bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3094: Discovery of a HeliconTM peptide inhibitor of the beta-catenin-TCF interaction with in vivo activity
Authors: White Brian H. , Si Yaguang , Cappucci Sarah , Li Zhi , Ramirez Jessica D. , Ponthier Charles M. , Visness Erica , Du Peicheng , Choi Minjung , Beerepoot Pieter C. , Ortet Paula C. , Jewett Ivan T. , Alfaro-Lopez Josue , Agarwal Sorabh , La Daniel , Fulgham Aaron , McGee John H. , Orford Keith , Hurov Jonathan B. , Tremblay Martin R. , Verdine Gregory L. 
Published: April 2023

Abstract
Wnt signaling pathway mutations leading to constitutive activation of the driver oncogene β-catenin occur in at least 20% of all human cancers, but β-catenin itself has remained undruggable by traditional modalities. In order to inhibit the activity of β-catenin, we have developed conformationally hyperstabilized α-helical peptides (Helicons) that are cellularly permeable and bind directly to β-catenin in order to block its interaction with TCF family of transcription factors.
Starting with a helical peptide derived from phage display, a combination of structural biology insights and medicinal chemistry optimization improved β-catenin binding of lead peptides to picomolar affinity. Cellular permeability was achieved by modification of physical properties as well as cyclization strategies to enforce helicity and manage backbone amide bonds. Helicons show excellent pharmacokinetic profiles suitable for intermittent dosing. β-catenin targeting helicons demonstrate on-target activity and potent inhibition of Wnt-driven tumor growth in vivo.
Citation Format: Brian H. White, Yaguang Si, Sarah Cappucci, Zhi Li, Jessica D. Ramirez, Charles M. Ponthier, Erica Visness, Peicheng Du, Minjung Choi, Pieter C. Beerepoot, Paula C. Ortet, Ivan T. Jewett, Josue Alfaro-Lopez, Sorabh Agarwal, Daniel La, Aaron Fulgham, John H. McGee, Keith Orford, Jonathan B. Hurov, Martin R. Tremblay, Gregory L. Verdine. Discovery of a HeliconTM peptide inhibitor of the beta-catenin-TCF interaction with in vivo activity [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 3094.
Abstract 3121: Exercise and tumor genomic landscapes in 2,879 patients with cancer
Authors: Tsai Brandon L. , Liu Lydia Y. , Eng Stefan E. , Underwood Whitney P. , Lee Catherine P. , Bliss Joshua W. , Boutros Paul C. , Jones Lee W. 
Published: April 2023

Abstract
Approximately two-thirds of cancer diagnoses globally are attributed to modifiable lifestyle factors such as smoking, diet and inactivity. Conversely, regular exercise is linked to decreased risk of multiple cancers. However, the underlying molecular mechanisms are not fully elucidated. Specifically, how exercise impacts tumor genomic landscapes has not been considered. To address this gap, we integrated clinical annotation of exercise exposure with tumor mutational profiling of 2,879 patients with cancer. Exercise exposure was evaluated by validated questionnaire and tumor genomic profiling of ≥ 505 commonly mutated cancer genes was performed using the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actional Cancer Targets (MSK-IMPACT) assay. Among the most represented cancer types were breast (n = 623), lung (n = 524), endometrial (n = 260), colorectal (n = 217) and prostate (n = 176). We found that exercise influences the genomic landscapes of tumors in a cancer-type specific manner. For instance, breast, colorectal and lung cancers from exercising patients had significantly lower tumor mutation burden (TMB) compared with non-exercisers. TMB of melanoma was significantly higher in exercisers versus non-exercisers. A pan-cancer analysis showed that mutations in SMAD3 were more frequent among exercisers, while mutations in STK11, KEAP1 and RBM10 were more frequent among non-exercisers. Overall, this study shows that exercise regulates tumor genomic landscapes and does so in a cancer-site specific manner.
Citation Format: Brandon L. Tsai, Lydia Y. Liu, Stefan E. Eng, Whitney P. Underwood, Catherine P. Lee, Joshua W. Bliss, Paul C. Boutros, Lee W. Jones. Exercise and tumor genomic landscapes in 2,879 patients with 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 3121.
Abstract 3192: Antitumor activity of ex vivo expanded tumor antigen priming cytotoxic T cells against malignant melanoma
Authors: Choi Jonggwon 
Published: April 2023

Abstract
Background: Dendritic cells have a unique ability to pick up antigen from tissues and migrate to the lymph nodes where they can cross-present cell-associated antigens with CD8+ T cells by MHC class I. Cytotoxic T lymphocytes remove malignant cells through recognition by T cell receptors of specific antigenic peptides that appear on the surface of cancer cells by the major histocompatibility complex class I/beta-2-microglobulin complex. In this study, we show that naive CD8+ T cells against the melan A antigens cells primed by DCs loaded with melan A antigens are able to kill malignant melanoma cell line (SK-MEL-28).
Methods: Peripheral blood mononuclear cells and Co-culture dendritic cells-T cells were seeded and MART-1 (100 ng/ml) reacted for 20 hours. ELISPOT ASSAY analyzes the degree of secretion of IFN-γ induced by Melan-A/MART-1 peptide stimulation in DC-T (1st week). In addition, the subtype analysis of T cells through FACS and the cytotoxicity activity of T cells was measured by tumor cell impedance with AXION.
Results: In ELISPOT ASSAY, it was observed that the number of positive spots increased significantly over time compared to 1st week. In FACS result analysis, CD4+ and CD8+ T cells increased, CD4+ T cell was observed as a dominant T cell subtype. As a result of cell impedance assay using Axion, it was observed that the number of tumor cells (SK-MEL-28) decreased according to the CTL:T ratio. In particular, cytotoxicity was observed immediately after co-culture and gradually showed cytotoxicity up to 72 hours.
Conclusion: Our study demonstrates that DCs loaded with killed allogeneic melanoma cells can cross-prime cytotoxic T cell which is specific for melan A antigen. In the future, additional T-cell studies targeting neoantigen and clinical studies applied to solid cancer patients will be conducted.
Keywords: Dendritic cell, CD4+/CD8+ T cell, Melan A antigen, Malignant melanoma
Citation Format: Jonggwon Choi. Antitumor activity of ex vivo expanded tumor antigen priming cytotoxic T cells against malignant 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 3192.
Abstract 3197: Adoptive T cell therapy using IL-7 and IL-15 expanded HER2-specific CD4 T cells for metastatic breast cancer
Authors: Gautam Namrata , Kodumudi Krithika , Snyder Colin , Beyer Amber , Costa Ricardo , Han Heather , Czerniecki Brian 
Published: April 2023

Abstract
BACKGROUND: Adoptive cell therapy (ACT) has had limited success due to low T cell infiltration in breast cancer (BC) patients. We have shown that administration of class II HER2 peptide pulsed type I polarized dendritic cell (DC1) vaccines leads to increase in CD4 T cells in the periphery of BC patients. In this study, we investigated the feasibility of expanding CD4 T cells from peripheral blood mononuclear cells (PBMC) of HER2-DC1 vaccinated BC patients.
METHODS: PBMCs from BC patients receiving HER2-DC1 vaccines were used for CD4 T cell expansion. PBMCs were co-cultured with HER2-DC1 at 10:1 ratio for initial activation followed by expansion with cytokines- IL-2 and IL-7 or IL-15. Expanded T cells were assessed for immune marker phenotyping by flow cytometry and TCRvb analysis. For TCRvB analysis, pre, post DC1, IL-7 and IL-15 expanded CD4 T cells were pelleted for DNA isolation and sequenced using Immunoseq Analyzer platform. In addition, we investigated the in vivo efficacy of adoptively transferred mouse IL-7/IL-15 expanded Her2 specific CD4 T cells in HER2+ TUBO mouse model.
RESULTS: Co-culturing of patient PBMCs with HER2-DC1 in the presence of cytokines IL-2, IL-7 and IL-15 expanded CD4 T cells ranging from 8-43 fold expansion in different samples with 92-98% CD4 phenotype. CD4 T cells expanded in IL-7 had stem like memory phenotype while IL-15 skewed to terminally differentiated CD4 T cells. IL-7 expanded T cells had significantly higher Tim3 and Ox40 expression, and effector memory proportion as compared to the IL-15 expanded T cells. Restimulation of expanded T cells with HER2 pulsed DCs showed HER2 specificity as measured by increased interferon-gamma production We identified top five clones in PBMCs from DC1-HER2 vaccinated BC patients compared to baseline. We observed differential abundance of TCR clones under IL-7 and IL-15 conditions and identified unique clones for IL-7 and IL-15. ACT using a combination of IL-7 and IL-15 expanded mouse CD4 T cells led to 50% tumor regression in HER2+ model.
CONCLUSION: These studies demonstrate that HER2 specific CD4 T cells can be successfully expanded from HER2-DC1 vaccinated patients. Post HER2 DC1 vaccine can generate a pool of antigen specific CD4 T cells and may offer a promising ACT for HER2 BC. Further studies are warranted to demonstrate the efficacy in the clinical setting.
Citation Format: Namrata Gautam, Krithika Kodumudi, Colin Snyder, Amber Beyer, Ricardo Costa, Heather Han, Brian Czerniecki. Adoptive T cell therapy using IL-7 and IL-15 expanded HER2-specific CD4 T cells for metastatic breast 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 3197.
Abstract 3199: Development of a flow cytometry-based assay for measuring specific CAR expression on LGR5-targeting CAR-T cells
Authors: Tyllis Timona , Abbott Caitlin , McPeake Dylan , Foeng Jade , Bandara Veronika , Gundsambuu Batjargal , Napoli Silvana , Mills Stuart , Thompson Emma , Tan Lih , Cowin Allison , Bonder Claudine , Sadlon Timothy , Barry Simon , McColl Shaun 
Published: April 2023

Abstract
The measurement of chimeric antigen receptor (CAR) expression is critical for the development, qualification and quantitation of CAR-T cells for clinical applications. There is a comprehensive range of tools commercially available for specifically measuring expression of the CAR on CD19-targeting CAR-T cells. However, with the rapidly expanding repertoire of CAR-T cells in development targeting a diverse range of tumour antigens, there is a paucity of readily implementable assays that specifically measure CAR expression, which is essential for translation into the clinic. We have developed several CARs targeting the cancer stem cell marker LGR5, one of which (CNA3103) is the lead candidate in an upcoming clinical trial in advanced metastatic colorectal cancer. Previously, the level of CNA3103 expression in this system has been determined indirectly by measuring expression of tEGFR on the CAR-T cell surface, taking advantage of co-expression of the CAR and tEGFR upon transduction with our lentiviral construct. tEGFR expression was found over many CAR-T cell manufacturing batches to report transduction efficiency reproducibly with high sensitivity. However, to specifically quantify expression of the CNA3103, an assay utilising an Fc-tagged recombinant human LGR5 protein, in combination with an anti-human IgG1 Fc-specific secondary antibody was developed. A number of optimisation steps including titration of multiple batches of rhLGR5-Fc, different anti-human IgG1 Fc-specific antibodies and a range of incubation parameters were tested. This resulted in development of an assay that yielded very similar reproducibility and sensitivity to that previously observed with the indirect tEGFR surrogate assay. Overall, the findings highlight the utility of using CAR-targeting recombinant proteins for evaluating CAR expression on CAR-T cells, providing a general flow cytometry-based staining strategy that may be adapted for assessing a diverse repertoire of CARs.
Citation Format: Timona Tyllis, Caitlin Abbott, Dylan McPeake, Jade Foeng, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Stuart Mills, Emma Thompson, Lih Tan, Allison Cowin, Claudine Bonder, Timothy Sadlon, Simon Barry, Shaun McColl. Development of a flow cytometry-based assay for measuring specific CAR expression on LGR5-targeting CAR-T 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 3199.
Abstract 3235: Protein kinase C is an upstream regulator of IL13Ra2 and small molecular activator enhances CAR T mediated killing
Authors: Subham Siddharth , Jeppson John D. , Schatmeyer Bryan , Forman Stephen J. , Brown Christine E. , Akhavan David 
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain cancer with a median survival of 16-20 months. Maximal safe resection and adjuvant chemotherapy improve survival but there is no cure and hence improved therapies are urgently needed. CAR T cell therapy has been FDA approved for hematologic malignancies but there are some barriers to their application for solid tumors in the clinic such as heterogenous tumor antigen expression. Chimeric Antigen Receptor (CAR) T Cells combine the cytolytic potency of T cells with the tumor specificity of an antibody. The interleukin 13 receptor alpha 2 (IL13Rα2) is an important target of CAR T cell therapy in ongoing GBM clinical trials. However, regulation of IL13Ra2 expression in GBM is unclear. Identifying upstream regulators of IL13Rα2 will not only help delineate IL13Rα2 carcinogenesis but also may help improve CAR T cell therapy. Utilizing knockout and overexpression constructs, we have identified protein kinase C family as an upstream regulator of IL13Rα2 transcription and translation in GBM cell lines. We have also identified a small molecule regulator of IL13Rα2, Ingenol-3-Angelate (I3A), that inhibits U87 tumor cell proliferation. Furthermore, I3A enhances IL13Rα2 re-directed CAR T cell mediated tumor cytolysis in vitro. Importantly, I3A treatment increases interferon gamma secretion by T cells. Taken together, our data implicates PKC isoforms as an upstream regulator of IL13Rα2. I3A treatment may serve as a therapeutic strategy to enhance CAR T mediated killing.
Citation Format: Siddharth Subham, John D. Jeppson, Bryan Schatmeyer, Stephen J. Forman, Christine E. Brown, David Akhavan. Protein kinase C is an upstream regulator of IL13Ra2 and small molecular activator enhances CAR T mediated killing [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 3235.
Abstract 3237: Dovitinib restricts EMT and promotes T cell recruitment to immune-desert gastric cancers via tumor-intrinsic IFN-γ signaling
Authors: Lu Heng , Cao Longlong , Soutto Mohammed , Bhat Nadeem , Chen Zheng , Peng Dunfa , Gomaa Ahmed , Nomura Sachiyo , Datta Jashodeep , Zaika Alexander , El-Rifai Wael 
Published: April 2023

Abstract
Background: Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumor-intrinsic and acquired immunotherapy resistance.
Methods: A novel immunophenotype-based subtyping algorithm was established to analyze tumor patient-derived bulk transcriptomic data. Gene set enrichment assays (GSEA), in vitro cell models, multiple syngeneic murine tumor models, and immune-checkpoint blockade (ICB) therapy were utilized.
Results: Our algorithm stratified human GC and showed that immune desert- and excluded-type tumors are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signaling is highly enriched in immune desert-type GC, and syngeneic murine tumors exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identifies a panel of receptor tyrosine kinases (RTKs) as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activates the tumor-intrinsic SNAI1/2-IFN-γ signaling axis and impedes the EMT program converting immune desert-type tumors to immune inflamed-type tumors, sensitizing these mesenchymal-like ‘cold’ tumors to CTLA4 blockade.
Conclusion: We develop a novel immunophenotype-based algorithm to reclassify GC into immune inflamed, excluded, and desert subtypes. Our analysis identified major signaling pathways and potential druggable targets relevant to patient groups, especially for refractory immune desert-type/‘cold’ tumors. Dovitinib, an RTK inhibitor, sensitizes desert-type immune-cold GCs to CTLA4 blockade and possibly in a broad spectrum of other solid tumors.
Citation Format: Heng Lu, Longlong Cao, Mohammed Soutto, Nadeem Bhat, Zheng Chen, Dunfa Peng, Ahmed Gomaa, Sachiyo Nomura, Jashodeep Datta, Alexander Zaika, Wael El-Rifai. Dovitinib restricts EMT and promotes T cell recruitment to immune-desert gastric cancers via tumor-intrinsic IFN-γ 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 3237.
Abstract 342: Differential CD45 isoform expression and function in AML versus healthy leukocytes
Authors: Ales Evan , Sackstein Robert 
Published: April 2023

Abstract
CD45 (the leukocyte common antigen) is a phosphatase present on all malignant and non-malignant leukocytes and hematopoietic progenitors and is the most abundant glycoprotein displayed by these cells. The human CD45 gene is alternatively spliced by reassortment of just three exons, exon 4 (“A”), exon 5 (“B”), and exon 6 (“C"), to create five distinct “R” isoforms (RO (no splice exons), RABC, RAB, RBC, and RB), with inclusion of A, B, or C exons enriching for expression of glycans (carbohydrates). Despite decades of investigation, the expression and phosphatase function of these isoforms on human AML cells remains unknown. To address this question, flow cytometry and western blot analysis was performed on AML primary cells (n=3) and KG1a and U937 cell lines versus healthy monocytes (n=3) utilizing exon-specific CD45-targetting mAbs. We then compared the contribution of CD45 phosphatase activity in KG1a and U937 cells versus healthy monocytes by employing a highly specific CD45 phosphatase inhibitor in cell culture for 24hrs, assessing induction of cell death after exposure to the inhibitor (n=3). Our results confirm reports of others indicating that "CD45RA- positivity" is a characteristic phenotype of AML cells, yet, distinctly, our data indicate that the most prevalent isoform identified on AML cells as "CD45RA-positive" is, actually, CD45RABC, the largest and most glycosylated isoform of CD45. This finding is in striking contrast to healthy monocytes, which do not express CD45RABC. Additionally, culturing of human AML cells with a CD45 phosphatase inhibitor induces rapid cell death within 24 hours but does not affect healthy monocytes. Thus, the conspicuous expression of the CD45 isoform CD45RABC among AML cells is associated with a survival advantage. Current studies in AML are directed to elaborating the prevalence of CD45RABC expression and uncovering the downstream effectors of its enzymatic activity to elucidate how such pathways sustain AML growth/survival.
Citation Format: Evan Ales, Robert Sackstein. Differential CD45 isoform expression and function in AML versus healthy leukocytes [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 342.
Abstract 345: Cutaneous T-cell lymphoma: ectopic expression of gametocyte specific factor 1 (GTSF1) stimulates the Th phenotype
Authors: Villarreal Amelia Martínez , Litvinov Ivan 
Published: April 2023

Abstract
Diagnosis of Cutaneous T-Cell Lymphomas (CTCL) can take up to 6 years, increasing the risk of disease progression in these patients. Transcriptomic analyses have helped identify several diagnosis biomarkers, such as TOX, KIRD3DL2, GTSF1 and others. Although not officially a Cancer-Testis (CT) antigen, ectopic expression of Gametocyte Specific Factor 1 (GTSF1), presents the same advantages than CT antigens. Its germline-cell restricted expression potentially makes this gene easily identifiable by the immune system and a therapeutic target with less side effects. The role of GTSF1 has been elucidated in mice, where it controls retrotransposon expression during germ-cell development. Here, we investigate the molecular function of GTSF1 in CTCL. Using shRNA-mediated GTSF1 knockdown in CTCL cell lines, our current work demonstrates an unexpected role of GTSF1 regulating the Th phenotype of CTCL cells. With multiple approaches (qRT-PCR, Western blotting and a dual-luciferase based retrotransposition assay) we concluded that GTSF1 knockdown does not lead to retrotransposon reactivation. Transcriptome analysis with RNA-Seq, followed by differential gene expression analysis with DESeq2 and pathway enrichment analysis with GO, KEGG, Reactome and WikiPathways, suggested an involvement of GTSF1 in the Th phenotype of CTCL cells. Differential gene expression analysis revealed 12,496 differentially expressed genes (p adjusted &lt; 0.05). Pathway enrichment analysis demonstrated an enrichment of several pathways including response to stimulus, immune response, response to cytokine and inflammatory response. More specifically, GTSF1 knockdown leads to an upregulation of the key cytokines associated with a Th1 phenotype, IFNG and TNF. Disease progression of CTCL is associated with a decrease in Th1 cytokine production and an enhanced Th2 cytokine production by malignant T cells. These findings shed light on the molecular function of GTSF1 as a regulator of the Th phenotype in CTCL and paves the way for the development of a valuable treatment target for CTCL patients.
Citation Format: Amelia Martínez Villarreal, Ivan Litvinov. Cutaneous T-cell lymphoma: ectopic expression of gametocyte specific factor 1 (GTSF1) stimulates the Th phenotype [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 345.