bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2547: YAP1 associates with the EPHA3 receptor tyrosine kinase to promote prostate cancer progression
Authors: Al-Mathkour Marwah M. , Dwead Abdulrahman M. , Khazaw Kezhan , Cinar Bekir 
Published: April 2023

Abstract
Metastatic castration-resistant prostate cancer is lethal, and the mechanisms contributing to this deadly disease are largely unknown. The disparity in our knowledge poses a significant barrier to developing effective therapeutics against advanced prostate cancer in humans. Evidence suggests that the ephrin family of receptor tyrosine kinase signaling may play a critical role in the pathobiology of prostate cancer progression. However, the mechanism is elusive. Our initial study showed that YAP1, in concert with the TEAD1 transcription factor, regulated EPHA3 expression. However, the significance of EPHA3 signaling in prostate cancer remains elusive. Here we investigated the role of EPHA3 signaling in prostate cancer cells. We showed that the expression of EPHA3 correlated with YAP1 in prostate cancer clinical samples. We also showed that EPHA3 knockout reduced cell growth in 2D and 3D cultures. In addition, EPHA3 loss sensitized castration-resistant prostate cancer cells to enzalutamide. Moreover, EPHA3 knockout reduced the GTPase activity of RHOA compared to cells with EPHA3-WT, which coincided with reduced phospho-ERK1/2 levels. Consistently, EPHA3 knockout reduces phosphor-ERK1/2, similar to the inhibition of phospho-ERK1/2 by an inhibitor of ROCK1 (Rho-associated coiled-coil-containing protein kinase 1). Besides, EPHA3 knockout reduced the expression of EMT markers ZEB1/2 and the cancer stem cell marker CD44 compared to the wild type. Furthermore, the levels of EPAH3 transcripts were higher in high-grade PC of AA patients compared to other races. Finally, AA and Caucasian Americans (CA) PC cell lines differentially express the member of ephrin-A and ephrin-B receptors. These observations suggest that the YAP1-EPHA3 signaling is a viable therapeutic target for patients with advanced prostate cancer.
Citation Format: Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Kezhan Khazaw, Bekir Cinar. YAP1 associates with the EPHA3 receptor tyrosine kinase to promote prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2547.
Abstract 2552: A novel RIP1-mediated canonical WNT signaling pathway promoting colorectal cancer metastasis
Authors: Park Jong Kuk , Kang A-Ram , Kwon Jin-Hee 
Published: April 2023

Abstract
RIP1 (receptor interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. We herein reveal new potential roles of RIP1 in controlling WNT/β-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). Firstly, we show that WNT3A treatment sequentially increases the expression levels of RIP1 and β-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary cancer, and metastatic cancer indicate that elevated RIP1 expression might be related to β-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells to mice demonstrates that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicate that WNT3A treatment induces direct binding between RIP1 and β-catenin, and that this stabilizes the β-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via down-regulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhances WNT3A-induced RIP1 and β-catenin protein expression and binding, and this stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration/invasion of CRC cells in vitro. The results of an in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verify the direct binding of RIP1 and β-catenin. Finally, RIP1 expression can destroy the β-catenin-β-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-β-catenin pathway that contributes to CRC malignancy by promoting EMT.
Citation Format: Jong Kuk Park, A-Ram Kang, Jin-Hee Kwon. A novel RIP1-mediated canonical WNT signaling pathway promoting colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2552.
Abstract 2634: AMB302/GR1017, an antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor shows therapeutic potency in orthotopic glioblastoma PDX and bladder cancer models with FGFR3-TACC3 fusion
Authors: Min Byeongkwi , Shi Lily , Kim Hye Jin , Kim Sangwoo , Fan Beibei , Lv Cao , Sun Yajun , Her Nam-Gu , Song Paul , Qin Gang , Nam Do-Hyun 
Published: April 2023

Abstract
Background: FGFR3-TACC3 (F3-T3) fusion leads to FGFR3 kinase activation constitutively and acts as a driver mutation in several solid tumors. AMB302/GR1017 is a novel FGFR3 targeting ADC that was developed using the intelligent Ligase-Dependent Conjugation (iLDC) technologies from GeneQuantum (GQ) that provide high homogeneity, excellent druggability and high linker stability, and contains a topoisomerase 1 inhibitor as a payload. Based on the preclinical characterization, AMB302/GR1017 shows impressive anti-tumor activities against glioblastoma (GBM) and bladder cancer (BC) models with either FGFR3 amplification or F3-T3 fusion, and demonstrates the potential as a first-in-class FGFR3 ADC against FGFR3 active solid tumor indications.
Methods: in vitro anti-tumor effects and mechanism of action for AMB302/GR1017 were assessed on patients-derived cells with F3-T3 using a 3D-spheroid high throughput assay. in vivo anti-tumor effect of AMB302/GR1017 were assessed on F3-T3 fusion GBM orthotopic PDX model and several FGFR3+ or F3-T3 fusion BC models
Results: AMB302/GR1017 was generated by linking FGFR3 targeting antibody (AimedBio) with TopoIx (GQ), a next generation Topoisomerase 1 inhibitor via a cleavable linker using the iLDC technologies. In a 3D-spheroid high throughput assay system, AMB302/GR1017 showed significant anti-tumor activity against glioblastoma patients-derived cells (PDCs) in F3-T3 dependent manner, which is superior to chemical conjugate applying the same antibody and Dxd payload. Also, AMB302/GR1017 prolonged the survival of GBM orthotopic PDX models with F3-T3 fusion by 200 % and achieved complete tumor regression in RT112 BC model with F3-T3 fusion. AMB302/GR1017 treatments were well-tolerated up to 200 mg/kg in a mouse safety study.
Conclusion: AMB302/GR1017 showed robust anti-tumor efficacies in F3-T3 fusion and FGFR3 overexpression models derived from GBM and BC in vitro and in vivo. In addition, AMB302/GR1017 was well tolerated with no adverse effects in rodent model. Our data suggest AMB302/GR1017 has a potential therapeutic option as a first-in-class FGFR3 targeting ADC for GBM, BC, and other solid tumors with FGFR3 overexpression or alterations.
Citation Format: Byeongkwi Min, Lily Shi, Hye Jin Kim, Sangwoo Kim, Beibei Fan, Cao Lv, Yajun Sun, Nam-Gu Her, Paul Song, Gang Qin, Do-Hyun Nam. AMB302/GR1017, an antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor shows therapeutic potency in orthotopic glioblastoma PDX and bladder cancer models with FGFR3-TACC3 fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2634.
Abstract 2829: Acetyl-CoA Acetyltransferase 2 confers radioresistance by inhibiting ferroptosis and enhancing the phosphorylation of AKT-S473 in esophageal squamous cell carcinoma
Authors: Jinghua Heng , Enmin Li , Liyan Xu 
Published: April 2023

Abstract
Purpose: The overall efficacy of patients with esophageal squamous cell carcinoma (ESCC) is not high due to the lack of markers to evaluate concurrent chemoradiotherapy (CCRT) resistance, which is dominated by radiotherapy. The aim of this study is to identify a radioresistant protein from proteomics and explore its molecular mechanism.
Methods and Materials: The proteomic data of pre-treatment biopsy tissues of 18 ESCC patients with CCRT (complete response CR group, n = 8; incomplete response &lt;CR group, n = 10) was collected, combined with PXD021701 to explore the radioresistant candidate. Subsequently, immunohistochemistry of 126 paraffin embedded biopsies was used for validation. The ESCC cell models with overexpression, knockdown or knockout of Acetyl-CoA Acetyltransferase 2 (ACAT2) were applied for exploring its effects on radioresistance using clonogenic assay underwent ionizing radiation (IR). ROS, C11-BODIPY, Fer-1 (ferrostatin inhibitor) and western blotting analysis were employed to reveal the potential mechanism ACAT2 triggered after IR.
Results: Enrichment analysis of differentially expressed proteins (&lt;CR vs. CR) showed that the pathways of CCRT resistance molecules in ESCC were related to lipid metabolism, while the sensitive ones were mainly aggregated to immunity pathways. ACAT2 was selected from proteomics and verified as a risk factor of overall survival and a radioresistant factor among ESCC patients with CCRT or radiotherapy by immunohistochemistry. ACAT2 overexpression conferred ESCC cell resistance to IR treatment, whereas the ACAT2 knockdown or knockout ones were sensitive to IR. ACAT2 knockout cells were prone to produce ROS and enhance lipid peroxidation after IR, which was rescued by Fer-1. ACAT2 knockout also inhibited GPX4 and phosphorylation of AKT-S473 site after IR.
Conclusion: ACAT2 is negatively associated with the response of radiotherapy and prognosis of ESCC patients, suggesting ACAT2 as an effective therapy target to enhance radiosensitivity of ESCC. This work was supported by the National Natural Science Foundation of China (82273108 and 82173034), the Innovative Team Grant of Guangdong Department of Education (2021KCXTD005), the Science and Technology Special Fund project of Guangdong Province in 2021 (No. 210729156901797) and the 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (2020LKSFG07B)
Citation Format: Heng Jinghua, Li Enmin, Xu Liyan. Acetyl-CoA Acetyltransferase 2 confers radioresistance by inhibiting ferroptosis and enhancing the phosphorylation of AKT-S473 in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2829.
Abstract 3014: Association between HLA-KIR allele interaction combinations and density of T-cell subsets in colorectal cancer
Authors: Thomas Claire Elizabeth , Huyghe Jeroen , Ugai Tomotaka , Yin Hang , Takashima Yasutoshi , Buchanan Daniel D. , Qu Conghui , Hsu Li , Costa Andressa Dias , Gallinger Stephen , Grant Robert , Thomas Sushma , Ogino Shuji , Phipps Amanda I. , Nowak Jonathan , Peters Ulrike 
Published: April 2023

Abstract
Background: Germline genetic factors central to immunity, such as human leukocyte antigen (HLA) variants, have been associated with several immune-related phenotypes such as response to immune checkpoint inhibitors. However, HLA and killer-cell immunoglobulin-like (KIR) gene combinations, which may modulate immune function, have not been studied in relation to T-cell density in cancer.
Methods: This study was conducted within 3 well characterized epidemiologic studies that collected colorectal tumor tissue blocks (N=484). We profiled the in-situ T cell landscape of CRC using digital imaging, machine learning, and a customized 9-plex multiplexed immunofluorescence panel with antibodies directed against CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, and MKI67. HLA and KIR variants were imputed from genome-wide array datasets through SNP2HLA and KIR*IMP methods. We used multivariable ordinal logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between HLA-KIR activation/inhibition ligand combinations with quartile of T cell densities in CRC adjusting for age, sex, GWAS panel, and the first two principal components of ancestry.
Results: Presence of KIR2DL2+HLAC1+ and KIR2DS2+HLAC1+ combinations were associated with lower odds of greater CD3+CD8+ T-cell density quartile, however these findings were not statistically significant [OR = 0.73, 95% CI (0.52, 1.02), p-value = 0.067; OR = 0.74 95% CI (0.53, 1.04), p-value= 0.082, respectively]. There was no association between HLA-KIR combinations and CD3+CD4+ T-cell density quartile. Further results will examine HLA and KIR genes individually, as well as additional combination variables and more specific T-cell density subsets.
Conclusions: Further investigation is needed to determine if germline genetics related to immune profile plays a role in T-cell densities in CRC.
Citation Format: Claire Elizabeth Thomas, Jeroen Huyghe, Tomotaka Ugai, Hang Yin, Yasutoshi Takashima, Daniel D. Buchanan, Conghui Qu, Li Hsu, Andressa Dias Costa, Stephen Gallinger, Robert Grant, Sushma Thomas, Shuji Ogino, Amanda I. Phipps, Jonathan Nowak, Ulrike Peters. Association between HLA-KIR allele interaction combinations and density of T-cell subsets in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3014.
Abstract 3105: Design principle of heparanase inhibitors: A combined in vitro and in silico study
Authors: Zhang Yuzhao , Xiong Meijun , Chen Zixin , Seabra Gustavo , Liu Jun , Li Chenglong , Cui Lina 
Published: April 2023

Abstract
Heparanase (HPSE) is an endo-β-D-glucuronidase and the only known enzyme responsible for the cleavage of heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). The enzymatic activity of HPSE mediates ECM remodeling, regulates growth factors, and modulates related signaling pathways, thus HPSE has emerged as a novel therapeutic target for various diseases, including most types of cancers. In the last two decades, a number of HPSE inhibitors have been reported by several labs worldwide, with most of them belonging to the heparan sulfate mimics category. So far, few of the small molecule HPSE inhibitors have progressed into clinical trials and none has gained approval by regulatory agencies, leaving a blank in HPSE drug discovery. Here we present the discovery of a novel HPSE small molecule inhibitor by high-throughput screening using an ultrasensitive HPSE enzymatic detecting probe developed in our lab and provide the mechanisms of action behind the small molecule’s HPSE inhibitory activity. By doing a series of molecular dynamics (MD) simulations, we discovered the binding profiles on the derivatives of the lead compound. We summarized the essential structural features of the lead compound to provide insights into the design of future HPSE small molecule inhibitors.
Citation Format: Yuzhao Zhang, Meijun Xiong, Zixin Chen, Gustavo Seabra, Jun Liu, Chenglong Li, Lina Cui. Design principle of heparanase inhibitors: A combined in vitro and in silico study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3105.
Abstract 3246: Targeting Syk reprograms tumor-associated macrophages and enhances responses to immune checkpoint blockade and radiation therapy in high-risk neuroblastoma
Authors: Rohila Deepak , Park In Hwan , Pham Timothy , Jones Riley , Tamayo Pablo , Yu Alice , Sharabi Andrew , Joshi Shweta 
Published: April 2023

Abstract
Neuroblastoma (NB) is the most common extracranial solid malignancy in children. As leading regulators of inflammation and tumor progression, tumor associated macrophages (TAMs) have gained major interest as immunotherapeutic targets in NB. Hence targeting or “re-educating” tumorigenic macrophages towards an immunostimulatory phenotype might improve responses to immunotherapy in this childhood cancer. Spleen tyrosine kinase (Syk) has recently been identified by our group as a novel immune-oncology target. We found that Syk is abundantly present in TAMs infiltrated in MYCN and non-MYCN amplified neuroblastoma tumors. Furthermore, genetic deletion or pharmacological inhibition of Syk markedly impaired neuroblastoma tumor growth. This effect was facilitated by macrophages that became immunogenic in the absence of Syk, skewing the suppressive tumor microenvironment towards immunostimulation and activating antitumor immune responses. Moreover, combining Syk inhibitor, R788 along with anti-PDL1 mAb and radiation provided a synergistic effect leading to complete tumor regression and durable anti-tumor immunity in aggressive MYCN-and non-MYCN-driven murine neuroblastoma tumor models. Collectively, our findings demonstrate the importance of Syk inhibitor, R788, in enhancing the anti-tumor immune responses in NB and support the clinical evaluation of R788 either alone or together with radiation and immune check point inhibitors as a potential treatment strategy for NB.
Citation Format: Deepak Rohila, In Hwan Park, Timothy Pham, Riley Jones, Pablo Tamayo, Alice Yu, Andrew Sharabi, Shweta Joshi. Targeting Syk reprograms tumor-associated macrophages and enhances responses to immune checkpoint blockade and radiation therapy in high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3246.
Abstract 3305: Clinical significance of circZKSCAN1 RNA in human hepatocellular carcinoma
Authors: Bang Minji , Kim Gyeonghwa , Hwangbo Eun , Jeon Mi Yeon , Hur Keun 
Published: April 2023

Abstract
Circular RNAs (CircRNAs) are type of noncoding RNAs without 5’ caps and 3’ tails that has been created by back splicing of mRNA. Recently, circRNAs are identified in many types of cancers, and its function has been elucidated as multiple miRNAs sponge. Hepatocellular carcinoma (HCC) is the most common type of malignancies. The incidence and mortality of HCC have been on the rise in recent years. Thus, it is necessary to identify further molecular mechanisms of HCC initiation and progression. In this study, we aim to investigate the clinical relevance of circRNAs encoded by the ZKSCAN1 (Zinc finger protein with KRAB and SCAN domains 1) gene in HCC.We analyzed clinical specimens from 100 pairs of HCC and corresponding normal liver (NL) tissues. Total RNAs were isolated from clinical tissues using qiagen kit. CircRNAs (circZKSCAN1) derived from ZKSCAN1 gene. The expression levels were determined by quantitative real-time PCR (qRT-PCR), and its expression was normalized with GAPDH. In addition, we analyzed the correlation between circZKSCAN1 expression and various clinicopathological features of HCC patients.CircZKSCAN1 expression was significantly down-regulated in HCC tissues compared to corresponding NL tissues (P&lt;0.001). In HCC patients, circZKSCAN1 expression was gradually suppressed according to state of malignant progression (P&lt;0.010). Further correlation analysis showed that circZKSCAN1 expression was significantly associated with T-stage (P=0.009), TNM stage (P=0.002), BCLC stage (P=0.0467), and survival (P&lt;0.001).Conclusively, we have determined clinical significances of circZKSCAN1 expression in HCC, which may provide clinical evidence for the potential of circZKSCAN1 as novel markers for diagnosis and predicting prognosis in HCC patients.
Citation Format: Minji Bang, Gyeonghwa Kim, Eun Hwangbo, Mi Yeon Jeon, Keun Hur. Clinical significance of circZKSCAN1 RNA in human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3305.
Abstract 336: Role of ST6GAL1 sialyltransferase in early stages of pancreatic cancer development
Authors: Bellis Susan L. , Chakraborty Asmi , Bhalerao Nikita , Marciel Michael , Hwang Jihye , Silva Austin 
Published: April 2023

Abstract
Increased cell surface sialylation is a prevalent feature of tumor cells. The addition of sialic acid (a negatively-charged sugar) to select surface receptors modulates the structure and function of these receptors, leading to changes in intracellular signaling and gene expression. Increased tumor cell sialylation occurs, in part, through the upregulation of sialyltransferases such as ST6GAL1, an enzyme that adds an α2-6 linked sialic acid to N-glycosylated proteins. ST6GAL1 is overexpressed in numerous malignancies, including pancreatic ductal adenocarcinoma (PDAC), and high expression correlates with a poor prognosis. Our group has shown that ST6GAL1 plays a causal role in promoting PDAC initiation and progression in tumor xenograft and genetically-engineered mouse (GEM) models. As one example, we developed a GEM model with conditional ST6GAL1 expression in the pancreas and crossed this line to the “KC” PDAC model, which expresses oncogenic Kras (KrasG12D). Mice with dual expression of ST6GAL1 and KrasG12D (”KSC” mice) exhibit greatly accelerated PDAC initiation, progression, and mortality when compared with KC mice. In light of ST6GAL1's known role in conferring progenitor-like cell characteristics, we postulated that ST6GAL1 activity contributes to PDAC initiation by fostering acinar to ductal metaplasia (ADM). During ADM, pancreatic acinar cells de-differentiate into ductal-like, progenitor cells and acquire greater proliferative potential as well as apoptosis resistance. Cells undergoing ADM are particularly vulnerable to Kras-dependent transformation. Using a variety of approaches and model systems including GEM organoids, 3D acinar cultures, acinar-like cell lines, and an in vivo assay for ADM, we uncovered a novel function for ST6GAL1 in promoting ADM. We further determined that high ST6GAL1 activity in acinar cells cooperates with KrasG12D to drive neoplasia. Finally, our studies suggest that the tumor-promoting effects of ST6GAL1 are mediated, at least in part, by ST6GAL1-mediated sialylation of EGFR. These collective results highlight a novel glycosylation-dependent mechanism involved in early stages of PDAC development.
Citation Format: Susan L. Bellis, Asmi Chakraborty, Nikita Bhalerao, Michael Marciel, Jihye Hwang, Austin Silva. Role of ST6GAL1 sialyltransferase in early stages of pancreatic cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 336.