bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3099: Biological evaluation of a novel AKR1C3 inhibitor in patient-derived prostate cancer cell line and xenograft models
Authors: Yang Joy C. , Ning Shu , Adomat Hans , Gleave Martin , Gao Allen , Evans Christopher P. , Liu Chengfei 
Published: June 2022

Abstract
INTRODUCTION AND OBJECTIVES: Prostate cancer is a highly heterogeneous cancer type with distinct genomic and phenotypic characteristics that drive tumorigenesis and the differential response to drug therapies. A limit number of prostate cancer cell lines and patient-derived xenograft (PDX) models hinders research to improve disease outcome. Some currently available PDX models were derived from the primary tumor samples are insufficient to recapitulate the clinical response at more advanced stages. In this study, we developed patient-derived models from patients with advanced disease and evaluated a novel AKR1C3 inhibitor in these models.
METHODS: Samples received from our Pathology Biorepository Shared Resource were divided into four groups and subjected to pathological staining, RNA extraction, xenografting in NSG mice via renal capsule and subcutaneous implantation in SCID mice and conditional reprogramed cultures (CRCs) or organoid culturing. The AKR1C3 inhibitor PB was modified from celecoxib. Androgen receptor (AR), AR-V7 and AKR1C3 expression were determined by western blot. The effects of the AKR1C3 inhibitor on enzalutamide sensitivity were characterized by growth assay and colony formation assay.
RESULTS: Eight PDX models have been developed from prostate cancer patients with high Gleason score and/or at the castration-resistant stages. Among the PDX models, one spontaneous indefinite cell line PS1172 was established. Early passage CRCs showed the epithelial morphology with AR positive expression. Through serially passaging PS1172 PDX with castration in SCID mice, the castration resistant cell line 1172CR was re-cultured from castration-resistant PS1172 PDX tumors. 1172CR cells were resistant to enzalutamide treatment and expressed high level of AKR1C3 and AR-V7. A novel AKR1C3 inhibitor (PB) which displayed superior potential to inhibit AKR1C3 activity and suppress enzalutamide resistant prostate cancer cell growth was tested in these models. At the same dose, PB significantly suppressed 1172CR cell growth and colony formation compared to indomethacin and enzalutamide. PB also significantly suppressed AR/AR-V7 protein expression compared to indomethacin in 1172CR cells.
CONCLUSION: PS1172 and castration-resistant 1172CR cells are novel models with significant characteristics such as AR-V7 and AKR1C3. These novel prostate cancer models are ideal for small molecule testing and resistant mechanism investigating.
Citation Format: Joy C. Yang, Shu Ning, Hans Adomat, Martin Gleave, Allen Gao, Christopher P. Evans, Chengfei Liu. Biological evaluation of a novel AKR1C3 inhibitor in patient-derived prostate cancer cell line and xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3099.
Abstract 3103: Liquid tumor orthotopic PDX models of acute leukemia
Authors: Chen Hongkui , Bi Lintao , Zhao Shizhu , Wang Shuai , Huang Wenqiang , Caggiula Josh , Van Loc , Wen Danyi 
Published: June 2022

Abstract
Liquid tumor orthotopic xenograft models were established by intra femoral injection on NCG mice using freshly prepared leukemia cells from peripheral blood (PB) or bone marrow (BM) of AML/ALL patient samples. The establishment of the orthotopic models were monitored by the flow cytometry analysis of peripheral blood of engrafted mice:CD45+/CD33+ for AML and CD45+/CD19+ for B-ALL. The double positive cells in the peripheral blood of the successfully transplanted model can reach 5-15%. Typically, it takes 120 -170 days to establish the P0 AML orthotopic model. It takes 45-60 days to establish the P0 ALL orthotopic model. Spleen from engrafted P0 mice was used for P1-P3 reconstitution of the orthotopic model. On these orthotopic models, we tested whether medicines such as etoposide, cytarabine, vincristine, ibrutinib and imatinib are sensitive. And anti-CD47 antibody was also tested on these models. NGS profiling was used to confirm the genotype of established orthotopic PDX.
Citation Format: Hongkui Chen, Lintao Bi, Shizhu Zhao, Shuai Wang, Wenqiang Huang, Josh Caggiula, Loc Van, Danyi Wen. Liquid tumor orthotopic PDX models of acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3103.
Abstract 311: Development of cludin-3 specific human monoclonal antibody(ABN501) as therapeutic anti-tumor agents
Authors: Choi Hong-Seok , Sim Euni , Kim Na Young , Lee Yong Jin , Lee Sae Hyung , Park Hayeon , Yang Hobin , Jo Jiwon , Seo Myeung-Ryun , Park Heegeon , Lee Ji-Hye , Hong Sungyoul , Shin Young Kee , Choi Jun-Young 
Published: June 2022

Abstract
The tight junctions of epithelial tissues, that most malignant tumors are derived from, are associated in cell-cell interactions. Among the tight junction proteins, claudin-3 (CLDN3) is overexpressed in many types of solid cancers, such as breast, ovarian, colorectal, and gastric cancers. Although CLDN3 can be potential therapeutic target due to the overexpression in various types of cancers, high homology with other CLDN family members is a hurdle to develop antibodies specifically targeting CLDN3. In this study, human IgG1 monoclonal antibody (ABN501) against CLDN3 was developed by scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. It was confirmed that ABN501 specifically bound to human and mouse CLDN3 without cross-reactivity to other CLDN family members. Sub-nanomolar affinity in binding kinetics of ABN501 was measured in CLDN3 expressing cell lines. We observed the antibody-dependent cytotoxicity (ADCC) activity of ABN501 with human NK cells expressing CD16a (NK-92MI-CD16a), in various cancer cell lines according to CLDN3 expression levels. We also confirmed that ABN501 specifically targeted CLDN3-expressing tumors in biodistribution assay using fluorescence-conjugated ABN501. In addition, ABN501 showed anti-tumor effects when treated with NK-92MI-CD16a in xenograft mice bearing CLDN3 expressing tumors. Taken these results together, we suggest that ABN501, specifically recognizing to CLDN3, can be used as therapeutic agents for CLDN3 positive cancer, and developed in many different forms to treat cancers with its specificity for cancer diagnosis, antibody-drug conjugates, and chimeric antigen receptor (CAR) immunotherapy.
Citation Format: Hong-Seok Choi, Euni Sim, Na Young Kim, Yong Jin Lee, Sae Hyung Lee, Hayeon Park, Hobin Yang, Jiwon Jo, Myeung-Ryun Seo, Heegeon Park, Ji-Hye Lee, Sungyoul Hong, Young Kee Shin, Jun-Young Choi. Development of cludin-3 specific human monoclonal antibody(ABN501) as therapeutic anti-tumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 311.
Abstract 3117: Next-generation characterization of patient-derived xenografts
Authors: Nakashima Jonathan , Do Long , Andrews Warren , Chien Yuan-Hung , Sperry Jantzen , Carapia Bianca , Yan Deborah , Rivera Giovanni , Federman Noah , Singh Arun , Eilber Fritz C. , Datnow Brian 
Published: June 2022

Abstract
Patient-derived xenografts (PDXs) have provided the research community with dynamic and robust translational model systems to study cancer biology and accelerate drug development. To advance translational oncology, we have developed a library of PDXs and provide next-generation sequencing characterization of these models. Here, we provide mutation and transcriptomic profiles of our PDX collection along with comparisons against matched normal and cancer patient profiles. Lastly, we provide a web portal providing comprehensive genomic profiles for every PDX model to identify mutation, copy number, fusions, microsatellite status, gene expression, and enriched pathways to facilitate identification of clinically relevant models.
Citation Format: Jonathan Nakashima, Long Do, Warren Andrews, Yuan-Hung Chien, Jantzen Sperry, Bianca Carapia, Deborah Yan, Giovanni Rivera, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow. Next-generation characterization of patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3117.
Abstract 3118: Functional characterization and therapeutic response differences between orthotopic and subcutaneous patient-derived xenograft models
Authors: Nakashima Jonathan , Do Long , Andrews Warren , Chien Yuan-Hung , Pedros Christophe , Sperry Jantzen , Carapia Bianca , Yan Deborah , Rivera Giovanni , Singh Arun , Eilber Fritz C. , Datnow Brian 
Published: June 2022

Abstract
Subcutaneous patient-derived xenografts (PDXs) have provided the research community with translational models to interrogate cancer biology and assist in drug development. Orthotopic PDXs provide an even more clinically relevant model system that recapitulates the tumor environment aspects of the human disease. Here, we compare the differences in gene expression signatures of PDX models when implanted subcutaneously or orthotopically. Furthermore, we evaluate differences in in-vivo pharmacological response between the two model systems and identify several functional characterizations that selectively enhance pharmacological response in favor of the orthotopic model.
Citation Format: Jonathan Nakashima, Long Do, Warren Andrews, Yuan-Hung Chien, Christophe Pedros, Jantzen Sperry, Bianca Carapia, Deborah Yan, Giovanni Rivera, Arun Singh, Fritz C. Eilber, Brian Datnow. Functional characterization and therapeutic response differences between orthotopic and subcutaneous patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3118.
Abstract 3131: High levels of potassium impair myeloid-derived suppressor cell functions
Authors: Puttalingaiah Ramesh Thylur , Ochoa Augusto C. , Sanchez-Pino Maria Dulfary 
Published: June 2022

Abstract
Excess salt consumption has been associated with elevated blood pressure, cardiovascular disease, obesity, diabetes, fatty liver, chronic inflammation, cancer, and autoimmune diseases. The direct impact of salts on immune cells is poorly studied; however, a recent report showed that a higher level of both sodium and potassium in the tumor microenvironment reduce tumor growth by enhancing T cell function. Separately, it was shown that intake of high levels of sodium reduced tumor growth by impairing myeloid-derived suppressor cell (MDSC) functions. Still, the effect of high levels of potassium on MDSCs has not been examined. Here, we hypothesize that an excess of potassium in an in-vitro culture of mouse bone marrow-derived MDSC (mBM-MDSC) and purified tumor-derived MDSC impairs the cellular metabolism and their immunosuppressive function. To explore this, we evaluated the effect of potassium (40 mM) on the oxygen consumption rate (OCR) as a measurement of mitochondrial oxidative phosphorylation (OXPHOS). We also tested the immunosuppressive function of MDSCs by protein expression of arginase I (ArgI), inducible nitric oxide synthase (iNOS), and the immune checkpoint PD-L1 on mBM-MDSC, as well as directly measuring their ability to inhibit T cell proliferation. While excess potassium does not influence the proliferation or viability of mBM-MDSCs, it does affect their immunosuppressive capacity by reducing ArgI, iNOS and PD-L1 expression. Furthermore, excess potassium increases the expression levels of the autophagosome marker LC3β, enhances OCR (an indicator of mitochondrial respiration), and improves the fitness of mitochondrial bioenergetics (maximum respiratory capacity). Interestingly, using the autophagy inhibitor 3-methyladenine (3-MA) in the presence of excess of potassium significantly reduces OCR and rescues ArgI expression compared to control or potassium treatment alone. Additionally, potassium significantly reduced the production of several chemokines and anti-inflammatory cytokines, including CXCL1, RANTES and IL-10, as well as the expression levels of C/EBP-β and phosphorylated AMPK, suggesting an alteration of key signaling pathways required for MDSC function. Collectively, this study provides evidence that high levels of potassium change the cellular metabolism of MDSC, reduce their immunosuppressive capacity, impair the signaling of AMPK, C/EBP-β, and promote autophagy. This may provide novel insights for further investigation on the impact of hyperkalemia or microenvironments with increased levels of potassium, such as intratumorally, on MDSCs and their role on tumor growth.
Citation Format: Ramesh Thylur Puttalingaiah, Augusto C. Ochoa, Maria Dulfary Sanchez-Pino. High levels of potassium impair myeloid-derived suppressor cell functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3131.
Abstract 3137: Elucidating the role of RNA-binding proteins in pancreatic cancer extracellular vesicle crosstalk
Authors: Finan Jennifer M. , Di Niro Roberto , Armstrong Randall , Brody Jonathan R. 
Published: June 2022

Abstract
Many solid tumors, including pancreatic ductal adenocarcinoma (PDAC) tumors, rely on pro-tumorigenic intercellular paracrine signaling during tumor progression. Extensive work has been done to understand paracrine signaling via cytokines, chemokines, and metabolites secreted from tumor cells, but only recent studies have begun to investigate the role of extracellular vesicles (EVs) and their cargoes in the tumor microenvironment. Studies have illustrated the ability of PDAC-derived EVs to activate and recruit pancreatic stellate cells in the tumor microenvironment; however, no work has been done in vivo to determine whether this EV uptake occurs within tumors. Additionally, little mechanistic work has been done to understand the functional consequences of EV cargo within recipient cells.
Based on transcriptomic and proteomic analysis of PDAC patient-derived EVs, mRNAs and RNA-binding proteins (RBPs) are enriched within EVs. Our lab focuses on the role of RBPs in PDAC, and thus, we will utilize enhanced crosslinking immunoprecipitation to identify the RBPs within PDAC EVs and evaluate their impact on the EV transcriptome. We have successfully isolated and characterized EVs via size exclusion chromatography isolation paired with western blotting for classical EV markers, fluorescent nanoparticle tracking analysis, and transmission electron microscopy. We have also demonstrated that we can identify mRNA cargoes that are bound and unbound by RBPs. Additionally, we have optimized PKH67 labeling and detection of PDAC EVs to assess specific and preferential uptake in vitro. Further, we are establishing the validated PalmGRET bioluminescent reporter in our patient derived cell lines to track PDAC EVs in a pancreatic orthotopic mouse model. Utilizing this method, we intend to identify cell types in the microenvironment that are importing PDAC EVs and perform functional studies to understand how these cells are impacted by EV signaling.
These studies will elucidate which cells in the PDAC tumor microenvironment import PDAC EVs, as well as interrogate the mechanistic role of PDAC EV crosstalk. This work will further characterize the role of RBPs in PDAC and begin to evaluate their role in a cell extrinsic manner.
Citation Format: Jennifer M. Finan, Roberto Di Niro, Randall Armstrong, Jonathan R. Brody. Elucidating the role of RNA-binding proteins in pancreatic cancer extracellular vesicle crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3137.
Abstract 3141: Toll-like receptor 4 knockout promotes cutaneous tumorigenesis in mice lack of Ikka heterozygous loss in keratinocytes
Authors: Singh Amit Kumar 
Published: June 2022

Abstract
Role of recognizing pathogen-associated molecular patterns in skin carcinogenesis has not been extensively studied. Toll-like receptor 4 (TLR4) recognizes gram-negative lipopolysaccharide. To explore the impact of interplay between TLR4-regulated microbiota and host epithelial cells on tumorigenesis, we adopted a mouse model that expresses hemizygous Ikkα gene induced by a keratin 5 Cre (K5.Cre, IkkααKC/+). IkkααKC mice die within 3 weeks after birth. Inducible Ikkα ablation mediated by K15.CrePR1 or K5.CreER results in spontaneous skin tumors. We found an increased incidence of spontaneous skin tumors in Tlr4-/-;IkkααKC/+ mice compared to Tlr4-/- or IkkααKC/+ mice. We detected markedly elevated bacteria numbers on the surface of skin tumors compared to the adjacent skin. Interestingly, the oral cavity of Tlr4-/-;IkkααKC/+ mice showed an elevated proportion of gram-negative bacteria compared to Tlr4-/- or IkkααKC/+ mice. To further determine the effect of bone marrow (BM)-derived hemopoietic cells on tumorigenesis, we performed BM transplant experiments. IkkααKC/+ mice with Tlr4-/- BM developed more cutaneous skin tumors than IkkααKC/+ mice with WT BM. Based on these findings, we hypothesized that Tlr4-/- hemopoietic cells regulate microbiota, which further results in altered skin carcinogenesis. We are revealing the detailed mechanism of how Tlr4-/- hemopoietic cells contribute to microbiota changes and tumorigenic promotion.
Citation Format: Amit Kumar Singh. Toll-like receptor 4 knockout promotes cutaneous tumorigenesis in mice lack of Ikka heterozygous loss in keratinocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3141.
Abstract 3143: RIG-I agonism promotes immune activation in syngeneic tumor model
Authors: Zielstorff Mark , Chen Yiping , Presland Jeremy , Byford Alan , Doty Amy , Munsell Erik , Parish Craig , Baltus Gretchen , Moy Lily , Addona George , Zhang-Hoover Jie 
Published: June 2022

Abstract
Activation of retinoic acid-inducible gene I (RIG-I) increases pro-inflammatory cytokine production, enhances antigen presentation, and promotes tumor cell apoptosis. Here we assessed the pharmacological activity of a RIG-I agonist encapsulated in lipid nanoparticle in the B16F10 mouse syngeneic tumor model. To probe whether additional pathways may complement RIG-I agonism, we tested our compound in combination with anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. The RIG-I agonist was administered intratumorally (IT) in B16F10 tumors. In one arm, tumors were collected four hours post treatment for cytokine analysis. In a separate arm, tumor size was measured twice a week for two weeks to assess efficacy. To understand the mechanism of action of the RIG-I agonist, high dimensional phenotyping of dissociated tumors collected at various time points was evaluated using CyTOF. Tumor-specific memory T cell response was evaluated by tumor re-challenge in vivo. Intra-tumoral dosing of the RIG-I agonist generated robust and dose-dependent production of type I IFN in the tumor that led to tumor efficacy in B16F10 model. Within 24 hours of the RIG-I agonist administration tumor infiltrating myeloid cells, NK cells, and T cells showed upregulation of activation markers such as CD69, CCR7, and Ki-67, and MHC I and PD-L1 were upregulated on CD45- cells. On day 10 of the treatment, the number of CD8+ T cells and NK cells in the tumor and their expression of granzyme B increased substantially. The RIG-I agonist dosed in combination with anti-PD-1 and anti-CTLA-4 monoclonal antibodies enhanced B16F10 tumor killing, including complete tumor regressions. No tumor growth was observed when these mice were re-inoculated with B16F10 cells. In conclusion, the RIG-I agonist encapsulated in lipid nanoparticle activates tumor infiltrating immune cells, promotes tumor killing, and combines favorably with anti-PD-1 and anti-CTLA-4 antibodies.
Citation Format: Mark Zielstorff, Yiping Chen, Jeremy Presland, Alan Byford, Amy Doty, Erik Munsell, Craig Parish, Gretchen Baltus, Lily Moy, George Addona, Jie Zhang-Hoover. RIG-I agonism promotes immune activation in syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3143.
Abstract 3144: Pleiotrophin drives a pro-metastatic immune niche within breast tumor microenvironment
Authors: Ganguly Debolina , Ngo Tuong V. , Coleman Morgan , Sorrelle Noah , Dominguez Adrian , Toombs Jason , Schmidt Marcel , Mora Fa V. , Ortega David G. , Wellstein Anton , Brekken Rolf A. 
Published: June 2022

Abstract
Immune cells in the tumor microenvironment (TME) can impact cancer cell invasion, seeding and colonization of secondary metastatic sites. Our findings show that Pleiotrophin (PTN), a unique and previously under-studied heparin binding cytokine, contributes to inflammation within the TME. PTN appears to be particularly efficient in recruiting neutrophils, which have been reported to cause immune suppression. Consequently, inhibition of PTN pharmacologically or genetically results in lower breast cancer metastasis to lungs and better survival in multiple mouse models of breast cancer. Corroborating our mouse studies, we have found that higher PTN expression in breast cancer patient plasma correlates with poor prognosis. Concurrently, stage IV breast cancer patients that have lower PTN expression have a highly significant survival advantage (median survival 78.27 months) over patients expressing high levels of PTN (median survival 27.5 months). Additionally, we have also found PTN positive cancer cells are enriched in metastatic lesions suggesting that PTN-high cancer cells are more successful at colonizing and surviving at the secondary site. Uncovering the function of PTN in these unique cancer cells might have a major impact in the clinical setting. Overall, our data suggests that PTN is important in driving a pro-metastatic immune niche within the TME that promotes tumor cell escape from the primary tumor and survival of metastatic cancer cells in secondary sites. Additionally, our studies highlight that inhibition of PTN has potential to reduce metastatic burden in breast cancer and suggest that future studies testing the combination of PTN inhibition with standard chemotherapy or immune therapy are warranted.
Citation Format: Debolina Ganguly, Tuong V. Ngo, Morgan Coleman, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Marcel Schmidt, Fa V. Mora, David G. Ortega, Anton Wellstein, Rolf A. Brekken. Pleiotrophin drives a pro-metastatic immune niche within breast tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3144.