purpose. Aim: The purpose was to elucidate the role of miRNAs in the pathophysiology of colon adenomas in the context of obesity and diabetes. Methods: We used serum samples from age- and gender-matched African Americans (n=18 per group) to ensure that the comparison of miRNA expression was not confounded by age or gender differences. The groups included patients without adenomas (Normal), patients with adenomas and obesity, and patients with adenomas and diabetes. RNA extraction and miRNA sequencing was rigorous, utilizing the miRNeasy Serum/Plasma Kit and Lexogen Small RNA-Seq Library Prep Kit, respectively. Illumina NextSeq 500 sequencing provided high coverage (15 million reads per sample). The alignment to the UCSC hg38 human genome and the use of the DESeq2 R package for differential expression analysis ensured robust statistical evaluation of miRNA expression changes. We identified miRNAs with significant fold changes (log2 FC ≥ 2 or ≤ -2) and p-values &amp;lt; 0.05.Results: In the Adenoma-Obese group, miR-455, miR-219b, miR-34a, miR-378a, miR-485, and miR-133b showed significant associations with obesity-related metabolic dysregulation. Notably, miR-34a, involved in cell cycle and apoptosis regulation, was upregulated, highlighting its role in obesity-related cancer pathogenesis. In the Adenoma-Diabetic group, miR-455 was upregulated, suggesting its involvement in insulin resistance and adenoma progression, while miR-219b was downregulated, potentially reflecting a compensatory response to hyperglycemia. Ingenuity Pathway Analysis (IPA) revealed that these miRNAs are linked to pathways involved in cancer, diabetes, and lipid metabolism. Key pathways, including insulin signaling, Wnt/β-catenin, and mTOR, underscore the interplay between metabolic disorders and colorectal adenoma progression. Conclusion: This study highlights distinct miRNA expression profiles associated with adenoma development in obesity and diabetes. miR-34a, miR-378a, and miR-455 emerged as potential biomarkers and therapeutic targets. Future research should validate these findings in larger cohorts to refine their utility in clinical applications. Citation Format: Hassan Brim, Adeyinka O. Laiyemo, Hassan Ashktorab. Differential serum mirnas in obese and diabetic African American colon adenoma patients [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 6688.