bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1970: Preclinical candidate TQB3824, a small molecule inhibitor of CDC7, shows strong antitumor efficacy in colorectal and pancreatic tumor models
Authors: Li Gang , Zhang Xiquan , Yang Ling , Tian Xin , xiong Zhong , Hu Lihong , xia Yuanfeng , chan Chi-chung , Ding Charles Z. , Chen Shuhui 
Published: July 2021

Abstract
Objective: Cell division cycle 7 (CDC7), a receptor serine/threonine kinase which features high-affinity with protein DBF4, plays an important role in DNA replication and DNA damage response via MCM2 phosphorylation. CDC7 has been reported to be up-regulated by about 50% in various human cancers and is being investigated as a therapeutic target in clinical trials. The purpose of this study is to investigate the in-vitro and in-vivo antitumor activities of TQB3824, a small molecule of CDC7 kinase inhibitor, in preclinical models with CDC7 overexpression.
Method: Kinase inhibition activities of TQB3824 were determined with CDC7/DBF4 kinase assays. Cellular anti-proliferative activities were evaluated in COLO205 cell line and NCI-H226 cell line, which features CDC7 overexpression and no CDC7 expression, respectively. Three CDX models, colorectal cancer COLO205/SW620 and pancreatic cancer CAPAN-1 with KRAS mutation, were used to test the efficacy of TQB-3824 in vivo.
Result: TQB3824 showed potent activities in both kinase inhibition and COLO205 cell anti-proliferation, with IC50 of 2.9 nM and 14.5 nM, separately. In contrast, TQB3824 showed much weaker anti-proliferative activity in NCI H226 cells with IC50 of 8154 nM. TQB3824 displayed strong antitumor efficacy in CDC7 highly expressed colorectal cancer CDX model COLO205 (TGI = 77% @5 mpk, BID), SW620 CDX model (TGI = 100% @5 mpk, BID), and pancreatic cancer CAPAN-1 CDX model (TGI = 115% @6 mpk, BID).
Conclusion: We have identified a novel potent CDC7 inhibitor TQB3824, which shows high antitumor efficacy in CDC7 overexpressed solid tumor models. TQB3824 represents a promising clinical candidate for treating solid tumors with high CDC7 expression.
Citation Format: Gang Li, Xiquan Zhang, Ling Yang, Xin Tian, Zhong xiong, Lihong Hu, Yuanfeng xia, Chi-chung chan, Charles Z. Ding, Shuhui Chen. Preclinical candidate TQB3824, a small molecule inhibitor of CDC7, shows strong antitumor efficacy in colorectal and pancreatic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1970.
Abstract 202: Identification of survival associated hub genes in prostate cancer patients from the TCGA database
Authors: Reyes Niradiz , Tiwari Raj , Geliebter Jan 
Published: July 2021

Abstract
Background: Prostate cancer is the most frequently diagnosed malignancy and the fourth leading cause of cancer-related death in the global male population. Although the disease has a relatively low mortality rate with some patients surviving for 10-20 years after treatment, others respond poorly to treatment and die of metastatic disease within 2-3 years. Therefore, there is an urgent need to develop strategies to identify patients with clinically significant prostate cancer requiring aggressive treatment to improve survival, while sparing others unnecessary side effects. The purpose of this study was to identify survival associated genes in prostate cancer patients from the TCGA database using bioinformatics tools.
Methods: Data from prostate cancer patients in the TCGA database were divided into two study groups: a high and a low expression group, relative to the median expression. The Gene Expression Profiling Interactive Analysis (GEPIA2) tool was used for the identification of the most differential survival genes. Metascape bioinformatics tool was subsequently used for clustering of genes based on processes, pathway enrichment analysis, and construction of Protein-Protein Interaction (PPI) network. Metascape was also used for molecular Complex Detection (MCODE) to identify the genes with the highest degree of connection, known as hub genes, and to screen modules of the PPI network.
Results: Bioinformatics analysis allowed the identification of 361 genes whose expression levels were significantly associated with overall survival in prostate cancer patients from the TCGA. Survival associated genes were primarily enriched in mRNA processing, DNA repair, ncRNA processing, DNA replication, macromolecule methylation, among others. The 12 most connected genes were selected as hub genes and Kaplan-Meier analysis was used to verify survival associated with this set of genes. Hub genes included several splicing factors and components of the processing machinery of cellular pre-mRNAs.
Conclusions: These hub genes may reveal basic mechanisms underlying the development of clinically relevant prostate cancer and contribute to the identification of novel markers for prognosis of this cancer.
Citation Format: Niradiz Reyes, Raj Tiwari, Jan Geliebter. Identification of survival associated hub genes in prostate cancer patients from the TCGA database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 202.
Abstract 2053: Molecular characterization of BRCA1c.5339T&gt;C missense mutation in DNA damage response of triple-negative breast cancer cells
Authors: Lee Jeong Dong , Kim Min Hwan , Choi Yeon A , Ryu Won-Ji , Han Hyun Ju , Choi Ae Ran , Kim Tae Yeong , Sohn Joo Hyuk 
Published: July 2021

Abstract
Purpose Recent studies re-classified the c.5339T-&gt;C; p.Leu1780Pro (L1780P) BRCA1 missense mutation as “likely pathogenic” in ACMG classification, which shows high prevalence in Korean population. This study aims to reveal the molecular mechanisms and therapeutic relevance of BRCA1 L1780P mutation in DNA damaging response of triple-negative breast cancer (TNBC) cells.
Method We established MDA-MB 231 and HCC1937 TNBC cell lines expressing BRCA1 wild-type and BRCA1 L1780P by stable transfection of plasmid DNAs. We performed cell proliferation assays of the TNBC cell lines with treatment of olaparib and carboplatin. We compared the protein and mRNA expression level of RAD51 in BRCA1 wild-type and L1780 transfected TNBC cell lines by western blot and RT-PCR, and BRCA1-mediated DNA damaging responses were evaluated by immunofluorescence staining of RAD51 upon olaparib and carboplatin treatment. The growth inhibitory potential of RAD51 inhibitor, RI-1 was tested in BRCA1 L1780P transfected TNBC cell lines.
Results BRCA1 L1780P transfected TNBC cells showed higher migration and invasion capacity, as well as increased sensitivity to olaparib and carboplatin compared to BRCA1 wild-type transfected cells. The induction of RAD51 expression on carboplatin treatment was significantly decreased in BRCA1 L1780P TNBC cells compared with BRCA1 wild-type cells. BRCA1 L1780P transfected TNBC cells showed also showed reduced nuclear RAD51 foci formation on carboplatin and olaparib treatment. The molecular interaction between p-BRCA1 and ATM was decreased by BRCA1 L1780P introduction in TNBC cells, suggesting BRCA1 L1780P mutation disrupts binding of p-BRCA1-ATM. In a cell proliferation assay, BRCA1 L1780P transfected TNBC cells were highly sensitive to RAD51 inhibitor (IC50 = 4.15μM).
Conclusion This study shows BRCA1 L1780P mutation causes defects in DNA damage responses of TNBC cells by disrupting molecular interaction between p-BRCA1 and ATM, resulting in RAD51 downregulation. The combinatory inhibition of RAD51 and PARP is a candidate strategy for TNBCs with BRCA1 L1780P mutation.
Keywords: Triple-negative Breast Cancer; BRCA1 L1780 Mutation; Homologous Recombination Deficiency; RAD51
Citation Format: Jeong Dong Lee, Min Hwan Kim, Yeon A Choi, Won-Ji Ryu, Hyun Ju Han, Ae Ran Choi, Tae Yeong Kim, Joo Hyuk Sohn. Molecular characterization of BRCA1c.5339T&gt;C missense mutation in DNA damage response of triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2053.
Abstract 2073: Co-Targeting PARP and ATR in biliary tract cancer
Authors: Nam Ah Rong , Jin Mei Hua , Oh Kyoung-Seok , Seo Hye Rim , Kim Jae-Min , Bang Ju-Hee , Yoon Jeesun , Kim Tae-Yong , Oh Do-Youn 
Published: July 2021

Abstract
Background: Targeting DNA damage response (DDR) has potential anti-tumor effects in diverse cancer types. Homologous-recombination DDR gene mutations are found in 28.9% of biliary tract cancer (BTC). We aimed to evaluate the anti-tumor effects of olaparib (PARP inhibitor) with or without ceralasertib (ATR inhibitor) in BTC.Methods: Ten BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1079, SNU1196, HuCCT-1, TFK-1, SNU2670, and SNU2773) were tested to evaluate the anti-tumor effects of olaparib alone and in combination with ceralasertib. MTT assay, colony formation assay, cell cycle analysis, western blot, comet assay and co-culture with human PBMC were used as experimental methods. Tumor xenograft model was established to test olaparib with or without ceralasertib in vivo.Results: Olaparib alone showed moderate anti-proliferative effects in all BTC cells and increased p-ATR and PD-L1 expression. Olaparib plus ceralasertib showed synergistic anti-proliferative effects and led to DNA damage breaks in vitro. Ceralasertib also downregulated PD-L1 level through p-STAT3 and YAP pathway with or without human PBMC conditions. In SNU478-xenograft models, Olaparib plus ceralasertib combination significantly suppressed tumor growth and downregulated PD-L1 and YAP, compared with monotherapy. It also effectively reduced CXCR2 and CXCR4 expression. Conclusion: Combination of olaparib plus ceralasertib showed potent anti-tumor effects in BTC cells. This study could provide the preclinical evidence of development of PARP and ATR dual inhibition in BTC patients. Clinical trial using olaparib and ceralasertib combination in advanced BTC is ongoing (ClinicalTrials.gov Identifier: NCT04298021).
Citation Format: Ah Rong Nam, Mei Hua Jin, Kyoung-Seok Oh, Hye Rim Seo, Jae-Min Kim, Ju-Hee Bang, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. Co-Targeting PARP and ATR in biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2073.
Abstract 2103: Distinct methylation patterns correlate with unique clinical and genomic profiles of brainstem gliomas
Authors: Chen Lee H. , Pan Changcun , Wang Sizhen , Yan Hai , Zhang Liwei 
Published: July 2021

Abstract
Gliomas of the brainstem and surrounding regions are devastating brain tumors with the highest mortality rates among all cancers. The locations of tumors make surgical resection difficult due to the risk of perioperative mortality. To understand the genetics and molecular biology of this disease, we performed a comprehensive study, combining epigenetic and genomic analyses with clinical features on 126 brainstem gliomas, including 33 diffuse intrinsic pontine gliomas. Based on DNA methylation data, we identified four distinct clusters named H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. Most of the tumors within H3-Pons and H3-Medulla harbored H3F3A mutations, but tumors in these two clusters use different escaping mechanisms for DNA damage response pathway. Most of the tumors in H3-Pons showed TP53 mutations, while H3-Medulla contain PPM1D mutations. We also analyzed the lengths of telomeres in these tumors by whole genome sequencing data, showing striking difference between clusters, suggesting the mechanisms of telomere maintenance differ between different subtypes of brainstem gliomas. Structural variations and alternative splicing based on RNA sequencing demonstrated possible different transcriptome profiling in methylation clusters, and pathway analysis showed different mechanisms in these samples. Our findings suggest that the integration of DNA methylation data into diagnosis could be utilized to better understand brainstem glioma and better defining the classification, therefore guiding future clinical management of patients.
Citation Format: Lee H. Chen, Changcun Pan, Sizhen Wang, Hai Yan, Liwei Zhang. Distinct methylation patterns correlate with unique clinical and genomic profiles of brainstem gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2103.
Abstract 2109: The bromodomain-containing protein ATAD2 promotes GR-mediated enzalutamide resistance in castration-resistant prostate cancer
Authors: De La Rosa Richard 
Published: July 2021

Abstract
The purpose of this study is to investigate how the activity of the glucocorticoid receptor (GR) is orchestrated to drive the development of enzalutamide resistance in metastatic, castration resistant prostate cancer (mCRPC). Enzalutamide (Enz) is the second-generation antagonist of the androgen receptor, the fuel for the development and progression of prostate cancer. Even though enzalutamide is an effective and well-tolerated treatment in a broad spectrum of patients with castration-resistant prostate cancer, almost all the patients become resistant to the drug eventually. One of the plausible mechanisms to account for the development of enzalutamide resistance is the activation of GR signaling. Upon Enz treatment, GR is upregulated, binds to the cis-regulatory elements of some AR target genes, activates the transcription of these downstream genes and thus circumvents the inhibitory effect of the AR antagonist on prostate cancer cell growth. Unfortunately, it is still unknown how GR-mediated enzalutamide resistance is controlled. Recently, a group of epigenetic regulators, bromodomain (BRD)-containing proteins, have been indicated to promote prostate cancer progression. They function as AR cofactors and dictate the transcriptional activity of the nuclear receptor in response to different ligands. Our prior work found that one of the BRD family members, called ATAD2, plays an essential role in orchestration of GR signaling in the presence of enzalutamide. ATAD2 is significantly elevated upon GR activation and positively regulates GR expression in return. Coimmunoprecipitation demonstrated that ATAD2 binds to GR in enzalutamide-resistant CRPC cells, and it is required for the GR-dependent transcriptional reprogramming in the presence of Enz. Most importantly, we demonstrated that CRPC cells that are Enz-refractory due to the activation of GR signaling become Enz sensitive when ATAD2 is depleted All these findings suggest that ATAD2 acts as a cofactor for GR to induce a gene expression pattern that results in Enz-refractory phenotype in CRPC cells. Our work will not only provide an in-depth insight into the mechanisms underlying enzalutamide resistance, but also lay the foundation for the development of novel therapeutic strategies targeting glucocorticoid receptor (GR) signaling to treat this lethal disease.
Citation Format: Richard De La Rosa. The bromodomain-containing protein ATAD2 promotes GR-mediated enzalutamide resistance in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2109.
Abstract 2118: Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia
Authors: Yang Hongbo , Zhang Hui , Luan Yu , Liu Tingting , Roberts Kathryn , Qian Mao-xiang , Zhang Bo , Yang Wenjian , Perez-Andreu Virginia , Xu Jie , lyyanki Sriranga , Kuang Da , Reshmi Shalini , Gastier-Foster Julie , Smith Colton , Pui Ching-Hon , Evans William , Hunger Stephen , Hunger Stephen , Platanias Leonidas , Relling Mary , Mullighan Charles , Loh Mignon , Yue Feng , Yang Jun 
Published: July 2021

Abstract
Inherited non-coding genetic variants confer significant disease susceptibility in many cancers. However, the molecular processes of by which germline variants contribute to somatic lesions are poorly understood. We performed targeted sequencing in 5,008 patients and identified a key regulatory germline variant in GATA3 strongly associated with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). By creating an isogenic cellular model with CRISPR-Cas9 system, we showed that this variant activated a strong enhancer that significantly upregulated GATA3 transcription, which in turn reshaped the global chromatin accessibility and 3D genome organization. Remarkably, this genotype switch induced a chromatin loop between the CRLF2 oncogene and a distal enhancer, similar to the somatically acquired super-enhancer hijacking event in patients. GATA3 genotype-related alterations in transcriptional control and 3D chromatin organization were further validated in Ph-like ALL patients. Finally, we showed that GATA3 directly regulates CRLF2 and potentiates the oncogenic effects of JAK-STAT signaling in leukemogenesis. Altogether, our results provide evidence for a novel mechanism by which a germline non-coding variant contributes to oncogene activation epigenetic regulation and 3D genome reprogramming.
Citation Format: Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Kathryn Roberts, Mao-xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga lyyanki, Da Kuang, Shalini Reshmi, Julie Gastier-Foster, Colton Smith, Ching-Hon Pui, William Evans, Stephen Hunger, Stephen Hunger, Leonidas Platanias, Mary Relling, Charles Mullighan, Mignon Loh, Feng Yue, Jun Yang. Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2118.
Abstract 2123: Chromatin profiling of glioblastoma tissues identifies core oncogenic dependency and therapeutic opportunities
Authors: Xu Liang , Chen Ye , Huang Yulun , Sandanaraj Edwin , Yu John S. , Lin Ruby Yu-Tong , Dakle Pushkar , Ke Xin-Yu , Chong Yuk Kien , Koh Lynnette , Mayakonda Anand , Nacro Kassoum , Hill Jeffrey , Huang Mo-Li , Gery Sigal , Lim See Wee , Huang Zhengyun , Xu Ying , Chen Jianxiang , Bai Longchuan , Wang Shaomeng , Wakimoto Hiroaki , Yeo Tseng Tsai , Ang Beng Ti , Müschen Markus , Tang Carol , Tan Tuan Zea , Koeffler Phillip H. 
Published: July 2021

Abstract
Background: Glioblastoma (GBM) is the most aggressive and therapy-refractory brain tumor in adults. Molecular profiling of GBM on the basis of gene expression, DNA methylation and genomic variations has advanced both cancer research and clinical diagnosis. However, the enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive.
Methods: Chromatin immunoprecipitation followed by sequencing analysis was applied to examine H3K27ac deposition and to map the active regulatory landscapes across 95 GBM biopsies and 12 normal brain tissues. RNA-sequencing analysis was performed to measure transcriptome and to classify transcriptional subtypes. Super-enhancer associated genes and master transcriptional factors were identified. Function of novel cancer associated genes was explored using both patient-derived GBM propagating cells and orthotopic xenograft models.
Results: Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of inter-tumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural and AC3-proneural. Subtype-specific enhancer domains contributed to transcriptional diversity and shaped subtype identity. Moreover, this study reveals novel oncogenic dependency of GBM on various super-enhancer-driven transcriptional factors and druggable targets (e.g., BRD4).
Conclusion: Through profiling of transcriptional enhancers, we provide clinically relevant insights into the molecular classification, pathogenesis and therapeutic intervention of GBM.
Citation Format: Liang Xu, Ye Chen, Yulun Huang, Edwin Sandanaraj, John S. Yu, Ruby Yu-Tong Lin, Pushkar Dakle, Xin-Yu Ke, Yuk Kien Chong, Lynnette Koh, Anand Mayakonda, Kassoum Nacro, Jeffrey Hill, Mo-Li Huang, Sigal Gery, See Wee Lim, Zhengyun Huang, Ying Xu, Jianxiang Chen, Longchuan Bai, Shaomeng Wang, Hiroaki Wakimoto, Tseng Tsai Yeo, Beng Ti Ang, Markus Müschen, Carol Tang, Tuan Zea Tan, Phillip H. Koeffler. Chromatin profiling of glioblastoma tissues identifies core oncogenic dependency and therapeutic opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2123.