bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2786: Seizure related 6 homolog (SEZ6), a cancer stem cell-specific secreted protein, is a novel GBM therapeutic target
Authors: Mukherjee Arani , Sengupta Shreoshi , Chowdhury Abhishek , Srivastava Anand , Somasundaram Kumar 
Published: March 2024

Abstract
Cancer Stem Cells (CSCs) are known to initiate a tumor, resist chemotherapy and radiotherapy, and also cause tumor recurrence. A deeper understanding of CSC biology is needed for a more effective therapeutic response. An integrative study of regulated transcriptome of human patient-derived Glioma Stem-like Cells (GSCs) using Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) identified a potential role for GSC in tumor angiogenesis. We chose Seizure Related 6 Homolog (SEZ6), one of the Wnt target genes, for further study, as its downregulation inhibited the potential of GSCs to induce angiogenesis without impacting GSC growth. SEZ6, a transmembrane protein, is shed upon cleavage by Beta-site APP cleaving enzyme 1 (BACE 1) and is known to be involved in normal neuronal functions; however, its role in cancer has not been studied yet.
SEZ6 silencing inhibited GSC-initiated tumor growth in an intracranial orthotopic mouse model due to reduced tumor angiogenesis and increased the mouse survival. Pre-treatment with a pharmacological inhibitor of BACE1 (BACE1i) prevented SEZ6 shedding from GSCs and inhibited the ability of the GSC-secretome to induce angiogenesis. Further investigations are ongoing to establish the use of BACE1i or BACE1-silencing as a novel therapeutic strategy to inhibit SEZ6-mediated tumor angiogenesis.
We also carried out a protein array-based investigation, which revealed that SEZ6 induced IL8 in endothelial cells to induce angiogenesis. Additional investigation showed that SEZ6 activated the TGFβ pathway in endothelial cells to induce IL8. SEZ6 interacted with TGFβRII as seen by confocal microscopy and co-immunoprecipitation. Generation of various deletion mutants of SEZ6 revealed that three Sushi [also known as complement control protein (CCP) module or the short consensus repeat (SCR)] domains, 3, 4, and 5, interacted with TGFβRII. Molecular docking and dynamic simulation studies identified Sushi-3 domain as the mediator of the interaction between SEZ6 and TGFβRII extracellular domain. Based on the above results, experiments are underway to design specific inhibitors of this interaction. We are also developing an improved BACE1 inhibitor that would inhibit the shedding of SEZ6 into the extracellular milieu to inhibit SEZ6 functions.
Thus, this study establishes that GSC-secreted SEZ6 activates the TGFβ pathway in endothelial cells to induce tumor angiogenesis and proposes a novel therapeutic target.
Citation Format: Arani Mukherjee, Shreoshi Sengupta, Abhishek Chowdhury, Anand Srivastava, Kumar Somasundaram. Seizure related 6 homolog (SEZ6), a cancer stem cell-specific secreted protein, is a novel GBM therapeutic target [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 2786.
Abstract 2790: Hematopoietic stem cells tropism and conditioned media for targeting the triple negative breast cancer stem cells and associated mechanism: An in vitro study
Authors: Mallick Sumit , P Sudheer Shenoy , Bose Bipasha 
Published: March 2024

Abstract
Triple-negative breast cancers are the most challenging to treat with targeted therapy because of their non-expression of cell surface receptors, unlike other types of breast cancer. However, conventional therapies such as chemotherapy, radiotherapy, and surgery are standard treatment modalities. Moreover, drug encapsulation strategies to deliver drugs at the targeted site have been sought-after alternatives. Hematopoietic Stem Cells (HSCs) have unique features to migrate towards inflammatory sites and other body organs during any injuries and release various cytokines, which lead to interaction with molecular pathways and results in reduced inflammation and tissue injuries. From this characteristic, we have hypothesized that hematopoietic stem cells can show tumor tropism and modulate the metabolic alteration in cancer and cancer stem cells, mainly focusing on Triple Negative Breast Cancer Stem Cells (TNBC CSCs). In this study, we have sorted both cancer stem cells and hematopoietic stem cells from TNBC and hematological cell lines, respectively. Sorted HSCs were cultured in specific conditions to prepare conditioned media. Then, both cell’ types were used for co-cultured assay and conditioned media cultured with TNBC-CSCs were performed. Metabolomics studies were performed to decipher the molecular interactions and TNBC-CSCs metabolic alterations. The result indicates that the HSCs are showing positive tropism towards TNBC stem cells. Furthermore, HSCs-derived conditioned media (CM) interact with the cell cycle pathway by downregulating the CDK genes and causing DNA breakage in the TNBC-CSCs. Moreover, the Metabolomics studies further confirmed that HSCs CM-derived cytokines interact with various pathways, dysregulating the TNBC-CSCs proliferation and altering the metabolic activities.
Citation Format: Sumit Mallick, Sudheer Shenoy P, Bipasha Bose. Hematopoietic stem cells tropism and conditioned media for targeting the triple negative breast cancer stem cells and associated mechanism: An in vitro study [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 2790.
Abstract 2840: Development, characterization, and validation of a systemic human mantle cell lymphoma model utilizing luciferase expressing Jeko-1 tumor cells
Authors: Harris David , Wong Andrew , Rainbolt Elizabeth , Westrick Nicole , Avery Justin , Kolb Joseph , Vunnava Aswani , Ward Zachary , Hall Chassidy , John Bincy 
Published: March 2024

Abstract
Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma that is clinically and biologically heterogenous. MCL murine models are scarce and reliable in vivo models are necessary for pre-clinical testing and identification of improved novel therapeutics. To address this need, we established and characterized a human MCL in vivo model by systemic implantation of the luciferase-expressing Jeko-1 cell line (Jeko-1-luc) into immunodeficient NCG mice. Tumor growth kinetics was evaluated by testing multiple cell inoculums, and disease progression was monitored by in vivo serial bioimaging, three-dimensional optical imaging (3D), and ex-vivo endpoint analyses. Jeko-1-luc tumor growth profile revealed moderate latency with a median survival of 40 days post implant. Subsequently, we utilized 3D optical imaging and ex-vivo imaging that confirmed the localization of tumor growth predominantly in lungs, spleen, and skeletal regions. Additionally, we determined the surface expression of selected B-cell lineage markers including CD19, CD20, and CD22. Next, we evaluated the efficacy and effect on survival in response to various standard of care agents including Vincristine, Rituximab, Palbociclib, Temsirolimus, and Cyclophosphamide. The quantification of tumor burden by in vivo and ex-vivo bioluminescent imaging demonstrated that the highest therapeutic activity and overall survival was achieved by Palbociclib and Vincristine. Flow cytometric analyses further demonstrated that tumor cells obtained from blood and selected tissues including spleen and bone marrow showed reduced tumor burden in treatment groups relative to the control group. Taken together, these results illustrate the translational value of the Jeko-1-luc model and provides a platform for evaluating novel treatment modalities for mantle cell lymphoma.
Citation Format: David Harris, Andrew Wong, Elizabeth Rainbolt, Nicole Westrick, Justin Avery, Joseph Kolb, Aswani Vunnava, Zachary Ward, Chassidy Hall, Bincy John. Development, characterization, and validation of a systemic human mantle cell lymphoma model utilizing luciferase expressing Jeko-1 tumor cells [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 2840.
Abstract 2849: Palbociclib as a novel therapeutic for desmoplastic small round cell tumor
Authors: Magrath Justin W. , Sampath Shruthi Sanjitha , Flinchum Dane A. , Hartono Alifiani B. , Goldberg Ilon N. , Boehling Julia R. , Savkovic Suzana D. , Lee Sean B. 
Published: March 2024

Abstract
Desmoplastic small round cell tumor (DSRCT) is an aggressive, pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. Targeted therapies are lacking and the current standard of care, multimodal therapy, is insufficient, leading to a 5-year survival rate of less than 25%. While the EWSR1-WT1 oncoprotein is critical to growth in vitro, its importance has yet to be examined in vivo. Further, the set of EWSR1-WT1 downstream targets critical to oncogenesis and the mechanism by which the two EWSR1-WT1 isoforms regulate them remain underinvestigated. Here we generate a toolkit of DSRCT cell lines that deplete EWSR1-WT1 in a doxycycline (dox)-inducible manner. This toolkit enabled us to establish the essentiality of EWSR1-WT1 not only in vitro but also for the first time in vivo. Using this toolkit, we performed RNA sequencing on four DSRCT cell lines and established the most comprehensive analysis of EWSR1-WT1 downstream targets to date. We discovered novel mechanistic insights into EWSR1-WT1 functionality including the uniqueness of its transcriptional alterations as compared to native WT1, the direct role of EWSR1-WT1 binding in gene upregulation, and the dominant role of the E-KTS isoform in transcription. Given the rarity of DSRCT, we focused on downstream targets with existing inhibitors and perform a drug screen that identified the CDK4/6 inhibitor palbociclib as a novel DSRCT therapeutic. We found that the E-KTS isoform of EWSR1-WT1 binds to the CCND1 promoter, leads to CCND1 expression, and stimulates DSRCT growth through the CCND-CDK4/6-RB axis. Palbociclib treatment conversely reduced DSRCT growth by preventing retinoblastoma phosphorylation and blocking the transition from G1 to S phase. Palbociclib treatment was effective not only in vitro but also in vivo where it significantly reduced tumor growth in two xenograft models of DSRCT. Given these novel findings and palbociclib’s previous approval by the FDA for the treatment of breast cancer, we advance palbociclib as an exciting DSRCT therapy that warrants urgent clinical investigation.
Citation Format: Justin W. Magrath, Shruthi Sanjitha Sampath, Dane A. Flinchum, Alifiani B. Hartono, Ilon N. Goldberg, Julia R. Boehling, Suzana D. Savkovic, Sean B. Lee. Palbociclib as a novel therapeutic for desmoplastic small round cell tumor [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 2849.
Abstract 2852: Novel combination therapy with a KAT6A/B inhibitor together with retinoids induces irreversible differentiation of neuroblastoma cells
Authors: Weichert-Leahey Nina , Berezovskaya Alla , Zimmerman Mark , Abraham Brian J. , Durbin Adam W. , Look A Thomas 
Published: March 2024

Abstract
Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system derived from migratory neural crest cells that have committed to become sympathetic neuroblasts, but their definitive differentiation is blocked. Neuroblastoma cell identity depends on the adrenergic core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive cell proliferation and the oncogenic gene expression program. Retinoic acid is used as differentiation therapy for patients with high-risk neuroblastoma, with the goal to block proliferation and drive sympathetic neuronal differentiation. We recently showed that retinoic acid re-organizes the enhancer landscape of neuroblastoma and promotes a new retino-sympathetic cell state characterized by MYCN downregulation, proliferative arrest, and sympathetic neuronal differentiation. However, the effects of retinoic acid on epigenetic rewiring of the adrenergic CRC and suppression of MYCN expression are reversible in vitro and in vivo, leading to tumor re-growth when the retinoic acid is withdrawn. Therefore, we sought to determine if retinoid-induced differentiation can be forced to progress to irreversible neuronal maturation by the addition of inhibitors of epigenetic modifying enzymes. Here, we conducted a drug screen of epigenetic modifying drugs alone and in combination with retinoic acid to determine their effects on neuroblastoma cell growth and differentiation. In this screen, we found that an inhibitor of the histone H3K23 acetyltransferases KAT6A/B, PF-9363, synergistically inhibits neuroblastoma cell growth in combination with retinoic acid. Moreover, retinoid-resistant neuroblastoma cell lines can be sensitized to retinoic acid when combined with a KAT6 inhibitor. Importantly, this combination treatment renders the differentiated cell state irreversible, such that it is maintained after retinoic acid is withdrawn, with continued suppression of the adrenergic CRC and MYCN expression. In conclusion, the retino-sympathetic differentiated cell state induced by retinoic acid in neuroblastoma becomes irreversible when the cells are also treated with an inhibitor of the KAT6A/B histone H3K23 acetyltransferases, implicating the essential role of these enzymes in restoring the proliferative immature progenitor phenotype in adrenergic neuroblastoma cells.
Citation Format: Nina Weichert-Leahey, Alla Berezovskaya, Mark Zimmerman, Brian J. Abraham, Adam W. Durbin, A Thomas Look. Novel combination therapy with a KAT6A/B inhibitor together with retinoids induces irreversible differentiation of neuroblastoma cells [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 2852.
Abstract 2876: Spatial immune cell atlas predicts the sensitivity to neoadjuvant PD-1 blockade treatment combined with radiotherapy in resectable esophageal squamous cell carcinoma
Authors: Yin Xiaoyang , Xu Kailun , Zheng Shu , Li Baosheng 
Published: March 2024

Abstract
Combination of radiotherapy and immunotherapy in neoadjuvant treatment seems a promising approach in resectable esophageal squamous cell squamous (ESCC). The clinical study of radiotherapy combined with PD-1 blockade therapy for neoadjuvant treatment of resectable ESCC shows good result. In order to investigate the underlying mechanism of the effectiveness of radiotherapy combined with immunotherapy in ESCC, we collected the pre and post neoadjuvant therapy samples from 5 responders and 5 non-responders ESCC patients and performed multiplexed tissue imaging using 28 markers. Using the detection measurements exported from QuPath, we performed the unsupervised clustering with Seurat and defined 20 cell types. Scimap was used to calculate the distance between different cell types. We found that CD4+ T, CD8+ T, cytotoxic CD8+ T cells and M1 macrophages showed an increase after treatment in both responders and non-responders. Tregs were decreased after neoadjuvant treatment in responder while there was no significant decrease in non-responder. And the distance between Tregs and cancer cells were increased in responders. Collectively, we provide an approach for investigating the underlying mechanism of the sensitivity to neoadjuvant PD-1 blockade treatment combined with radiotherapy in resectable ESCC using spatial multiplexed imaging.
Citation Format: Xiaoyang Yin, Kailun Xu, Shu Zheng, Baosheng Li. Spatial immune cell atlas predicts the sensitivity to neoadjuvant PD-1 blockade treatment combined with radiotherapy in resectable esophageal 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 2876.
Abstract 2878: Hyperthermia increases the efficacy of aminolevulinic acid-mediated photodynamic therapy in human osteosarcoma cells
Authors: Baugher Paige J. 
Published: March 2024

Abstract
Osteosarcoma is a malignant osteoid tumor that arises from mesenchymal cells exhibiting osteoblastic differentiation. Common treatments for this neoplasm include limb-salvage surgery and/or amputation of the affected limb, either of which can substantially decrease quality of life. Therefore, other, less invasive treatments should be explored. Photodynamic therapy (PDT) represents a more targeted, less invasive treatment possibility for osteosarcoma. Previous data from my laboratory demonstrated that aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) can be used to induce significant cell death in human osteosarcoma MG-63 cells in vitro. However, delivering high doses of drugs to deep osteosarcoma tumors could prove difficult, so we aim to explore the use of combination therapies to increase the efficacy of ALA-PDT in human osteosarcoma cells. Previous studies have shown that hyperthermia (increased temperature) can induce cell death in cancer cells. Furthermore, data suggest that combining PDT with hyperthermia can induce cell death in cancer cells synergistically by activating differential death-inducing pathways. However, hyperthermia in combination with ALA-PDT has not been explored in human osteosarcoma. Therefore, we aim to investigate the possibility that hyperthermia in combination with ALA-PDT can increase cell death in human osteosarcoma cells compared to ALA-PDT alone. Data from our lab show that compared to normal body temperature (37°C), cell death in MG-63 human osteosarcoma cells was not significantly increased by mild hyperthermia alone (40°C and 43°C respectively), while moderate hyperthermic temperatures alone (46°C and 49°C) did significantly increase cell death. We also found that at moderately hyperthermic temperatures, ALA-PDT does not increase cell death any further compared to moderate hyperthermia alone. Furthermore, we found that at the mildly hyperthermic temperature of 40°C, cell death was not significantly increased any further by ALA-PDT compared to ALA-PDT alone. However, our data do show that at a temperature of 43°C, hyperthermia plus ALA-PDT increased cell death compared to ALA-PDT alone. Therefore, our data suggest that inducing mild hyperthermia could increase the efficacy of ALA-PDT in human osteosarcoma cells.
Citation Format: Paige J. Baugher. Hyperthermia increases the efficacy of aminolevulinic acid-mediated photodynamic therapy in human osteosarcoma cells [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 2878.
Abstract 2919: Targeting regulatory T cells to boost immunity against melanoma
Authors: Miao Wanying , Jin Yingai J. , Jain Vaibhav , Gregory Simon , Zhang Jennifer Y. 
Published: March 2024

Abstract
Tumor-infiltrated regulatory T-cells (Treg) restrict the function of effector T-cells and thereby promote tumor growth. Disrupting the immunosuppression of Treg cells presents an attractive strategy for cancer immunotherapy; However, the risk of autoimmunity, resulting from systemic Treg depletion, limits its therapeutic effectiveness. Here, we show that genetic depletion of Ube2n in Treg cells inhibits tumor growth which is correlated with a markedly enhanced infiltration of cytotoxic immune cells. Notably, the deletion of Ube2n in a fraction of Treg cells was sufficient to produce a long-lasting anti-tumor effect, without apparent systemic autoimmune responses. The antitumor effect persists following adoptive T-cell transfer to an otherwise immunodeficient mouse tumor model. Through flow cytometry, immunostaining and T-cell targeted single-cell sequencing analyses, we demonstrate that the loss of Ube2n dampens Treg suppressive function, as indicated by markedly increased numbers of cytotoxic CD8 T-cells in the tumor microenvironment (TME). Further, differentially expressed genes analyses show a downregulation of Mki67 and an upregulation of Ifng in Ube2n deficient Tregs, concomitant with amplification and activation of effector T-cells. Our findings uncover a hitherto unexplored role of Ube2n in orchestrating the differentiation and functions of Treg in TME, highlighting the therapeutic potential of targeting this pathway to enhance and reprogram anti-tumor immunity.
Citation Format: Wanying Miao, Yingai J. Jin, Vaibhav Jain, Simon Gregory, Jennifer Y. Zhang. Targeting regulatory T cells to boost immunity against melanoma [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 2919.