bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2347: Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability
Authors: Negussie Mikias B. , Krishna Saritha , Wei Ying , Gonzales Cesar Nava , Mehari Mulki , Hervey-Jumper Shawn L. 
Published: March 2024

Abstract
Introduction
Drug repurposing serves as a promising avenue for glioblastoma treatment, especially as new evidence emerges about the role of neuronal activity dependent tumor proliferation. Structure based drug discovery with virtual screening requires highly accurate 3D information about the target of choice. Recent developments in machine learning based protein structure prediction have allowed for the exploration of chemical space with virtual screening tools not previously accessible via traditional methods. Netrin-G1 (NTNG1) is an axonal guidance molecule implicated in glioblastoma with high functional connectivity to the cortex. In this study, we explore pharmacologic inhibition of NTNG1 with a clinically approved compound.
Methods
We perform protein structure predictions with AlphaFold2, followed by structure relaxation in an explicit solvent environment with NAMD 2.14. A final confirmation of NTNG1 was used as input to an AutoDock Vina based virtual screening platform. Zuclopenthixol (ZP) was chosen from a list of hits for microelectrode array (MEA) experiments in a mouse neuron/patient-derived tumor cell co-culture environment.
Results
A list of clinically approved compounds were returned from our virtual screen. ZP was chosen for validation studies, as it readily crosses the blood-brain barrier and occupies the entire TSP1 binding site in NTNG1. Preliminary results from MEA studies suggest ZP reduces tumor-mediated hyperexcitability and adequately modulates a protein-protein interaction between NTNG1 and TSP1.
Conclusion
By demonstrating that ZP decreases tumor-mediated hyperexcitability, this study offers evidence for the novel application of ZP to reduce glioblastoma proliferation. Further work will focus on survival analyses in mice treated with ZP and validation of experimental compounds that are structurally similar to ZP.
Citation Format: Mikias B. Negussie, Saritha Krishna, Ying Wei, Cesar Nava Gonzales, Mulki Mehari, Shawn L. Hervey-Jumper. Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability [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 2347.
Abstract 2381: The bispecific antibody KA-3001, targeting PSMA and CD28, specifically enhances T cell activation within prostate tumors
Authors: Liang Jiabei , Su Chen , Peng Hao , Hao Feng , Liu Tongtong , Ning Jinying , Wu Guojin 
Published: March 2024

Abstract
Immunotherapy, which involves blocking PD-1 signaling, has revolutionized the treatment paradigm for advanced solid tumors. However, prostate cancer exhibits a low response ratio to anti-PD-1 therapy. In this study, we have developed a bispecific antibody (BsAb), KA-3001, targeting PSMA and human CD28, aiming to enhance T cell activation in the tumor microenvironment. KA-3001, in a regular IgG1 format, features an identical light chain and was designed using our common light chain bispecific antibody discovery platform with knob-into-hole technology. Mutations in the Fc domain were introduced to eliminate ADCC, ADCP, and CDC activity. KA-3001's two Fabs demonstrate high affinity for PSMA and relatively low affinity for CD28. In comparison to REGN5678, KA-3001 exhibits significantly stronger binding to PSMA-expressing prostate tumor cells, along with relatively lower CD28 activation, minimizing toxicity while maintaining anti-tumor efficacy. In PBMC humanized immunodeficient mouse tumor models, KA-3001 effectively suppresses the growth of 22Rv1 tumors with or without PD-1 antagonist antibody. Furthermore, KA-3001 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody through various treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. The BsAb demonstrates neither aggregation nor degradation. In conclusion, the BsAb KA-3001, developed using our common light chain antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of prostate cancer.
Citation Format: Jiabei Liang, Chen Su, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu. The bispecific antibody KA-3001, targeting PSMA and CD28, specifically enhances T cell activation within prostate tumors [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 2381.
Abstract 241: Patient-derived organoids as a reliable screening platform for assessing ADC efficacy and specificity
Authors: Mori Daniele , Adegbenro Vineeta , Morales Francisco , Overmeer René , Lukovac Sabina , Boj Sylvia , Derksen Merel 
Published: March 2024

Abstract
Antibody-drug conjugates (ADCs) are a new class of pharmaceutical drugs designed to deliver cytotoxic agents to cells expressing specific antigens selectively. Based on Paul Ehrlich’s “magic bullet” concept, ADCs are designed to target cancer cells, minimizing systemic toxicity typical of conventional chemotherapy. ADCs structurally consist of a particular monoclonal antibody linked to a cytotoxic agent.
Patient-derived Organoids (PDOs) provide a new tool for studying cancer biology and patient stratification. PDOs are adult stem cell-based culture systems maintaining the patient-specific genetic and phenotypic characteristics, including surface marker expression. HUB Organoids has generated a large biobank of PDOs characterized on the genomic and transcriptomic level.
The work presented here shows the suitability of the organoid platform for performing ADC screening. Organoids were selected based on their target-antigen (TA) expression, assessed by flow cytometry and RPKM. Organoid killing was assessed with a viability readout (CellTiter Glo) after six days of treatment. Results of viability screening show a correlation between TA-targeting ADC-induced organoid killing and TA expression in the organoids.
These results reveal that PDOs hold value for the preclinical development of ADCs and for evaluating their tumor specificity. Moreover, PDOs have the potential to predict patient specific response to ADCs.
Citation Format: Daniele Mori, Vineeta Adegbenro, Francisco Morales, René Overmeer, Sabina Lukovac, Sylvia Boj, Merel Derksen. Patient-derived organoids as a reliable screening platform for assessing ADC efficacy and specificity [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 241.
Abstract 2436: In-depth analysis of microRNA signature in breast cancer derived extracellular vesicles: A potential biomarker repository for breast cancer diagnosis
Authors: Kim Jee Ye , Kim Min Woo , Kim Young , Moon Sol , Lee Suji , Lee Hyojung , Kim Joon Ye , Kim Seung Il 
Published: March 2024

Abstract
Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. With the rising incidence of breast cancer, early and accurate diagnosis is pivotal in improving survival rates and patient outcomes. Our study addresses to identify vesicles associated with breast cancer in scope of miRNA signature. We focused on isolating breast cancer-derived extracellular vesicles (BEVs) from the bloodstream with immune affinity capture techniques. Then, we analyzed the miRNA profiles of BEVs in plasma samples from 120 breast cancer patients, 46 individuals with benign tumors, and 45 healthy controls. In this study, we analyzed to discover miRNA candidates for diagnosis of breast cancer with The Gene Expression Omnibus (GEO) database and found 379 down-regulated and 584 up-regulated differentially expressed miRNAs (DEMs) in tissue samples across 5 GEO datasets, and 28 down-regulated and 80 up-regulated DEMS in blood samples. Subsequently, we measured the expression levels of these 10 candidate miRNAs in BEVs from breast cancer cells and compared them with EVs from human mammary cells (MCF10a), using our BEV isolation method. The expression profiles of these miRNAs in BEVs were significantly elevated, supporting their potential as surrogate markers for breast cancer diagnosis. When comparing the AUC values of 10 candidate miRNAs through ROC analysis, 5 EV miRNAs (miR-21, miR-106b, miR-181a, miR-484, and miR-1260b) showed a high AUC values above 0.8. Subsequently, we verified a distinct signature of 5 EV miRNAs that effectively differentiate breast cancer patients from normal controls with 57.14% of sensitivity and 95% of specificity. Overall, our study not only complements existing diagnostic methods with high accuracy but also provides a deeper understanding of the molecular aspects of breast cancer, heralding a significant advancement in precision medicine and personalized cancer care.
Citation Format: Jee Ye Kim, Min Woo Kim, Young Kim, Sol Moon, Suji Lee, Hyojung Lee, Joon Ye Kim, Seung Il Kim. In-depth analysis of microRNA signature in breast cancer derived extracellular vesicles: A potential biomarker repository for breast cancer diagnosis [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 2436.
Abstract 2440: Cancer driver mutations as quantitative biomarkers of cancer risk interspecies analyses using CarcSeq
Authors: Harris Kelly L. , Gong Binsheng , Parsons Barbara , Faske Jennifer , Xu Joshua 
Published: March 2024

Abstract
Unmet needs in cancer risk assessment include the ability to predict rodent life-time tumor responses from short-term exposures and a scientific basis for rodent to human extrapolation. As an approach to address these needs, the use of hotspot cancer driver mutations (CDMs) as biomarkers of cancer risk was integrated with an error-corrected, next generation sequencing (NGS) approach. We have developed and investigated the sensitivity of a high-throughput NGS method capable of detecting a panel of the most prevalent point mutations observed in human oncogenes and tumor suppressor genes. This method, CarcSeq, involves performing multiple, high-fidelity PCR reactions to amplify the most prevalent mutations reported to occur in human tumors, tagging the amplicons with 9 bp unique identifier sequences at each end, constructing libraries using Illumina ChIP Seq kits, sequencing the libraries on an Illumina NextSeq500 platform and generating single-strand consensus sequences (SSCS), bioinformatically, as a means of error-correction. We validated CarcSeq mutant fraction measurements through observations related to known cancer driver tissue-specificities and mutation spectra for normal human breast and lung, ductal carcinoma, and lung adenocarcinoma samples. Performance of a reconstruction experiment established CarcSeq has a sensitivity of 104. The approach has now been adapted to analyze analogous conserved codons in rat and mouse. For each of the three species, the developed panel includes 13-15 amplicons encompassing known cancer driver genes (e.g., KRAS, PIK3CA, and TP53) encompasses the equivalent of 30 known human hotspot codons and has a combined target sequence length of ~1 kb. Amplicons were generated from DNA isolated from 16-week-old, untreated rodent tissue samples with known differences in spontaneous tumor incidence: female Wistar, Sprague Dawley, and F344 rat mammary samples and male and female B6C3F1 and CD-1 mouse lung samples. The rodent panel was optimized to generate ~100,000 SSCS/amplicon. CDMs were observed at conserved codons in young, untreated rodents, and results are consistent with what was expected based on strain differences in spontaneous tumorigenesis.
Citation Format: Kelly L. Harris, Binsheng Gong, Barbara Parsons, Jennifer Faske, Joshua Xu. Cancer driver mutations as quantitative biomarkers of cancer risk interspecies analyses using CarcSeq [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 2440.
Abstract 2469: PROTAC mediated NR4A1 degradation as a novel strategy for cancer immunotherapy
Authors: Wang Lei , Xiao Yufeng , Luo Yuewan , Master Rohan , Mo Jiao , Kim Myung-Chul , Liu Yi , Maharjan Chandra , Patel Urvi , Li Xiangming , Shaffer Donald , Kevin Guertin , Zhuang Haoyang , Moser Emily , Smalley Keiran , Zhou Daohong , Zheng Guangrong , Zhang Weizhou 
Published: March 2024

Abstract
An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple cell types in the TME and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer such as melanoma.
Citation Format: Lei Wang, Yufeng Xiao, Yuewan Luo, Rohan Master, Jiao Mo, Myung-Chul Kim, Yi Liu, Chandra Maharjan, Urvi Patel, Xiangming Li, Donald Shaffer, Guertin Kevin, Haoyang Zhuang, Emily Moser, Keiran Smalley, Daohong Zhou, Guangrong Zheng, Weizhou Zhang. PROTAC mediated NR4A1 degradation as a novel strategy for cancer immunotherapy [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 2469.
Abstract 249: Deciphering the impact of TRIB3-ELF4 interaction in regulating CDK6 on cancer stem cell activity in endometrial cancer
Authors: Wang Wen-Ling , Chang Wen-Wei 
Published: March 2024

Abstract
Background: Endometrial cancer (EC) is the most common gynecological tumor among women worldwide, posing a serious threat to women's health. ELF4 (E74 like ETS transcription factor 4), a member of the ETS family, plays a role in facilitating cancer progression. Our previous work demonstrated the role of direct binding between ELF4 and tribbles pseudokinase 3 (TRIB3) in promoting β-catenin expression. In this study, we further explore ELF4's involvement in the maintenance of cancer stem cells (CSCs) in EC.
Methods: The vital role of ELF4 in EC was determined through gain- and loss-of-function assays. ELF4 was silenced in two EC cell lines, AN3CA and HEC-1A, and primary EC cells from a Taiwanese patient (EMC6), using RNA interference techniques. The expression of ELF4, TRIB3, and CDK6 in human EC samples was assessed using immunohistochemistry. Tumorsphere formation assays, quantitative real-time PCR, and immunoblotting quantified CSC activity and the involvement of related signaling pathways. Transcriptional regulation associated with ELF4 was investigated using luciferase reporter assays and chromatin immunoprecipitation.
Results: Analysis of the TCGA database via the TISIDB web tool revealed that elevated ELF4 levels correlated with higher histological grades, advanced clinical stages, and poorer overall survival in EC patients. A grade-dependent increase in ELF4 expression was observed using tissue microarrays. Knockdown of ELF4 in EC cell lines and patient-derived EC cells significantly reduced cell proliferation, cell cycle progression, migration, invasion, and CSC activity. RNA-seq data analysis of ELF4-knockdown EC cells identified CDK6 as a potential downstream target of the ELF4/TRIB3 interaction. Knockdown of ELF4 and TRIB3 significantly downregulated CDK6 expression. Co-expression of TRIB3 and ELF4 enhanced CDK6 expression, and their expression was positively associated with CDK6 in EC specimens. We also demonstrated that CDK6 facilitates EC-CSC activity. Knockdown of CDK6 significantly attenuated tumorsphere formation and reduced the levels of cancer stemness-related proteins, including OCT4, NANOG, and c-MYC.
Conclusion: Our study demonstrates the essential roles of ELF4 and TRIB3 in regulating CDK6 expression, contributing to the maintenance of EC-CSCs.
Citation Format: Wen-Ling Wang, Wen-Wei Chang. Deciphering the impact of TRIB3-ELF4 interaction in regulating CDK6 on cancer stem cell activity in endometrial cancer [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 249.
Abstract 2501: High mutation burden and ultraviolet light signature in conjunctival squamous cell carcinoma
Authors: Esmaeli Bita , Gleber-Netto Frederico O. , Sagiv Oded , Pickering Curtis R. , Gross Neil , Ning Jing , Yeshi Melisachew M. , Mitku Jonas , Tetzlaff Michael T. , Nagarajan Priyadharsini 
Published: March 2024

Abstract
Purpose: Conjunctival squamous cell carcinoma (conjSCC) is endemic in sub-Saharan Africa and is a major cause of ocular morbidity and mortality. This study aims to evaluate Tumor Mutation Burden (TMB), genomic signature, and histologic characteristics of conjunctival squamous cell carcinoma (conjSCC) in two cohorts of patients; one from the USA and one from Ethiopia.
Methods: Whole exome sequencing data, PD-L1 expression, histologic features, and human papillomavirus (HPV) status were analyzed in conj SCC tumors of 25 patients treated at an Ethiopian (ETH) cancer center and 29 patients treated at a US cancer center. Genomic alterations in conjSCC were compared with SCCs from other anatomic sites using data from The Cancer Genome Atlas (TCGA).
Results: TMB was found to be relatively high in conjunctival SCC (3.01/Mb, log10), was comparable to TMB values associated with cutaneous SCC, and was higher than most other SCC types available in the TCGA database. ETH samples had higher tumor mutational burden compared to the US cohort (3.34 vs 2.73). Solar elastosis was seen in a higher percentage of tumors from Ethiopia compared with the US cohort (78% vs. 10%). HPV status was similar between the cohorts (ETH: 21%, MDA: 28%). PD-L1 positivity defined as &gt; 1% of tumor cells was seen in 33 of 53 tumors (62%). Mutations associated with ultraviolet light (UV) signature were the most frequently encountered signatures in both cohorts (SBS7b: 74% and SBS7a: 72%). UV signatures were more prevalent in the ETH cohort compared with the US cohort.
Conclusions: Conjunctival SCC is associated with a high TMB providing the opportunity for immune checkpoint inhibitor therapy for patients with locally advanced and/or metastatic conjunctival SCC. Clinical trials are needed to assess the efficacy of immune checkpoint inhibitors in patients with conjunctival SCC, particularly in sub-Saharan Africa where this cancer is more frequently seen, and is associated with significant morbidity and mortality.
Citation Format: Bita Esmaeli, Frederico O. Gleber-Netto, Oded Sagiv, Curtis R. Pickering, Neil Gross, Jing Ning, Melisachew M. Yeshi, Jonas Mitku, Michael T. Tetzlaff, Priyadharsini Nagarajan. High mutation burden and ultraviolet light signature in conjunctival squamous cell carcinoma [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 2501.
Abstract 2513: MAGE-A3, MAGE-A4, and PD-L1 protein show co-expression in colon, lung and bladder cancer
Authors: Gonzalez Rachel , Guo YiChen , Yom Jina , Gilmore Bailey , Zewdu Eden , Han Xi-Andy , Kong Dehe , Qu Tianli , Ren Qi , Hu Xiaomin , Zhang Ranran , Wu Zhaohui , Strom Alex , Liu Xuan , Fu Wei 
Published: March 2024

Abstract
PD-L1 programmed death ligand 1/CD274 has been shown to be an excellent immune therapy target for many tumors. Currently, studies have shown PD-L1in combination with other immune therapy targets can improve patient outcomes generating the need for new targets. One candidate is the cancer testis antigen Melanoma Antigen Gene Family (MAGE-A) because these genes have limited expression in normal tissues and high expression in cancer. Clinical trials have already begun targeting MAGE-A3 and MAGE-A4 proteins in multiple tumor types. Protein assessment of individual MAGE-A family members has been challenging due to sequence homology as high as ninety-five percent between members. Previously, with the use of CytoSections two highly specific antibodies for immunohistochemistry to MAGE-A3 (clone OTI1H1) and MAGE-A4 (clone OTI2C1) were found. In this study, the MAGE-A3 and MAGE-A4 antibodies were screened with PD-L1 on colon, lung, and bladder cancers. Results show detection of both MAGE-A3 and MAGE-A4 in 25% of colon; 30% of lung; and 20% of bladder cancers. More than 70% of the lung and bladder cancers were positive for MAGE-A4 but only six of twenty-four colon cancers were positive for MAGE-A4. The results show 60 percent of the positive for MAGEA3 or MAGEA4 in colon, lung, and bladder cancers were also positive for PD-L1. This study suggests that MAGE-A3 and MAGE-A4 have tumor specific expression patterns and a potential to be a co-immunotherapy target with PD-L1.
Citation Format: Rachel Gonzalez, YiChen Guo, Jina Yom, Bailey Gilmore, Eden Zewdu, Xi-Andy Han, Dehe Kong, Tianli Qu, Qi Ren, Xiaomin Hu, Ranran Zhang, Zhaohui Wu, Alex Strom, Xuan Liu, Wei Fu. MAGE-A3, MAGE-A4, and PD-L1 protein show co-expression in colon, lung and bladder cancer [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 2513.