bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5667: EZH2 inhibition targets B7-H3 in Myc amplified medulloblastoma
Authors: Shishido Katherine , Venkataraman Sujatha , Vibhakar Rajeev , Velpula Kiran , Asuthkar Swapna 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The most aggressive MB subtype Group 3, is characterized by Myc amplifications. However, targeting Myc has proven unsuccessful, necessitating alternative therapies for MB. The histone methyltransferase, enhancer of zeste homolog 2 (EZH2), is well-known for its role in catalyzing the tri-methylation of H3K27 (H3K27me3). Recent studies have demonstrated that EZH2 is overexpressed in Group 3 MB and that Myc and EZH2 regulate the expression of the B7 homolog 3 (B7-H3). As we previously showed the oncogenic functions of B7-H3 in Group 3 MB, this study aims to investigate the efficacy of EZH2 inhibition to reduce B7-H3 levels in an effort to improve treatment options and patient survival. Datamining studies conducted using MB patient datasets showed a positive correlation between EZH2 and B7-H3 transcripts. Additionally, we showed that inhibition of EZH2 using EPZ005687 in Myc-amplified MB cell lines downregulated B7-H3 and Myc expression. Furthermore, targeting EZH2 through shRNA and pharmacological inhibition reduced the viability and augmented apoptosis, as indicated by LDH, MTT, clonogenic, and FACS assays. We additionally tested the consequences of EZH2 inhibition on the C17.2, murine neural stem cells, and C17.2 NSC transformed with EZH2 oncogene (C17.2_EZH2OX). Furthermore, the C17.2_EZH2OXcells were susceptible to EPZ005687 treatment compared to C17.2 control cells, as demonstrated by MTT and FACS. Collectively, our study highlights the therapeutic benefits of targeting EZH2 in Myc-amplified MB cell survival.
Citation Format: Katherine Shishido, Sujatha Venkataraman, Rajeev Vibhakar, Kiran Velpula, Swapna Asuthkar. EZH2 inhibition targets B7-H3 in Myc amplified medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5667.
Abstract 5679: Application of a hypoxia metric to investigate tumor mutational burden and cancer cell immunogenicity in vitro
Authors: Khouzam Raefa Abou , Zeinelabdin Nagwa Ahmed , Sharda Mohak , Nawafleh Husam , Mahmood Ayda shah , Khan Munazza Samar , Venkatesh Goutham Hassan , Chouaib Salem , Rao Shyama Prasad 
Published: June 2022

Abstract
Hypoxia afflicts the microenvironment of solid tumors fueling tumor malignancy. Using an 8-gene in vitro hypoxia signature, we have recently shown that pancreatic cancer patients with highly hypoxic tumors experience worse survival and exhibit markers of an immunosuppressed microenvironment. Simultaneously, we obtained evidence of increased mutation count in more hypoxic tumors, which accommodates previous reports associating hypoxia with the regulation of tumor mutational burden (TMB) and genomic instability. These two features could enhance tumor immunogenicity by increasing neoantigen expression, enabling immune recognition and tumor eradication. In this work our aim is to further elucidate the underlying role of hypoxia in generating TMB and genomic instability, and how it contributes to cancer cells immunogenicity. To this end, we applied our recently identified 8-gene hypoxia signature to score the hypoxic response of different cancer cells, considering their median expression levels of the signature genes upon exposure to hypoxia (1% oxygen). The hypoxia score was then applied as a metric to distinguish between the highest and lowest scoring cells, enabling a novel approach for evaluating the intrinsic impact of hypoxia on immunogenicity. After twenty passages under hypoxic conditions (1% oxygen), scored cancer cells were subjected to whole exome sequencing (WES) using the Ion Chef System. Following data processing using appropriate bioinformatic tools, variants were called in the hypoxia-treated cells using their normoxic (21% oxygen) counterparts as controls. We first demonstrated that hypoxia induced an increase in TMB in all cell lines. More interestingly, higher scoring cells were found to display, on average, higher TMB than lower scoring cells, suggesting that cells that have a lower hypoxia score tend to be less mutable. Copy number alterations, mutational signature and neoantigen load predictions generated from the WES data will be discussed. The microarray analysis of transcriptomic data from these hypoxia-treated cells, as well as the relationship between the high TMB, high neoantigen load and increased activation of immune response pathways will also be illustrated.
Citation Format: Raefa Abou Khouzam, Nagwa Ahmed Zeinelabdin, Mohak Sharda, Husam Nawafleh, Ayda shah Mahmood, Munazza Samar Khan, Goutham Hassan Venkatesh, Salem Chouaib, Shyama Prasad Rao. Application of a hypoxia metric to investigate tumor mutational burden and cancer cell immunogenicity in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5679.
Abstract 5700: Increasing efficacy of iBET-151, a small molecule inhibitor of BET protein in combination with paclitaxel in gastric cancer
Authors: Kang Sun Kyoung , Cho Sang Woo , Kwon Woo Sun , Kim Tae Soo , Chung Hyun Cheol , Rha Sun Young 
Published: June 2022

Abstract
Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), which contributes to the development and progression of GC. BRD4 is one of the leaders for epigenetic regulation and is known to regulate the expression of oncogenes such as c-MYC, BCL-2, and CDK4. In a previous study, we evaluated the efficacy of iBET-151 in a large panel of GC cell lines and xenograft mouse models. We found that iBET-151 showed a modest growth-inhibitory effect in GC cells. Recent report showed, lowering the expression of BCL-2 and BCL-xL, which are the targets of BRD4, induces sensitivity to paclitaxel, frequently used antimitotic agent in GC. Therefore, we evaluate iBET-151 plus paclitaxel as a new combination treatment regimen for GC. The synergistic effect and possible mechanisms of iBET-151 with paclitaxel were evaluated in 49 GC cell lines or 10 GC organoids using cell proliferation assay, flow cytometry, western blotting, colony formation, and migration assays. We found that the addition of iBET-151 increased the sensitivity to paclitaxel alone treatment from 15% to 50% in approximately 70% (34/49) of GC cells. iBET-151 plus paclitaxel significantly promoted cell-cycle arrest at G1 or G2/M phase and increased sub-G1 phase and cleaved PARP expression, which correlates to increased cell death. Also, combined treatment suppressed c-Myc, Bcl-2, and Bcl-xL expression in AGS, YCC-1, YCC-32, and YCC-34. We found BET proteins were overexpressed in most patient-derived GC organoids whereas c-Myc, BCL-2, and BCL-xL were expressed at variable levels. We observed that there was a synergistic growth inhibition in 6 out of 10 (60%) organoids. The data suggests iBET-151 and paclitaxel have a synergistic effect not only in GC cell lines but also in GC organoids. In summary, our data show the combination of iBET-151 and paclitaxel resulted in markedly higher anti-tumor effects compared with either treatment alone for GC. With further studies to validate the efficacy and biomarker explorations, the combination of iBET-151 and paclitaxel represents a promising therapeutic strategy in GC.
Citation Format: Sun Kyoung Kang, Sang Woo Cho, Woo Sun Kwon, Tae Soo Kim, Hyun Cheol Chung, Sun Young Rha. Increasing efficacy of iBET-151, a small molecule inhibitor of BET protein in combination with paclitaxel in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5700.
Abstract 5702: Cancer-specific glycosylation regulated by epigenomic alteration in renal cell carcinoma
Authors: Kitazume Yoshiko , Arai Eri , Matsuda Atsushi , Ohara Kentaro , Maeshima Akiko Miyagi , Yoshida Teruhiko , Kuno Atsushi , Kanai Yae 
Published: June 2022

Abstract
Background and Aims: Cancer-specific glycosylation plays an important role in the development and progression of cancer. Epigenetics may contribute to forming cancer-specific glycosylation by regulating the expression of glycogenes. Although comprehensive analysis of epigenetics is routinely performed, comprehensive glycan analysis, especially using human clinical samples, has been limited due to technical underdevelopment. Our aims are to understand the significance of glycosylation and its epigenetic regulation on renal carcinogenesis and to identify cancer-specific glycosylation as a potential diagnostic marker and a novel therapeutic target.
Materials and Methods: Comprehensive glycomics and methylome analysis were performed by lectin microarray and Infinium HumanMethylation450 BeadChip on 50 non-cancerous renal cortex tissue (N) and 50 clear cell renal cell carcinoma (RCC) (T) microdissected from formalin-fixed and paraffin-embedded tissue samples.
Results: Compared to N samples, T samples showed higher fluorescence intensity for lectins recognizing mannose-type glycans, and lower intensity for lectins recognizing sialyl and fucosyl groups. In RCC, the metabolism of N-glycans may remain in an immature state. By hierarchical clustering using lectin microarray data, T samples were divided into Clusters A and B with significant differences in patients’ outcome. Increased high-mannose type N-glycan and core fucosylation and decreased sialylation were observed in T samples of Cluster A. According to these results, glycosylation profiles showed heterogeneity associated with patients’ outcome among RCCs, and immature N-glycan may be specific in some RCCs. Methylome analysis suggests that specific glycosylation profiles of RCCs may be induced by DNA methylation alteration on glycogenes. Association between DNA methylation and mRNA expression was confirmed on some glycogenes using real-time reverse transcription PCR. As a result of examining whether the signal intensity pattern of each lectin reflects the prognosis of clear cell RCC, we could identify the lectins that reflect the RCCs prognosis.
Conclusion: In RCC, the metabolism of N-glycans may remain in an immature state. The glycan profiles show heterogeneity among individual RCCs, and some of the specific glycan profiles may be associated with patients’ outcome. Cancer-specific glycan profiles may be regulated by epigenetic alteration of glycogenes.
Citation Format: Yoshiko Kitazume, Eri Arai, Atsushi Matsuda, Kentaro Ohara, Akiko Miyagi Maeshima, Teruhiko Yoshida, Atsushi Kuno, Yae Kanai. Cancer-specific glycosylation regulated by epigenomic alteration in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5702.
Abstract 5728: A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in NSCLC
Authors: Dorso Madeline 
Published: June 2022

Abstract
FOXA1 is a pioneer factor that is essential to steroid receptor function in hormone-dependent adenocarcinomas, including breast and prostate cancer. FOXA1 expression is also observed in other tumors of epithelial lineage such as non-small cell lung cancer (NSCLC), but whether and how it is required for tumor growth in these contexts is not known. Analyzing data from genome-scaled pooled loss-of-function screens, we identified and validated a subset of NSCLC cell lines with reduced cellular fitness following FOXA1 knockout. We performed a rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME) screen to nominate candidate factors that may cooperate with FOXA1 to mediate oncogenic transcription programs. This screen revealed a chromatin-localized interaction between FOXA1 and the glucocorticoid receptor (GR). Depletion of GR expression using shRNA or CRISPR/Cas9 suppressed the proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC models, suggesting GR specifically contributes to tumor growth in the FOXA1-dependent context. To assess the potential therapeutic utility of targeting the FOXA1-GR signaling axis, we employed two structurally distinct ligand antagonists of GR from ORIC Pharmaceuticals: ORIC-101, a steroidal antagonist, and OP-4954, a non-steroidal antagonist. Both antagonists inhibited dexamethasone stimulated GR-transactivation of a glucocorticoid response element (GRE)-luciferase reporter with equal potency. However, proliferation and colony formation of the FOXA1/GR-dependent NSCLC cells were only inhibited upon treatment with ORIC-101, and not OP-4954. Gene expression analysis uncovered a discrete set of GR target genes, including SFTPB, TRAF4 and SGK1, whose expression was reduced by ORIC-101 but unaffected or even induced by OP-4954. The specific inhibition of GR target gene expression and attendant induction of apoptosis by ORIC-101 suggest a hierarchy of GR targets relevant to the FOXA1/GR-growth program in NSCLC. Finally, we evaluated the in vivo therapeutic potential of ORIC-101 using NSCLC xenografts and found that single-agent ORIC-101 exhibited potent antitumor effects in these models. Taken together, these data establish a model of FOXA1-GR-dependent tumor growth amongst a subset of NSCLCs and demonstrate that effective blockade of this complex is a rational therapeutic avenue to be explored in the clinic.
Citation Format: Madeline Dorso. A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5728.
Abstract 5750: Quantification of histone methylation regulator-associated modification patterns was a potential biomarker for prognosis and associated with immunotherapy in gastric cancer
Authors: Kang Jiapeng , Yang Lu , Lin Jialin , Zhou Dan , Fang Canbin , Ye Feng , Tang Weiwei 
Published: June 2022

Abstract
Background: Histone methylation (HM) is an abundant form of histone modification and recent studies have highlighted it strongly related to tumorigenicity and progression. However, histone methylation modification patterns and potential roles in gastric cancer have not been systematically elucidated.
Method: In this study, we curated 53 histone methyltransferase regulators and 9 histone demethylase regulators. Identified histone methylation(HM)modification clusters based on the expression of 62 HM regulators. Principal component analysis (PCA) served to construct histone methylation score (HMScore) base on differential genes among three HM clusters. Evaluating the relationship between HMScore and clinical prognosis, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration and immunotherapy.
Results: We identified distinct three HM modification clusters in patients with gastric cancer based on the expression of 62 HM regulators, which were association with different clinical prognosis, biological pathways and tumor microenvironment characterization. Based on HMScore to quantitatively evaluate the histone methylation modification patterns in gastric cancer patients. We founded that patients with a low-HMScore group(score&lt;2.276) was association with poor prognosis. In addition, high-HMScore group(score≥2.276) displayed tumor mutation burden-high (TMB-H) and microsatellite instability-high (MSI-H), and correlation analysis indicated that HMScore was positively correlated with tumor mutation burden. Immune infiltration correlation analysis showed that HMScore strongly negative related to MDSC cell, mast cell and regulatory T cell. Survival analysis indicated that patients with TMB-H and high-HMScore were related to long clinical prognosis in gastric cancer. Moreover, patients with high-HMScore group had high abundance of PD-L1, and high-HMScore was confirmed sensitive response to immunotherapy in gastric cancer.
Conclusion: This study provided a new model to evaluate individual gastric cancer histone methylation modification patterns. HMScore was benefit to evaluate clinical prognosis value and guide strategies to improve treatment in gastric cancer.
Citation Format: Jiapeng Kang, Lu Yang, Jialin Lin, Dan Zhou, Canbin Fang, Feng Ye, Weiwei Tang. Quantification of histone methylation regulator-associated modification patterns was a potential biomarker for prognosis and associated with immunotherapy in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5750.
Abstract 5755: Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients
Authors: Gao Feng , Liu Xuejiao , Wang Xiaojuan , Wang Chunyang , Ma Tonghui , Yang Changsheng 
Published: June 2022

Abstract
BACKGROUND: Homologous recombination deficiency (HRD) is associated with tumorigenesis. Therapy directed toward HRD has been approved in breast and ovarian cancer, however, whether there is a chance of benefit for patients with other cancers remains unknown. Herein, we investigated the mutation characteristics of homologous recombination-related (HRR) genes in Chinese patients with sarcoma to explore possible benefit opportunities for sarcoma patients.
METHODS: The genetic landscape of HRR genes was assessed in 700 Chinese sarcoma patients with different subtypes including Rhabdomyosarcoma (RMS, n = 67), Liposarcoma (LPS, n = 58), Osteosarcoma (n = 34), Synovial sarcoma (n = 30), Leiomyosarcoma (n = 29), Ewing's sarcoma (EWS, n = 27), Angiosarcoma (n = 20), other rare (n = 375) and unknown subtypes (n = 60). Molecular profiles were performed by using next generation sequencing (NGS)-based Onco Panscan plus࣪ at Genetronhealth, a laboratory accredited by College of American Pathologists and Clinical Laboratory Improvement Amendments.
RESULTS: Among the 700 patients, the overall mutation frequency of HRR genes was 19.0%. Correspond to specific subtypes, the mutation frequency of HRR genes were higher in Leiomyosarcoma (27.6%, 8/29), Angiosarcoma (25.0%, 5/20) and LPS (17.2%, 10/58) compared with RMS (14.9%, 10/67), Osteosarcoma (14.7%, 5/34), Synovial sarcoma (13.3%, 4/30) and EWS (3.7%, 1/27). ATRX was the most commonly mutated gene (5.1%, n = 36) and was preferentially identified in Leiomyosarcoma (10.3%) and Angiosarcoma. (10.0%), followed by ARID1A (3.1%, n = 22), ATM (2.1%, n = 15) and FANCA/C/D2/E/F/G/L (1.7%, n = 12). The median tumor mutational burden (TMB) was 2.35 in patients with HRD and 0.94 in patients without HRD. Although BRCA1 and BRCA2 mutations were less common overall (1.1% and 0.7%), a significant proportion of BRCA1 and BRCA2 mutations was found in Angiosarcoma, Liposarcoma and Leiomyosarcoma (5.0%, 3.4% and 3.4%, respectively).
CONCLUSION: Our results reported the genetic landscape of HRR genes in Chinese sarcoma patients, providing a reference for the clinical application of PARP inhibitors.
Citation Format: Feng Gao, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Changsheng Yang. Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5755.
Abstract 5758: Characteristic profile of blood-based ctDNA suggests angiogenesis and immune escape in hepatocellular carcinoma
Authors: Yan Lin Chia , Miao Liu , Xue Hu , Li Huang Meng 
Published: June 2022

Abstract
Background: Circulating tumor DNA (ctDNA) is a type of DNA released from tumor cells captured in blood circulation system. It provides a noninvasive approach to interrogate a patient’s genomic landscape and actionable mutations with well application prospect. However, the difference of genomic profiles between tissue and ctDNA still brings confusions to related researches. Therefore, we tried to elucidate whether blood-based ctDNA has its own characteristic profile to reflect tumor status in hepatocellular carcinoma (HCC).
Methods: Tumor tissue and blood samples from 118 HCC patients of Xiangya Hospital Central South University, were analyzed using NGS (panel on 147 gene). NGS data from a Chinese population extended cohort (385 tissues and 79 blood samples) of HCC were used to validate the mutation characteristics. Data from HCC cohorts of The Cancer Genome Atlas (TCGA) was used to analyze the disease-free survival (DFS) of different mutations.
Results: In the hospital cohort, there were 9 high-frequency mutant genes in tissue and blood, including TP53 (74.58% vs 74.58%), MSH2(23.73% vs 8.47%), LRP1B (20.34% vs 23.73%), ATM (18.64% vs 13.56%), CTNNB1 (11.86% vs 13.56%) et.al which consistent with previous reports. There were 32 genes (74.04%) with a mutation frequency of more than 6% that were unique to blood samples. In extended cohort, the mutation profile was similar to the hospital cohort, in which 35 genes (52.24%) specific in ctDNA profile and 18 genes of them identical to the hospital cohort. Interestingly, when these ctDNA-specific genes were analysed by gene ontology, most genes were involved in angiogenesis. The prognostic analysis in ctDNA-specific genes showed that patients with higher level of MAP3K1 had worse DFS (p=0.028). In addition, the gene co-expression network analysis showed MAP3K1 and NOTCH1/2/3 expression had a significant positive correlation, that Notch family members were also belonged to the ctDNA-specific genes and associated with tumor immune escape.
Conclusions: The results showed the mutation characteristic of tissues and ctDNA in HCC, and suggest that angiogenic and tumor immune escape related ctDNA-specific genes might be able to predict recurrence risk independently of baseline tissue samples.
Citation Format: Lin Chia Yan, Liu Miao, Hu Xue, Huang Meng Li. Characteristic profile of blood-based ctDNA suggests angiogenesis and immune escape in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5758.