bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1725: Role of PRMT5 in neuroendocrine prostate cancer development
Authors: Nam Hye Seung , Deng Xuehong , Hu Chang-Deng 
Published: March 2024

Abstract
Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer responsible for an estimated 20-30% of castration resistant prostate cancer (CRPC) deaths. While NEPC can arise de novo, the majority of these cases emerge as treatment-induced NEPC (tNEPC). Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC.
Methods: Here we generated an in vitro cell culture model and mouse model to mimic the clinical conditions in androgen signaling inhibitor (ASI) or androgen deprivation treatment (ADT) We developed an in vitro cell culture and in vivo model to mimic the clinical conditions in enzalutamide-resistant prostate cancer. Regulation and role of protein arginine methyltransferase 5 (PRMT5) and its cofactor methylosome protein 50 (MEP50) were determined by treating cells and mice tumors with doxycycline inducible-shRNAs and catalytic inhibitors followed by analysis of cell viability, neurite growth, and effects on neuroendocrine related gene transcription. Pro-NEPC development effects were analyzed by immunofluorescence, immunohistochemical analysis, and western blot. PRMT5:MEP50-dependent methyltransferase activity was further validated by observing histone deposition levels via western blot and ChIP-qPCR. For clinical correlation, PRMT5 and MEP50 expression levels were comprehensively analyzed in both CRPC and NEPC patient prostate tissue samples.
Results: Our clinical and computational analyses have identified increased expression of PRMT5:MEP50 in NEPC. Overexpression of PRMT5 and MEP50 in prostate cancer cells is sufficient to induce neuroendocrine differentiation (NED) in prostate cancer cells. Gene depletion of PRMT5 and MEP50 prevented the NE phenotype induced by androgen receptor inhibition and resensitized the prostate cancer cells to ASI/ADT. PRMT5 and MEP50 facilitate chromatin modulation through the dimethylation of H4R3, which is highly correlated with the NED phenotype. Moreover, overexpression of PRMT5 and MEP50 in mouse prostate induces NEPC development, and gene downregulation can prevent NED in a xenograft mouse model. Elevated PRMT5 and MEP50 correlated with increased recurrence in prostate cancer patients receiving ADT and their recurrence probability after the treatment.
Conclusion: Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC.
Citation Format: Hye Seung Nam, Xuehong Deng, Chang-Deng Hu. Role of PRMT5 in neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1725.
Abstract 1742: A universal spike-in normalization strategy for CUT&RUN, CUT&Tag and ATAC-seq
Authors: Traynor Sarah , Townsley Bradley , Weber Julianna , Jelinek Mary Anne , Egan Brian , Delatte Benjamin 
Published: March 2024

Abstract
The development of simple and efficient genome-wide approaches has recently democratized the study of epigenetics. For instance, CUT&RUN and CUT&Tag were developed as fast and affordable alternatives to ChIP-seq, whereas ATAC-seq readily identifies regions of open chromatin. These methods are ideal to look for genome-wide alterations in chromatin structures but are only semi-quantitative and can miss global changes when performed without normalization spike-ins. In fact, many standard computational pipelines fail to detect a reportedly substantial global H3K27me3 decrease in the presence of GSK126, a therapeutic target for lymphoma and potent inhibitor of the EZH2 methyltransferase. To overcome this challenge, we developed a spike-in approach using Drosophila melanogaster nuclei for normalization of ATAC, CUT&RUN and CUT&Tag experiments using human cells. The addition of the spiked-in nuclei allowed for the detection of the expected global changes in open regions of chromatin (ATAC-seq), H3K27me3 (CUT&Tag), R-loops (CUT&Tag), EED and p53 binding (CUT&RUN) upon treatment of K562 cells with GSK126. By contrast, these same changes were all missed when omitting the spike-in nuclei. This streamlined spike-in normalization strategy can be easily applied to any number of cells and on a large variety of conditions.
Citation Format: Sarah Traynor, Bradley Townsley, Julianna Weber, Mary Anne Jelinek, Brian Egan, Benjamin Delatte. A universal spike-in normalization strategy for CUT&RUN, CUT&Tag and ATAC-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1742.
Abstract 1749: Esophageal adenocarcinoma single-cell resolution ecotypes and subtypes mediate chemoradiation resistance
Authors: Ye Rui , Qiao Yawei , Bai Shanshan , Sei Emi , Hu Min , He Jianzhong , Li Nan , Wang Yifan , Lopez Pablo , Zhang Wei , Ye Fei , Weston Brian , Coronel Emmanuel , Ross William , Ge Phillip , Manoop Bhutani , Navin Nicholas , Lin Steven 
Published: March 2024

Abstract
Esophageal adenocarcinoma (EAC) is an aggressive and lethal disease with a 5-year survival rate less than 20%. The current standard of care for locally advanced EAC patients is neoadjuvant chemoradiation (CRT) followed by surgery and the pathological response rate is low in clinic. An unresolved question is how the cancer cells and their tumor microenvironment (TME) mediate CRT resistance in EAC. To address this question, we performed single-cell RNA sequencing on 84 longitudinal samples from a cohort of patients (N=47) containing 20 good responders (GR) and 27 non-responders (NR). In total, we obtained 302,918 single cells which enabled us to delineate the phenotypic heterogeneity landscape in EAC at baseline, and identify reprogramming in both the immune and tumor cells during treatment that lead to CRT resistance. We identified 4 major cell type compartments in the EAC TME: lymphoid cells (T cells, NK cells, B cells, and plasma cells), myeloid cells (macrophages, neutrophils, dendritic cells, and mast cells), stromal cells (fibroblasts and endothelial cells) and epithelial cells. Our data shows that the TME enriched in lymphoid cells, including resident and effector memory CD8 T cells, follicular helper CD4 T cells, and B cells was associated with better CRT responses. Moreover, a significant myeloid cell infiltration was observed across most patients during CRT and the infiltrated macrophages from GR harbored a more pro-inflammation phenotype. In addition, we identified 4 major ecotypes of the TME cells and 4 major expression subtypes of the cancer cells. Notably, the interactions between TME ecotypes and cancer subtypes are significantly associated with CRT responsiveness. In summary, this study has provided valuable insights into the biology of EAC CRT response, and identified novel predictive biomarkers and actionable targets to enhance CRT efficacy.
Citation Format: Rui Ye, Yawei Qiao, Shanshan Bai, Emi Sei, Min Hu, Jianzhong He, Nan Li, Yifan Wang, Pablo Lopez, Wei Zhang, Fei Ye, Brian Weston, Emmanuel Coronel, William Ross, Phillip Ge, Bhutani Manoop, Nicholas Navin, Steven Lin. Esophageal adenocarcinoma single-cell resolution ecotypes and subtypes mediate chemoradiation resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1749.
Abstract 1807: New strategies to target the pseudokinase receptor PTK7 in the Wnt pathway
Authors: Borg Jean-Paul , Pierre Manon , Ganier Laetitia , Daulat Avais , Molliex Amandine , Duez Julien , Sanchez Maxime , Lallemand Etienne , Goncalves Anthony , Bollot Guillaume 
Published: March 2024

Abstract
Colorectal cancer (CRC) remains the second cause of death by cancer worldwide and its survival is currently estimated at 60%1. There is therefore a crucial need to identify biomarkers and new targets for therapy. In 90% of CRC, the Wnt/β-catenin pathway is constitutively activated due to mutations of β-catenin, APC (Adenomatous Polyposis Coli) or axin-12. These alterations cause an accumulation of β-catenin and lead to an over-transcription of target genes involved in tumorigenesis3-4. Studies of our team pointed out an overexpression of the Protein Tyrosine Kinase 7 (PTK7) in CRC, an event associated with metastatic development, reduced metastases-free survival, and resistance to chemotherapy. In CRC cells, the pseudokinase PTK7 has pro-metastatic and pro-migratory functions, and thus appears to be a promising new therapeutic target5-6. The role of PTK7 in the Wnt/β-catenin pathway has been demonstrated in several studies7-8. Our group identified β-catenin as a partner of PTK7. We selected a first series of small molecules inhibitors targeting PTK7/β-catenin interaction9. This strategy could represent, in the future, a new therapeutic strategy to inhibit CRC cell growth dependent on the Wnt signaling pathway. However, the compounds identified had weak activity, with an IC50 of around 10-25 mM. We have set up a new method with SYNSIGHT to select more potent chemical inhibitors targeting PTK7/β-catenin in CRC in order to counteract the Wnt/β-catenin signaling pathway deregulation. References: 1Colorectal cancer (Source : Globocan 2020); 2Cancer Genome Atlas Network. Nature. 2012; 3He, T. C. et al. Science. 1998; 4Tetsu, O. & McCormick, F. Nature. 1999; 5Lhoumeau, A.-C. et al. PLOS ONE. 2015; 6Lhoumeau, A.-C. et al. J. Immunol. 2016; 7Puppo, F. et al. EMBO Rep. 2011; 8Peradziryi, H. et al. EMBO J. 2011; 9Ganier, L. et al. ACS Chem. Biol. 2022; 10Daulat, A. M. & Borg, J.-P. Trends Cancer. 2017; 11Stamos, J. L. & Weis, W. I. Cold Spring Harb. Perspect. Biol. 2013.
Citation Format: Jean-Paul Borg, Manon Pierre, Laetitia Ganier, Avais Daulat, Amandine Molliex, Julien Duez, Maxime Sanchez, Etienne Lallemand, Anthony Goncalves, Guillaume Bollot. New strategies to target the pseudokinase receptor PTK7 in the Wnt pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1807.
Abstract 1809: Discovery of novel AXL and MER inhibitors as potential anticancer and immunomodulatory drugs
Authors: Hsieh Hsing-Pang , Li Mu-Chun , Yen Wan-Ching , Wu Su-Ying , Yeh Teng-Kuang , Kuo Ching-Chuan , Ueng Shau-Hua , Wu Han-Chung 
Published: March 2024

Abstract
In cancer progression, abnormal AXL expression can promote tumor growth, metastasis, and chemotherapy resistance, while MER can identify apoptotic cancer cells and induce immune suppression in the tumor microenvironment. Combining AXL and MER inhibitors could generate a synergistic effect, enhancing antitumor responses, and further suppressing resistance formed by monotherapy with AXL selective or MER selective inhibitors. According to the explicit function of AXL and MER, the development of dual AXL and MER inhibitors may provide tremendous advantages to cancer patients. Drawing on our experience in the discovery of an anti-EGFR and anti-HER2 clinical candidate, we introduced several AXL-active and MER-active pharmacophores into DBPR112. Furthermore, we modified the scaffold and the solubilizing groups to improve the drug-like properties. Our comprehensive structure-activity relationship study led to the discovery of several potent dual AXL and MER inhibitors. Among approximately 200 synthesized compounds, BPR5K230 demonstrated strong inhibitory activities against AXL and MER, along with favorable oral bioavailability (F% = 55%) and promising in vivo antitumor effects in various mouse xenograft models, including MDA-MB-231, 4T1, and MC-38 tumor models. BPR5K230 effectively addressed sorafenib resistance in the Hepa 1-6 model and exhibited significant synergistic antitumor effects when combined with an anti-PD-L1 antibody in the EMT-6 model. As a result, BPR5K230 represents a promising dual AXL/MER kinase inhibitor, and further preclinical evaluation is underway for its development as a potential anticancer and immune-modulating drug.
Citation Format: Hsing-Pang Hsieh, Mu-Chun Li, Wan-Ching Yen, Su-Ying Wu, Teng-Kuang Yeh, Ching-Chuan Kuo, Shau-Hua Ueng, Han-Chung Wu. Discovery of novel AXL and MER inhibitors as potential anticancer and immunomodulatory drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1809.
Abstract 1824: Hexadecanoic acid mediated cell cycle arrest involving inhibition of cell migration
Authors: Wright Sasha-gay A. , Aiken William , Asemota Helen , Foster Kimberly , Delgoda Rupika 
Published: March 2024

Abstract
The Caribbean region accounts for the highest incidence and mortality rates of prostate cancer in the world. This warrants the need for targeted therapy as currently the most prevalent and effective option include chemotherapeutic drugs. Previous studies showed that an enriched sample extracted from the Jamaican Round Leaf yellow yam exhibited antiproliferative effects on DU145 prostate cancer cells. Based on the results obtained, this present study aims at exploring the underlying mechanism of action as well as the antimetastatic activities that the yam derived hexadecanoic acid may exhibit. Flow cytometry analysis was used to assess cell cycle arrest exhibited by hexadecanoic acid on the hormone insensitive DU145 prostate cancer cells. The western blot analysis was then utilized to determine the effects of the hexadecanoic acid enriched sample on cyclins in the cells. Transwell migration assays were then used to evaluate cell metastatic capabilities. Hexadecanoic acid enriched sample induced G1 S cell cycle arrest in the hormone insensitive prostate cancer cell line. Western blot assays also indicated that cell death was possibly induced through the cell cycle regulatory protein, cyclin D1 as its expression was downregulated in the treatment groups. Additionally, the observed metastatic inhibition of prostate cancer cells due to the action of the hexadecanoic acid in the wound healing assay may be attributed to a mechanism involving cyclin D1 as studies have indicated that abnormal Ccnd1 Cdk4 expression promotes tumor growth and metastasis. These results are substantial as it indicates a mechanistic pathway through which hexadecanoic acid is able to cause antiproliferative effects through a cell cycle arrest of hormone insensitive prostate cancer cell lines.
Citation Format: Sasha-gay A. Wright, William Aiken, Helen Asemota, Kimberly Foster, Rupika Delgoda. Hexadecanoic acid mediated cell cycle arrest involving inhibition of cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1824.
Abstract 1829: Brusatol overcomes tyrosine kinase inhibitors resistance in myeloid leukemia cells by inhibiting translation of fast turnover protein cyclin D1 and Mcl-1
Authors: Hua Huiming , Yang Ying , Lin Guangfuxin , Zhang Jingyi , Waxman Samuel , Jing Yongkui 
Published: March 2024

Abstract
Myeloid leukemia is characterized with fast proliferation and apoptosis evasion, which are controlled by mutant or activated tyrosine kinase signalings. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML) significantly improved the therapy, but not cure, due to the general resistance. Overactivated mTOR protein translation pathway is believed to be one of the mechanisms causing resistance and that targeting protein translation should be one effective approach to overcome resistance. Brusatol is a quassinoid extracted from the fruit of Brucea javanica and an inhibitor of protein translation. We tested its antiproliferation and apoptosis induction in a variety of AML and CML cell lines as well as in TKI resistant cell lines. Brusatol effectively inhibits the growth of seven leukemia cell lines with GI50 values less than 20 nM. Brusatol induces apoptosis in AML cell lines and induces G0/G1 phase arrest in CML cell lines. Brusatol decreases the levels of fast turnover protein cyclin D1 and Mcl-1. In FLT3-ITD inhibitor sorafenib resistant MOLM-13/Sor cell line brusatol exhibits similar growth inhibition and apoptosis induction with the parental MOLM-13 cells, associated with inhibition of Mcl-1 and FLT3-ITD proteins. In BCR-ABL inhibitor imatinib resistant K562/STI cell line brusatol is effective as in parental K562 cells, associated with inhibition of cyclin D1 and BCR-ABL proteins. Brusatol at 2 mg/kg effectively inhibit tumor growth of K562 xenografts without causing toxicity to normal organs. These data indicate that brusatol inhibits oncogenic protein translation and has potential to be used to treat TKI resistant leukemia.
Citation Format: Huiming Hua, Ying Yang, Guangfuxin Lin, Jingyi Zhang, Samuel Waxman, Yongkui Jing. Brusatol overcomes tyrosine kinase inhibitors resistance in myeloid leukemia cells by inhibiting translation of fast turnover protein cyclin D1 and Mcl-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1829.
Abstract 1855: Proteomics driven biomarker discovery for high-grade serous ovarian carcinoma from archived tissue specimens
Authors: Shenoy Anjana , Arad Gali , Kovalerchik Dimitri , Manor Amit , Simchi Nitzan , Daitchman Dina , Pevzner Kirill , Seger Eran 
Published: March 2024

Abstract
High-Grade Serous Ovarian Carcinoma (HGSOC) is a highly aggressive and heterogeneous cancer with variable treatment responses. Current treatment strategies, including surgical resection and chemotherapy, are often ineffective due to a lack of molecular markers to predict drug sensitivity and patient prognosis. Mass spectrometry-based proteomics analysis is a powerful tool for biomarker discovery, but it is restricted by the availability and quality of archived clinical specimens.
In this study, we developed a proteomics-based biomarker discovery pipeline that optimizes the extraction and sample preparation from archived tissue specimens of HGSOC patients. Macrodissection of the tumor rich tissue areas of interest ensured sample purity and statistical power for comparative analysis.
Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we conducted a comprehensive, global proteomics analysis of FF tissue specimens from 25 HGSOC patients to associate proteomic profiles with patient outcomes. Combining high-resolution mass spectrometry proteomics of clinical samples with advanced computational tools for clinical data mining, we were able to identify pathways associated with HGSOC that hold clinical significance.
Our unique biomarker discovery platform provides a novel strategy for detecting cancer vulnerabilities from archived tissue samples and identifying proteomic biomarkers linked with treatment response and patient prognosis beyond BRCA mutation status.
Citation Format: Anjana Shenoy, Gali Arad, Dimitri Kovalerchik, Amit Manor, Nitzan Simchi, Dina Daitchman, Kirill Pevzner, Eran Seger. Proteomics driven biomarker discovery for high-grade serous ovarian carcinoma from archived tissue specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1855.
Abstract 1858: Discovery of AT86474, a highly efficacious anti-ROR1 ADC utilizing a proprietary payload
Authors: Tan Ban Xiong , Zhang Xi Yun , Wu You Xue , Cheng Yin Wen , Liu Shao Jun , Du Ping , Zhong Chen , Zou Bin 
Published: March 2024

Abstract
ROR1 is a pseudo kinase that is involved in the non-canonical Wnt signaling pathway and is highly expressed during early embryonic development. In adult tissues, ROR1 is expressed at very low levels but its increased expression is observed in hematological cancers and a broad range of solid tumors. AT86474 is a highly homogeneous antibody drug conjugate incorporating AxcynCYSTM technology that allows reproducible site-specific conjugation with DAR4 composition greater than 97%. AT86474 utilizes a proprietary payload derived from an FDA approved drug that was optimized in-house for increased potency and with altered PK properties to limit systemic exposure. In vitro, the payload displays broad sub-nanomolar activity across multiple cancer cell lines, including those resistant to paclitaxel, DM1, MMAE and DXd. The payload is conjugated via an enzyme-cleavable linker optimized for solubility, stability, and high drug to antibody ratios. AT86474 uses a humanized and optimized monoclonal antibody that demonstrates selective binding to ROR1-positive cells and subsequent internalization, sub-nanomolar potency in vitro and strong bystander effects. AT86474 was evaluated in a preclinical CDX mouse model of ovarian cancer, where substantial tumor growth inhibition was observed with two weekly doses at as low as 1 mg/kg. As ROR1 over-expression is also observed in many solid tumors, such as pancreatic, gastric, breast and lung cancers, the use of AT86474 can be expanded to benefit a large patient population.
Citation Format: Ban Xiong Tan, Xi Yun Zhang, You Xue Wu, Yin Wen Cheng, Shao Jun Liu, Ping Du, Chen Zhong, Bin Zou. Discovery of AT86474, a highly efficacious anti-ROR1 ADC utilizing a proprietary payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1858.