bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2939: ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEA, activates myeloid cells in primary human tumors in vitro and induces anti-tumor immunity in vivo
Authors: Hägerbrand Karin , Sundstedt Anette , Levin Mattias , de Coaña Yago Pico , Varas Laura , Ljung Lill , Nilsson Anneli , Celander Mona , Jimenez David Gomez , Andersson Hampus , Lindstedt Malin , Ellmark Peter 
Published: April 2023

Abstract
Alligator’s Neo-X-Prime platform aims to enable antigen presenting cells to efficiently enhance priming of tumor neoantigen-specific T cells. We have demonstrated that binding of a CD40 x TAA bispecific antibody (bsAb) to CD40 on dendritic cells (DCs) and a tumor-associated antigen (TAA) on tumor exosomes or tumor debris leads to activation of the DC, uptake of the tumor material, cross-presentation of a tumor-derived antigen and priming of tumor antigen-specific T cells. This has the potential to result in an increased quantity and/or quality of the tumor-targeting T cell pool and enhanced anti-tumor activity. Herein, we present ATOR-4066, a Neo-X-Prime bsAb targeting CD40 and CEA (CEACAM5), a TAA highly expressed in several cancers. Using in vitro models, we have demonstrated CEA-dependent activation of CD40-expressing cells, and an ability to mediate co-localization of CEA-expressing tumor debris and CD40 expressing antigen presenting cells. In addition, ATOR-4066 was shown to activate CD40-expressing cells in the presence of primary human tumor cells from CEA+ colorectal and gastric cancer patients. Furthermore, in vitro treatment of primary colorectal and gastric tumor-derived cell cultures and tumoroids with ATOR-4066 induced activation of tumor-infiltrating immune cells. In vivo studies using human CD40 transgenic mice bearing CEA-transfected MC38 tumors showed superior anti-tumor effects of ATOR-4066 compared to a CD40 mAb, demonstrating the ability of ATOR-4066 to efficiently induce a tumor-targeting immune response. Overall, these data show the ability of ATOR-4066 to remodel the immune microenvironment and activate tumor-infiltrating immune cells in primary human tumors expressing CEA, demonstrating the promise of this new candidate drug for further clinical development.
Citation Format: Karin Hägerbrand, Anette Sundstedt, Mattias Levin, Yago Pico de Coaña, Laura Varas, Lill Ljung, Anneli Nilsson, Mona Celander, David Gomez Jimenez, Hampus Andersson, Malin Lindstedt, Peter Ellmark. ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEA, activates myeloid cells in primary human tumors in vitro and induces anti-tumor immunity in vivo [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 2939.
Abstract 3149: Prediction of metabolic drug targets for cancer patients with poor prognosis by using genome-scale metabolic models and survival analyses
Authors: Lee Sang Mi , Lee GaRyoung , Kim Hyun Uk 
Published: April 2023

Abstract
Cancer metabolism has been extensively explored to identify biomarkers and novel drug targets for effective cancer treatment. In particular, it is expected that metabolism-derived data somehow reflects unique features associated with a cancer patient’s prognosis. Here, we introduce a computational framework that predicts metabolic drug targets by considering metabolites associated with poor prognosis. For inputs, the computational framework requires genome-scale metabolic models (GEMs) and survival data that represent each of cancer patients with diverse prognoses. GEM is a computational model that allows predicting fluxes of entire metabolic reactions in a patient-specific manner. By using this computational framework, a risk score, which reflects the prognosis of cancer patients, was first established on the basis of metabolites significantly associated with survival. Finally, metabolic reaction targets were predicted that could reduce the risk score (i.e., improving the prognosis) upon their knockdown in silico. In this study, this framework was applied to bladder cancer patients as a proof-of-concept demonstration, and predicted 13 metabolic reaction targets. These metabolic reaction targets were expected to be also effective to bladder cancer patients with poor prognosis. The computational framework developed in this study is distinct from previous drug targeting methods because it also considers unique metabolic features associated with cancer patients with poor prognosis in order to identify drug targets that are effective to both low-risk and high-risk groups of cancer patients.
Citation Format: Sang Mi Lee, GaRyoung Lee, Hyun Uk Kim. Prediction of metabolic drug targets for cancer patients with poor prognosis by using genome-scale metabolic models and survival analyses [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 3149.
Abstract 3170: Predicting the signals of adverse drug reactions on the basis of medical data
Authors: Jeon Junhyeok , Hong Eujin , Kim Hyun Uk 
Published: April 2023

Abstract
Multiple drugs are often prescribed for the better treatment of a disease. While the use of multiple drugs is to improve the overall therapeutic efficacy, it can also lead to unintended adverse drug reactions (ADRs) from drug-drug interactions (DDIs). More than 30% of ADRs have been reported to be caused by DDIs. Because of the importance of DDIs and ADRs, many computational models have been developed to predict DDIs and/or ADRs. However, these computational models mostly make predictions on the basis of molecular features of drugs without considering clinical factors, which consequently does not allow predictions in a person-specific manner. To address this problem, we present a machine learning model that predicts the signals of ADRs potentially caused by DDIs on the basis of medical data. Medical data used for model development come from MIMIC-IV, and include age, ethnicity, gender, patients’ disease information (i.e., ICD-10) and information on drugs administered (e.g., molecular structure and dose). The medical data were subjected to extensive preprocessing based on a domain knowledge, and multiple machine learning methods were examined to predict the ADR signals using the preprocessed dataset. ADR signals are captured by classifying whether each of the selected laboratory measurements (e.g., hematocrit, creatinine, and hemoglobin) is normal. The best-performing model showed the average AUROC of more than 0.8. The machine learning model developed in this study can be useful for examining potential harms when considering multiple drugs, including anticancer drugs.
Citation Format: Junhyeok Jeon, Eujin Hong, Hyun Uk Kim. Predicting the signals of adverse drug reactions on the basis of medical data [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 3170.
Abstract 3202: NanoBiT technologies for CAR-T characterization and potency testing
Authors: Gilden Julia K. , Stecha Pete , Paguio Aileen , Hartnett Jim , Binkowski Brock , Lazar Dan , Fan Frank , Cong Mei 
Published: April 2023

Abstract
Despite significant clinical advances in CAR-T cell therapies for cancer, the ability to precisely and reproducibly analyze the potency of these drug products remains a challenge. As new CAR-T products and production methodologies are developed, it is becoming increasingly important to be able to rigorously evaluate the relative potencies of each batch. We have developed two MOA-based bioluminescent assays that overcome challenges in quantitative assessment of T cell therapies. Both assays rely on split NanoBiT luciferase technology. In the HiBiT Target Cell Killing Assay, incubation of CAR-T cells with target cells stably expressing HiBiT results in lysis of the target cells and release of HiBiT proteins. These HiBiT proteins bind with high affinity to LgBiT in the detection reagent and form functional NanoBiT luciferase, resulting in production of light in proportion to target cell lysis. Lumit Immunoassays are a simple and homogeneous method for measuring cytokine production from engineered T cells. Monoclonal antibodies are covalently labeled with LgBiT and a low-affinity tag, SmBiT, which have negligible association in solution. When the antibodies are brought together by a common analyte, such as a cytokine, SmBiT and LgBiT can compliment to form NanoBiT luciferase and produce light in proportion to the concentration of analyte in the sample. Lumit Immunoassays can be run directly on cells, removing media transfer, dilution, and wash steps that can be common sources of error. These luminescent assays are homogenous, fast, highly sensitive, and have robust assay windows. They represent a new set of tools for development and characterization of T cell-based immunotherapies.
Citation Format: Julia K. Gilden, Pete Stecha, Aileen Paguio, Jim Hartnett, Brock Binkowski, Dan Lazar, Frank Fan, Mei Cong. NanoBiT technologies for CAR-T characterization and potency testing [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 3202.
Abstract 328: Acetylation regulates the oncogenic functions of PRMT5
Authors: Vo Tam Thuy Lu , Do Yen Thi , Pham Thi Tuyet Mai , Shin So-Jin , Kim Jin Young , Lee Seungmee , Ha Eunyoung , Seo Ji Hae 
Published: April 2023

Abstract
Protein arginine methyltransferase 5 (PRMT5) is an enzyme responsible for symmetric arginine methylation, which governs multiple crucial cellular events. PRMT5 expression and activity are dysregulated in many malignancies. PRMT5 dynamically shuttles between the cytosol and nucleus, and different subcellular localizations of PRMT5 imposes distinct cellular functions. However, the biological significance and underlying regulatory mechanism of PRMT5 translocation remain elusive. Herein, we found that PRMT5 acetylation/deacetylation status is a major determinant of its translocation and oncogenic function. PRMT5 acetylation not only drives its cytoplasmic localization but also enhances its methyltransferase activity, promoting cancer cell proliferation. On the other hand, PRMT5 deacetylation translocates PRMT5 into nucleus, to protect cells under the stress condition. Our current findings demonstrate that the acetylation/deacetylation-dependent subcellular localization of PRMT5 is a key regulator of its oncogenic properties.
Citation Format: Tam Thuy Lu Vo, Yen Thi Do, Thi Tuyet Mai Pham, So-Jin Shin, Jin Young Kim, Seungmee Lee, Eunyoung Ha, Ji Hae Seo. Acetylation regulates the oncogenic functions of PRMT5 [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 328.
Abstract 3293: CADM1 is a serum marker for small-cell lung cancer associated with poor prognosis and metastasis
Authors: Ito Takeshi , Funaki Toko , Iwanari Hiroko , Tanaka Goh , Nagase Takahide , Hamakubo Takao , Murakami Yoshinori 
Published: April 2023

Abstract
Small-cell lung cancer (SCLC) is aggressive neuroendocrine cancer that accounts for approximately 15% of lung cancer. Although chemotherapy is effective for SCLC, resistant tumors develop rapidly; therefore, early detection in the initial screening and after chemotherapy is one of the critical issues in controlling SCLC progression. For this purpose, neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) are used as tumor markers for SCLC but are not sensitive enough, especially in the early stages. Previously we found that Cell adhesion molecule 1 (CADM1) is highly expressed in SCLC, and an SCLC-specific splicing variant, CADM1v8/9, is selectively cleaved by ADAM17 protease to release the extracellular fragments. Here, we report that soluble CADM1v8/9 fragments (sCADM1v8/9) can be a serum marker of SCLC associated with poor prognosis and metastasis. Immunohistochemical analysis showed that the expression of CADM1 was observed in 83% of the resected SCLC cases and strongly correlated with that of INSM1, a marker of neuroendocrine differentiation. The high expression of CADM1 was associated with poor prognosis and nodal involvement, which was supported by experimental data showing that CADM1 promoted subcutaneous tumor growth and lymph node metastasis of SCLC cells in nude mice. Moreover, sCADM1v8/9 distinguished 47% of SCLC, including a significant portion of patients with limited disease SCLC, independent of and partly overlapped with the cases detected by ProGRP or NSE. Notably, a high amount of sCADM1v8/9 was observed in SCLC cases with liver metastasis or pleural effusion. Furthermore, serum levels of sCADM1v8/9 well reflected the change in tumor burden before and after chemotherapy. These findings indicate that detecting sCADM1v8/9 in sera would provide clinical benefits in diagnosis, follow-up, and metastasis prediction of SCLC cases.
Citation Format: Takeshi Ito, Toko Funaki, Hiroko Iwanari, Goh Tanaka, Takahide Nagase, Takao Hamakubo, Yoshinori Murakami. CADM1 is a serum marker for small-cell lung cancer associated with poor prognosis and 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 3293.
Abstract 330: EP300 loss drives tumorigenesis in bladder cancer via activation of IL-6/JAK/STAT3 signaling
Authors: Gao Sizhi P. , Rodrigues James A. , Sabel Amanda R. , Luo Jiaqian , Ziyu Chen , Tang Xinran , Mascareno Eduardo A. , Rustgi Naryan , Al-Ahmadie Hikmat , Kim Kwanghee , Pietzak Eugene J. , Iyer Gopakumar V. , Solit David B. 
Published: April 2023

Abstract
Bladder cancer (BLCA) is the sixth most common cancer in the U.S with 83,730 new cases, accounting for 17,200 deaths in the year 2021 and 212,536 deaths worldwide. EP300, a histone acetyltransferase gene, is mutated in ~17% of BLCA and in other cancer types such as endometrial cancer. The mechanisms by which EP300 mutations contribute to tumorigenicity of BLCA is not currently understood. To determine the phenotypic effects of loss-of-function EP300 mutations, we generated isogenic BLCA cells with EP300 knocked out (KO) using CRISPR/CAS9. Conspicuous changes in phenotypes consistent with more aggressive forms of cancer were observed in EP300-null BLCA clones, including luminal-basal histotype plasticity, anchorage-independent growth, enhanced in vitro and in vivo cell proliferation and enhanced invasion in Boyden chamber assays. To identify mechanisms whereby EP300 KO promotes increased oncogenicity, we performed phospho Tandem Tag Mass Spectrometry (TMT MS) using lysates from parental and EP300 KO cells. A notable finding was significantly increased expression of phosphorylated STAT3 (pSTAT3), which we subsequently confirmed by western blot. siRNA knockdown and selective inhibitor experiments indicated JAK1 as the upstream activator of pSTAT3 in BLCA cells. Studies of conditioned media (CM) from the EP300 KO cells using ELISA and neutralizing antibodies demonstrated that secreted IL-6 ligand and soluble IL-6R in the CM drove STAT3 activation through the IL-6 family common signaling subunit, gp130, i.e. trans-signaling. BLCA RT112 cells express an oncogenic FGFR3-TACC3 fusion and are sensitive to the FDA-approved FGFR kinase inhibitor erdafitinib. pSTAT3 expression was not dependent on FGFR3 signaling in EP300 KO RT112 cells, and EP300 KO was sufficient to confer erdafitinib resistance in a BLCA context. In sum, our results uncover that EP300 loss enhances IL-6/JAK/STAT3 signaling which promotes BLCA tumorigenesis and FGFR inhibitor resistance. Our findings elucidate a role for cytokine induced sterile inflammation in EP300-mediated tumorigenesis in bladder cancers and suggest that targeting the IL-6/JAK/STAT3 axis may represent a novel therapy strategy to overcome FGFR3 inhibitor resistance.
Citation Format: Sizhi P. Gao, James A. Rodrigues, Amanda R. Sabel, Jiaqian Luo, Chen Ziyu, Xinran Tang, Eduardo A. Mascareno, Naryan Rustgi, Hikmat Al-Ahmadie, Kwanghee Kim, Eugene J. Pietzak, Gopakumar V. Iyer, David B. Solit. EP300 loss drives tumorigenesis in bladder cancer via activation of IL-6/JAK/STAT3 signaling [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 330.
Abstract 3317: Expression of glucose transporter-1 in follicular lymphoma affected tumor-infiltrating immunocytes and was related to progression of disease within 24 months
Authors: Ma Jianli , Deng Yuwei , Zhao Shu , Yang Ming , Yu Yutian , Zhang Qingyuan , Yu Jinming 
Published: April 2023

Abstract
Objective Follicular lymphoma (FL) occurring progression within 24 months (POD24) after initial immunochemotherapy has poor prognosis. GLUT1 affects glycolysis within tumor microenvironment (TME) and promotes tumor progression. However, its specific mediated mechanism remains unclear in FL.
Methods Baseline GLUT1 expression, infiltrations of M2 macrophage, and CD8+ T-cells were assessed by immunohistochemistry in FL with POD24 and long-term remission respectively. The spatial features of TME were assessed by MIBI-TOF and proteomics. Predictive immunophenotypes for POD24 occurrence was analyzed by random forest algorithm. The lactate production and the induction of M2 macrophages were detected when GLUT1 was transfected or knocked down in DOHH2. The activation of PI3K/Akt/mTOR signaling in DOHH2 and WSU-FSCCL cells co-cultured with induced inhibitory immunocytes was tracked by western blotting.
Results The FL with POD24 exhibited higher baseline GLUT1 expression and increased infiltration of various inhibitory immunocytes. Spatial signatures of 69 immunophenotypes could predict POD24 occurrence. The activation of PI3K/Akt/mTOR signaling pathway was not significant in both groups. The supernatant of DOHH2-GLUT1 cells which had more lactate content could induce more M2-type macrophages than that of DOHH2/siRNA GLUT1 cells. When co-cultured with exhausted CD8+ T cells, M2-type macrophages and Tregs, compared with WSU-FSCCL cells, DOHH2 cells with high GLUT1 expression induced more M2-type macrophages and was triggered activation of PI3K/Akt/mTOR signaling pathway.
Conclusion Tumor cells overexpressing GLUT1 could domesticate immunocytes to form an immunosuppressive TME, which promotes occurrence of POD24 and gradually activates PI3K/Akt/mTOR pathway of tumor cells in FL.
Clinical correlation between GLUT1 expression and tumor-infiltrating macrophages and CD8+ T cells GLUT1 expression High n(%) Low n(%) P value CD206 expression High 16(43.2) 5(18.5) 0.037 Low 21(56.8) 22(81.5) CD8 expression High 27(73.0) 12(44.4) 0.021 Low 10(27.0) 15(55.6)
Citation Format: Jianli Ma, Yuwei Deng, Shu Zhao, Ming Yang, Yutian Yu, Qingyuan Zhang, Jinming Yu. Expression of glucose transporter-1 in follicular lymphoma affected tumor-infiltrating immunocytes and was related to progression of disease within 24 months [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 3317.
Abstract 3392: Antitumor activity of a potent MNK inhibitor NSP-1047 in acute myeloid leukemia
Authors: Li Bing , Huang Qionglin , Zhang Ke , Zhang Jianming 
Published: April 2023

Abstract
MAPK-interacting kinases (MNKs) phosphorylate the eukaryotic initiation factor 4E (eIF4E) and promote the synthesis of tumorigenic proteins. MAPK/MNK/eIF4E pathway is activated in many kinds of haematological and solid tumors. Here, we report the discovery of a novel polycyclic compound NSP-1047, which potently inhibits MNK1 and MNK2, and has sub-nanomolar cellular potency inhibiting phosphorylation of eIF4E. NSP-1047 potently inhibits the expression of multiple immune checkpoint proteins, including PD-1, Tim-3, and Lag-3, and it also inhibits the secretion of several inflammatory cytokines, such as IL-6, IL-8 and IL-10. NSP-1047 displays excellent ADME and pharmacokinetic properties, and demonstrates potent in vivo antitumor activity in acute myeloid leukemia animal models with tumor regression.
Citation Format: Bing Li, Qionglin Huang, Ke Zhang, Jianming Zhang. Antitumor activity of a potent MNK inhibitor NSP-1047 in acute myeloid leukemia [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 3392.
Abstract 340: Investigating the role of HMGA2 and AR crosstalk in prostate cancer cell proliferation
Authors: Awolowo Mojisoluwa Simisoluwa , Campbell Taaliah , Hawsawi Ohuod , Odero-Marah Valerie 
Published: April 2023

Abstract
Prostate cancer (PCa) is the most common non-skin cancer in men, and second leading cause of death. PCa occurs when cells within the prostate grow uncontrollably, creating small tumors. Generally, the growth/proliferation of the prostate is regulated by the male hormone, androgen, that binds androgen receptor (AR), a nuclear receptor that functions as a transcription factor and regulates the development and proliferation of the prostate as well as PCa. Interestingly, AR has become one of the leading pathways targets to slow down prostate cancer progression. In fact, enzalutamide a second-generation antiandrogen drug works to inhibit AR translocation into the nucleus. High Mobility Group AT-Hook (HMGA2) is a transcription factor protein that alters the structure of DNA by binding to the promoter region to regulate the transcription of genes. The expression of HMGA2 is associated with cancer proliferation and metastasis and is higher in PCa patients compared to men without cancer. Additionally, this gene has two isoforms HMGA2 full-length/wild-type and truncated (missing the carboxyl terminus). Preliminary studies shown that AR is localized in the nucleus of HMGA2 wild-type but not truncated overexpressing cells. Our hypothesis is that HMGA2 wild-type promotes AR translocation to the nucleus which leads to increased cell proliferation in PCa cells. We utilized HMGA2-wild-type and HMGA2-truncated overexpressing LNCaP cells and C4-2B enzalutamide resistant cells to knockdown either AR or HMGA2 with siRNA followed by western blot analysis, cell proliferation assay, and immunofluorescence. Our results show that HMGA2 siRNA led to decreased expression of wild-type (25 kDa long form) and truncated isoform (17 kDa) protein expression, and cell proliferation when compared to control siRNA. However, AR knockdown decreased AR expression in both cell lines but only decreased cell proliferation in HMGA2-wild-type and C4-2B enzalutamide-resistant cells. This suggests that HMGA2 wild-type works with AR to promote cell proliferation, whereas HMGA2-truncated promotes cell proliferation by an AR-independent mechanism. Therefore, we need to examine how current PCa treatments such as enzalutamide that target AR work in patients expressing differing HMGA2 isoforms.
Grant/Other Support: RISE: 5R25GM0058904, NIH/NIMHD 2U54MD007590; 5U54MD013376-8281; NSF S-STEM 2030608.
Citation Format: Mojisoluwa Simisoluwa Awolowo, Taaliah Campbell, Ohuod Hawsawi, Valerie Odero-Marah. Investigating the role of HMGA2 and AR crosstalk in prostate cancer cell proliferation [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 340.