bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4997: PLK1 promotes the metastasis and drug resistance in melanoma
Authors: Mao Fengyi , Kong Yifan , Li Chaohao , Zhang Yanquan , Rao Xiongjian , Zhang Qiongsi , Wang Xinyi , Li Zhiguo , Liu Xiaoqi 
Published: April 2023

Abstract
Melanoma is one of the most frequently diagnosed cancers in the caucasian population of both genders. The survival rate of advanced melanoma patients will be exceedingly poor, as low as 27.3%. BRAF-V600E is the most common mutation found clinically, resulting in the constitutive activation of the MAPK signaling pathway. Vemurafenib, a specific inhibitor of mutant BRAF, has shown an impressive response in phase 3 clinical trials and was approved by FDA in 2011. However, due to the rapid development of resistance, the duration of response under a single treatment is frequently short, highlighting the urgent requirement for novel therapy in melanoma treatment. Polo-like kinase 1 (PLK1), a crucial cell cycle regulator, participates in multiple mitotic processes, including centrosome maturation, mitotic entry, spindle assembly, sister chromatid segregation, mitotic exit, and cytokinesis. Compared to normal tissues, the expression level of PLK1 significantly upregulates in multiple cancers. More importantly, the expression level of PLK1 negatively correlates with the melanoma patients’ survival rate based on the TCGA database. Besides, PLK1 is identified as an oncogene to promote proliferation, motility, and resistance to various drugs. In the present study, we found that overexpression of PLK1 promotes tumor growth, metastasis, metabolic reprogramming, and vemurafenib resistance in the BrafCA/Ptenloxp mouse melanoma model. Through phosphorylation, overexpressed PLK1 stabilizes BACH1, a critical transcriptional factor of multiple metastatic and metabolic genes, and protects it from degradation. Subsequently, a higher level of BACH1 leads to increasing metastasis, upregulation of glycolysis, and suppression of OXPHOs. Besides, we have validated the strong synergy between PLK1 inhibitor volasertib and vemurafenib in treating melanoma carrying BRAF-V600E. Our in vitro and in vivo experiments have shown an improved efficacy of this combined therapy on inhibition of cell proliferation, induction of cell death, and suppression of cell metastasis compared to mono-treatment. In short, our data has indicated PLK1 as a potent and promising target in cancer treatment.
Citation Format: Fengyi Mao, Yifan Kong, Chaohao Li, Yanquan Zhang, Xiongjian Rao, Qiongsi Zhang, Xinyi Wang, Zhiguo Li, Xiaoqi Liu. PLK1 promotes the metastasis and drug resistance in melanoma. [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 4997.
Abstract 4999: Preclinical evaluation of MCLA-129, a bispecific antibody targeting EGFR and c-MET on solid tumor cells, in comparison with amivantamab
Authors: de Gorter David J.J. , Deshiere Alexandre , Kramer Arjen , van Rosmalen Martijn , Mortensen Franziska , Geuijen Cecile 
Published: April 2023

Abstract
The HGF/c-MET pathway is frequently upregulated in tumors that are resistant to EGFR tyrosine kinase inhibitors. MCLA-129 is an antibody-dependent cellular cytotoxicity (ADCC) enhanced Biclonics® that targets epidermal growth factor receptor (EGFR) and c-MET in non-small cell lung cancer (NSCLC) and other solid tumors. MCLA-129 is a potent inhibitor of tumor growth applying various mechanisms of action (MOA), including inhibition of c-MET and EGFR signaling, antibody-dependent cellular phagocytosis (ADCP) and ADCC. Here we compared the MOA of MCLA-129 with the MOA of the EGFR-c-MET bispecific antibody amivantamab. The binding of MCLA-129 to tumor cells expressing different levels of EGFR and c-MET was quantified using radiolabeled antibodies. Scatchard plot analysis showed that the affinity of MCLA-129 for both c-MET and EGFR is in the low nanomolar range. In FACS, MCLA-129 and amivantamab show similar binding to tumor cells harboring EGFR or c-MET exon14-skipping mutations. Crossblock experiments with the c-MET binding antibody onartuzumab analog showed that MCLA-129 competes for the same HGF-binding region of c-MET, which is distinct from the binding site of amivantamab according to Neijssen et al, 2021 (PMC8113745). MCLA-129 and amivantamab did not downmodulate EGFR or c-MET. ADCP was also comparable for MCLA-129 and amivantamab, as measured with monocyte-derived macrophages incubated with pHrodo-labeled target cells with readout of tumor cell phagocytosis on the Incucyte® system. In contrast, MCLA-129 displayed ADCC activity similar to or more potently than amivantamab in an ADCC reporter assay with either high affinity FcγRIII 158V-variant or low affinity 158F-variant effector cells in absence or presence of soluble EGFR and soluble c-MET. MCLA-129-induced ADCC appears to be less affected than amivantimab by the presence of soluble EGFR and soluble c-MET. In conclusion, MCLA-129 is a Biclonics® common light chain bispecific antibody with multiple MOA including inhibition of c-MET and EGFR ligand binding, ADCP and ADCC comparable or more potent than amivantamab. A phase 1/2 clinical trial of MCLA-129 in solid tumors is ongoing. These data support the further clinical development of MCLA-129 in patients with NSCLC and other solid tumors.
Citation Format: David J.J. de Gorter, Alexandre Deshiere, Arjen Kramer, Martijn van Rosmalen, Franziska Mortensen, Cecile Geuijen. Preclinical evaluation of MCLA-129, a bispecific antibody targeting EGFR and c-MET on solid tumor cells, in comparison with amivantamab. [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 4999.
Abstract 5014: HPK1 gene knockout reporter cell line: an efficient drug screening system
Authors: Zhai Yunpeng , Li Lidan , Hao Jianyu , Hu Yuqing , Ning Jinying , Hao Feng 
Published: April 2023

Abstract
Immunotherapy is the stimulation of the immune system, improving on the ability of immune system to treat cancer. It is expected to be the most effective therapy for patients with tumor metastasis. Checkpoint inhibitor (CPI) therapy is a form of cancer immunotherapy which can block inhibitory checkpoints, restoring immune system function. Tumor cells could recruit immunomodulatory cells and induce inhibitory signals, resulting in losing immunomodulatory. Therefore, there is an urgent need to develop new therapeutic agents that work in concert with CPI. HPK1, also known as MAP4K1, can act as a negative regulator of activation signals generated by T cell receptor (TCR). The development and screening of HPK1 inhibitors have great potential in the cancer immunotherapy. Herein, we constructed a HPK1 knockout reporter cell line Jurkat-NFAT-Luc2-HPK1-Knockout-Cell-Line by CRISPR/Cas9 which can be used in high-throughput HPK1 inhibitors screening. Wild type cells were incubated with HPK1 inhibitors and luciferase signals were compared in HPK1-knockout cells. Our HPK1 knockout reporter cell line has high sensitivity and specificity. The reporter system can achieve high-throughput compound library screening. After selected the compound with selective inhibitory activity, further validation and optimization would be performed. Moreover, we constructed a Jurkat-HPK1-HiBiT reporter cell line by CRISPR/Cas9. It can be used in the screening of HPK1 degradants. We believe that HPK1 gene editing cell lines play an important role in the high-throughput screening of drugs. It could facilitate the development of drugs in tumor immunotherapy.
Citation Format: Yunpeng Zhai, Lidan Li, Jianyu Hao, Yuqing Hu, Jinying Ning, Feng Hao. HPK1 gene knockout reporter cell line: an efficient drug screening system. [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 5014.
Abstract 5052: IB-DNQ enhances radiation induced ferroptosis in NQO1-positive cancer cells
Authors: Huang Xiumei , Su Xiaolin , Boudreau Matthew W. , Hergenrother Paul J. 
Published: April 2023

Abstract
Cancer is the second leading cause of death worldwide. Current treatments for solid cancers are associated with inherent resistance mechanisms and are ineffective against non-cycling cancer cells. Thus, there is a critical need to develop novel tumor-selective combination therapies to overcome resistance while optimally spare normal tissues. In this study, we investigate the mechanistic basis for tumor-selective potentiation of ionizing radiation (IR) in combination with IB-DNQ, a novel NQO1-bioactivatable agent. We found that combination of a low dose of ionizing radiation (IR, 2 Gy) with a sublethal dose of IB-DNQ dramatically increased Fe2+ leakage and induced elevated lipid peroxidation and ferroptosis in NQO1-positive cancer cells via upregulating the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis. Knockdown of endogenous ACSL4 significantly inhibited lipid peroxidation via downregulating the expression of PTGS2 and dramatically inhibited the cell death that induced by IR or IB-DNQ alone or combination treatment. We further found that this combination treatment significantly decreased IR or IB-DNQ alone mediated upregulation of the expression of GPX4 that led to the accumulation of lipid peroxides, which suggests that IR or IB-DNQ-induced expression of GPX4 may function as a negative feedback loop to restore cell survival upon a sublethal dose of IR or IB-DNQ treatment. Finally, we demonstrated that this combination therapy synergistically suppressed tumor growth and dramatically extended mouse lifespan in orthotopic pancreatic and non-small-cell lung cancer xenograft models. Together, our study provides novel preclinical evidence for new combination therapy in NQO1-positive solid tumors that may overcome IR-induced resistance.
Citation Format: Xiumei Huang, Xiaolin Su, Matthew W. Boudreau, Paul J. Hergenrother. IB-DNQ enhances radiation induced ferroptosis in NQO1-positive cancer cells. [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 5052.
Abstract 5183: Development of an aerosol-based immunotherapy for lung cancer
Authors: Li Yongren , Zhao Zhen , Fetse John , Hasan Reaid , Mamani Umar-Farouk , Guo Yuhan , Cheng Kun 
Published: April 2023

Abstract
Lung cancer is one of the leading causes of cancer death and the second most cancer in the world. Compared to systematic administration, local delivery of therapeutic agents to the lung increases their accumulation in lung cancer cells and reduces the toxicity in other organs. We previously discovered an anti-PD-L1 peptide that can be potentially uses for lung cancer therapy. This project aims to develop an aerosolized formulation of the anti-PD-L1 peptide for the treatment of lung cancer. We hypothesize that the aerosolized peptide has higher accumulation in the lung compared to systematic formulations, leading to high therapeutic index with less side effects. We developed a spray freeze-drying procedure and optimized the formulation to prepare the peptide dry powders. The median mass aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the aerosols were determined by an 8-stage Andersen Cascade Impactor. The morphology of the aerosols was studied using a scanning electron microscope (SEM). The stability of the aerosols in lung fluid was evaluated. Blocking assay suggested that the aerosolized formulation maintains the blocking efficiency of the peptide. Intratracheal administration of the peptide dry powder shows a high accumulation of the peptide in the lung.
Citation Format: Yongren Li, Zhen Zhao, John Fetse, Reaid Hasan, Umar-Farouk Mamani, Yuhan Guo, Kun Cheng. Development of an aerosol-based immunotherapy for lung 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 5183.
Abstract 5196: Novel humanized CD36 mouse model for therapeutic studies
Authors: Wang Linlin , Liu Chang , Soto Rebecca , Shang Chengzhang , Lin Qingcong 
Published: April 2023

Abstract
Activation of oncogenic signaling pathways can be mediated by various transporters on tumor cells that facilitate trafficking of lipids. CD36 has been identified as a fatty acid transporter and participates in tumor growth and drug resistance. To explore potential therapeutic strategies targeting CD36, we generated a human CD36 knockout/knock-in in situ (B-hCD36) mouse model to evaluate the efficacy of anti-human CD36 antibodies. We first confirmed human CD36 gene and protein expression in B-hCD36 mice by RT-PCR and flow cytometry, respectively. We next observed that the overall development, differentiation, and distribution of splenic, blood and lymph node immune cells were similar between wild-type C57BL/6 and B-hCD36 mice. Lastly, in vivo efficacy studies using anti-human CD36 antibodies alone or in combination with anti-mouse PD-1 antibodies, were effective in controlling MC38 tumor growth in B-hCD36 mice. Our data demonstrates that B-hCD36 mice are a powerful preclinical model for in vivo efficacy evaluation of anti-human CD36 antibodies.
Citation Format: Linlin Wang, Chang Liu, Rebecca Soto, Chengzhang Shang, Qingcong Lin. Novel humanized CD36 mouse model for therapeutic studies. [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 5196.
Abstract 5319: EU-OPENSCREEN - An open-access initiative in chemical biology to support anti-cancer drug discovery
Authors: Stechmann Bahne , Wit Charlotte 
Published: April 2023

Abstract
Over the past two decades, an increasing number of small molecule drugs that target unique molecular changes underlying a specific cancer have been approved, and small molecule drugs represent a major therapeutic class for cancer treatment. Chemical ‘probes’ are also indispensable tools to advance our understanding of pathologies at the molecular and cellular level and to validate novel drug targets.
A major bottleneck in identifying and developing these chemical compounds in academia is often access to robust disease-relevant assays, high-throughput screening platforms, comprehensive screening libraries, medicinal expertise for the hit-to-lead optimization. In order to democratize access to these resources for a broader scientific community, the publicly funded EU-OPENSCREEN (www.eu-openscreen.eu) initiative has been established with the aim to accelerate drug discovery efforts in an open-access setting in collaboration with researchers from academia and industry.
EU-OPENSCREEN’s 30 expert centers offer access to their cancer target-based and phenotypic drug screening expertise, capabilities in developing disease-relevant assays and hit-to-lead optimization capabilities. The identified bioactive ‘hit’ compounds will be progressed into high-quality chemical starting points to be further developed into drug leads or chemical probes for the elucidation of mechanisms of cancer onset, progression, resistance and effects of drug therapy. All generated tool compounds and associated bioactivity data are made available to the global scientific community.
Here we will present an overview of anti-cancer drug discovery projects of EU-OPENSCREEN and explain the opportunities and benefits for other international scientists to collaboratively develop novel anti-cancer drug leads and chemical probes.
EU-OPENSCREEN receives funding from the European Union's Horizon 2020 and Horizon Europe research and innovation programs under grant agreements No 654248 and 101058620.
Citation Format: Bahne Stechmann, Charlotte Wit. EU-OPENSCREEN - An open-access initiative in chemical biology to support anti-cancer drug discovery. [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 5319.
Abstract 5333: Combining chemoproteomics with machine learning identifies functionally active covalent fragments for hard-to-drug cancer drivers
Authors: Hermann Johannes C. , Everley Robert , Marholz Laura , Berberich Matthew , Yang Tzu-Yi , Chao Yu-Hsin , Awol Abduselam K. , Shaghafi Michael , Yoon Han , Varma Rohan , Stein Reed , Krug Karsten , Lachtara Emily , Erlanson Daniel , Varma Chris , Webster Kevin R. 
Published: April 2023

Abstract
a) Many cancer drivers are considered “undruggable” and without targeted treatments because they lack binding sites for conventional small molecules. Here, we introduce The FRONTIER™ Platform applying machine learning (ML), chemoproteomics and covalent chemistry to identify binding sites and cell-active covalent fragments across the human proteome, including against most cancer drivers and previously “undruggable” targets. Molecules tested in functional assays are active and can serve as starting points for new drug discovery initiatives.
b) We are using mass spectrometry and data analysis workflows to perform high-throughput chemoproteomic profiling experiments. These experiments identify hits across the proteome using different cancer-relevant cell backgrounds and characterize binding sites for drug discovery. Customized ML algorithms using chemoproteomic, genomic and structural data to characterize and prioritize identified binding sites for covalent drug discovery. The performance of the platform allows the profiling of thousands of compounds from a custom-built library that has been optimized by ML for covalent fragment-based drug discovery. The nature of the fragment hits and the ability to map them to and focus on preferred binding sites for covalent drugs enables accelerated lead generation.
c) We show details of the platform highlighting library design concepts and the hotspot map with binding site prioritization algorithms. We show coverage and applicability across important cancer target classes and signaling pathways. Covalent fragment hits have been identified for multiple difficult cancer targets, including KRAS, p53, STAT3, KEAP1, PTPN11 and others. The platform also identifies ligands for novel allosteric binding sites in established oncology targets such as CDK4, PI3KCA and BTK. We will highlight how discovered ligands show functional activity in orthogonal assays, demonstrating their fitness for drug discovery campaigns and target validation experiments.
d) Undruggable targets across a variety of cancer target classes have become druggable.
Citation Format: Johannes C. Hermann, Robert Everley, Laura Marholz, Matthew Berberich, Tzu-Yi Yang, Yu-Hsin Chao, Abduselam K. Awol, Michael Shaghafi, Han Yoon, Rohan Varma, Reed Stein, Karsten Krug, Emily Lachtara, Daniel Erlanson, Chris Varma, Kevin R. Webster. Combining chemoproteomics with machine learning identifies functionally active covalent fragments for hard-to-drug cancer drivers. [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 5333.
Abstract 5343: Evaluating the screened polyphenolics molecules as potential chemosensitizers against the oncogenic signalling proteins in lung cancer
Authors: Arora Swati , Sheoran Sumit , Basu Tanmayee , Subbarao Naidu , Upadhyay Atul Kumar , Vuree Sugunakar 
Published: April 2023

Abstract
Background: Lung cancer is the most commonly diagnosed cancer globally. There are numerous agonists and antagonistic treatment interventions available for therapy. However, all of them possess different detrimental consequences in addition to resistance and remission in sufferers. Medicinal plants have traditionally been employed to treat a wide range of ailments and problems.
Methodology: A total of 550 flavonoids and small molecules retrieved from literature and databases (Chembl, and PubChem) were analysed for molecular docking, biological activities, ADME, and drug-like properties through SwissADME and PreADMET, Molecular Simulation, and cytotoxicity studies. Simultaneously, review literature is employed to identify the novel protein targets viz. ROS1 (3ZBF) & EGFR (6DUK). Additionally, the crystal structures of the proteins were obtained from PDB and their domains and active sites were predicted using ScanProsite, MOTIF Search, metaPOCKET2, and PrankWeb tools. Finally, the proteins and ligands were energy-minimized using Chimera and open babel tool and subjected to virtual screening and molecular docking using GOLD. Furthermore, the molecular simulation was performed at 100ns by utilizing GROMACS, and cytotoxicity studies were performed by employing the A549 Lung cancer cell line.
Results: Diosmin (64.57) and Hesperidin (60.98) had the greatest binding affinity with the identified targets, i.e., ROS1 (3ZBF) and EGFR(6DUK) respectively against Lung Cancer, and remained stable during 100ns of molecular simulation. Furthermore, we have performed cytotoxicity studies on A549 cell lines that show both the compounds have significant anticancer activity and do not affect healthy cells in the range of, i.e., Diosmin (500 µg/ml to 0.024 µg/ml.) and Hesperidin (500 µg/ml to 125 µg/ml).
Conclusion: After the analyses, we can conclude that it has the potential to be exploited as a novel therapeutic agent in the treatment of lung cancer.Keywords: Diosmin, Hesperidin, In-silico, A549, Lung Cancer, Simulation
Citation Format: Swati Arora, Sumit Sheoran, Tanmayee Basu, Naidu Subbarao, Atul Kumar Upadhyay, Sugunakar Vuree. Evaluating the screened polyphenolics molecules as potential chemosensitizers against the oncogenic signalling proteins in lung 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 5343.