bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5145: Targeting TREX1 induces innate immune response in chemoresistant small cell lung cancer
Authors: Murayama Takahiko , Mahadevan Navin R. , Tani Tetsuo , Ma Xueying , Watanabe Hideo , Barbie David A. , Cañadas Israel 
Published: April 2023

Abstract
Small cell lung cancer (SCLC) is the most lethal type of lung cancer. The uniqueness of this tumor consists of an initial exquisite response to chemotherapy. However, at relapse, which occurs nearly in all patients, the tumor is resistant to all available therapies, causing a premature death of the patient. Despite the addition of immune checkpoint blockade (ICB) therapy to standard chemotherapy, response rates are modest and only a very small fraction of SCLC patients responds to these therapies. The mechanistic basis for acquired chemoresistance and impaired immunogenicity in SCLC remains to be elucidated. Here, we report that the expression of three prime repair exonuclease 1 (TREX1) is strongly induced in chemoresistant SCLCs. ATAC-seq and ChIP-seq analyses revealed a significant increase in chromatin accessibility of TREX1 gene locus in drug resistant SCLC cells. Depletion of TREX1 in SCLC cells caused the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway due to the cytoplasmic accumulation of DNA damage-associated double-stranded DNA (dsDNA) and micronuclei. Furthermore, targeting TREX1 induced an innate immune response and re-sensitized chemoresistant SCLC cells to chemotherapy. These findings suggest that TREX1 upregulation may be an important mediator of cGAS/STING pathway inactivation in cancer, contributing to the survival of resistant cells, and its inhibition may represent a promising therapeutic strategy to potentiate the efficacy of chemotherapy and immunotherapy in chemoresistant and immunologically ‘cold’ tumors, such as SCLC.
Citation Format: Takahiko Murayama, Navin R. Mahadevan, Tetsuo Tani, Xueying Ma, Hideo Watanabe, David A. Barbie, Israel Cañadas. Targeting TREX1 induces innate immune response in chemoresistant small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5145.
Abstract 5163: Local delivery of mRNA immunotherapy encoding HPV16 antigen, IL-12, and LIGHT/TNFSF14 results in superior immunogenicity and tumor clearance in a murine model of HPV16-driven cancer
Authors: Liu Weiqun , Da Silva Diane M. , Lemmens Edward E. , McKinlay Colin J. , Nath Sangeeta , Leong Meredith L. , Deutsch Samuel , Kast W. Martin , Haabeth Ole Audun W. 
Published: April 2023

Abstract
While intramuscular vaccination with HPV16 antigens has been shown to induce robust tumor-specific immune responses in the periphery, this has led to limited efficacy in the clinic. One potential explanation is the lack of sufficient infiltration of antigen-specific T cells into the tumor. The few T cells that make their way into the tumor are met with a plethora of negative signals that suppress their activity and abrogate local T cell expansion. To overcome this limitation of intramuscular cancer vaccines, we have developed an approach using in situ vaccination with a combination of immune modulators and tumor antigens, all encoded by mRNAs and delivered using nanoparticles. In this study, we show the superior efficacy and immunogenicity of a locally delivered mRNA cancer vaccine over that of an intramuscular HPV16 cancer vaccine. Both routes of administration result in robust induction of antigen-specific T cells, but local administration of mRNA-encoded antigens and immune modulators also resulted in enhanced infiltration of immune cells into the tumor, local Th1/M1 cytokine induction, and more-complete tumor clearance. Specifically, we found that the inclusion of the immunomodulators IL-12 and TNFSF14/LIGHT enabled tumor clearance in a murine tumor model. While tumors treated with mRNA-encoded HPV16 antigen alone induced robust systemic antigen-specific responses, minimal levels of local T cell expansion and infiltration, proinflammatory cytokine induction, and tumor control were observed. By contrast, tumors treated with mRNA-encoded HPV16 antigen, IL-12p70, and TNFSF14 completely cleared large established HPV16 expressing tumors with long-lasting recurrence free survival and immune memory. This observation was replicated in in a second murine tumor model, confirming the superior potency of locally delivered mRNA cancer vaccines in combination with immunomodulators. Consequently, we are developing a locally administrated mRNA therapy for the treatment of patients with cervical intraepithelial neoplasia (CIN).
Citation Format: Weiqun Liu, Diane M. Da Silva, Edward E. Lemmens, Colin J. McKinlay, Sangeeta Nath, Meredith L. Leong, Samuel Deutsch, W. Martin Kast, Ole Audun W. Haabeth. Local delivery of mRNA immunotherapy encoding HPV16 antigen, IL-12, and LIGHT/TNFSF14 results in superior immunogenicity and tumor clearance in a murine model of HPV16-driven 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 5163.
Abstract 5474: Combined use of MRI and TAM analysis in GB monitoring
Authors: Giordano Carolina , Pepa Giuseppe Maria Della , Romano Simona , Marrone Laura , Donzelli Carlo Maria , Romano Maria Fiammetta , Gaudino Simona 
Published: April 2023

Abstract
Glioblastoma (GB) is the most frequent and aggressive primary brain tumor. It is a highly infiltrating tumor. Complete eradication by surgery is difficult. The probability of survival beyond two years is very low. Magnetic resonance imaging (MRI) is a routine procedure for diagnosing gliomas. However, morphological MRI often fails to identify and quantify the presence of infiltration in peritumoral non-enhanced areas, resulting in inaccuracy in the assessment of invasive margins. Up to 50% of the patients show pseudo-progression. Morphological MRI fails to distinguish the marked enhancement in the tumor bed caused by radionecrosis from actual tumor progression. Diagnosis of GB recurrence through MR morphological sequences has a sensitivity and specificity of about 68% and 77%. Such percentages rise thanks to the use of non-morphological sequences (PWI, DWI, MRS), which are used in routine tumor protocols only in large centers and interpreted by expert neuroradiologists. Biomarkers in conjunction with MRI may help improve the classification, prognosis, and treatment choice. GB is highly infiltrated with monocytic cells, tumor-associated macrophages (TAMs), that invade the peripheral blood. Our group has recently identified a splice isoform of FK506-binding protein 51 (FKBP51) as a reliable TAM marker. We found an expansion in circulating CD163/FKBP51s monocytes in a cohort of GB patients. In patients with an MRI diagnosis of complete surgical tumor removal, these monocytes dramatically decreased. In patients with an MRI diagnosis of residual tumor, most of the peripheral CD163 monocytes that in the preoperative stage were FKBP51s- had turned into FKBP51s+. CD163/FKBP51s+ monocytes helped to distinguish between radionecrosis and actual tumor progression. These results suggest that circulating CD163/FKBP51s+ monocytes are associated with GB and can be helpful in monitoring GB patients.
Citation Format: Carolina Giordano, Giuseppe Maria Della Pepa, Simona Romano, Laura Marrone, Carlo Maria Donzelli, Maria Fiammetta Romano, Simona Gaudino. Combined use of MRI and TAM analysis in GB monitoring. [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 5474.
Abstract 5570: Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients
Authors: Kim Jae-Yoon , Park Seong-Hwan , Kim Seon-Young , Yoon Seok Joong , Kim Seon-Kyu 
Published: April 2023

Abstract
Background: Although recent advances in high-throughput technology and data-driven approach have provided many insights into non-muscle invasive bladder cancer (NMIBC), previous studies are still limited in their ability to predict the clinical behavior of NMIBC. Here, using deep learning method with long term follow-up data, we identified a prognostic gene set consisting of a small gene group for precisely predicting NMIBC heterogeneity.
Methods: We sought to identify progression-associated genes in patients with NMIBC using Cox regression analysis and verified their predictive values using a fully connected neural network (FNN) algorithm in five independent cohorts comprising more than 800 NMIBC patients. Based on these genes, a prognostic index (PI) in NMIBC progression was also developed. The association between the PI and prognosis of NMIBC patients was evaluated using Kaplan-Meier plots and log-rank tests.
Results: Gene expression profiling in NMIBC patients identified a prognostic gene set consisting of 1,789 genes for predicting NMIBC progression in a patient cohort (training set, n = 103). Their prognostic significances were validated based on FNN algorithm in other four independent cohorts (validation sets, n = 722). Pathway enrichment analysis revealed a twenty-three gene signature including known prognostic transcription factors such as FOXM1 and E2F1 along with novel genes. We incorporated these genes into the PI system, which was a significant prognostic indicator of NMIBC progression. The PI system was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade (each P &lt; 0.001). The subset analysis also revealed that the PI system could identify patients who would benefit from BCG immunotherapy.
Conclusions: The twenty-three gene-based PI represents a promising diagnostic tool for the identification of high-risk NMIBC patients who would display different clinical behaviours as well as response to BCG immunotherapy.
Citation Format: Jae-Yoon Kim, Seong-Hwan Park, Seon-Young Kim, Seok Joong Yoon, Seon-Kyu Kim. Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients. [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 5570.
Abstract 5659: Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrant O-glycosylated proteins
Authors: Aasted Mikkel K.M. , Groen Aaron C. , Keane John T. , Dabelsteen Sally , Tan Edwin , Schnabel Julia , Liu Fang , Lewis Hyeon-Gyu S. , Theodoropulos Constantine , Posey Avery D. , Wandall Hans H. 
Published: April 2023

Abstract
The lack of antibodies with sufficient cancer selectivity is currently limiting the treatment of solid tumors by immunotherapies. Most current immunotherapeutic targets are tumor-associated antigens also found in healthy tissues. Such targets often do not display sufficient cancer selectivity to be used for potent antibody based immunotherapeutic treatments, such as chimeric antigen receptor (CAR) T cells. Many solid tumors, however, display aberrant glycosylation that results in the expression of tumor-associated carbohydrate antigens that are not present on healthy tissues. Targeting aberrantly glycosylated glycopeptide epitopes within existing or novel glycoprotein targets may provide the cancer selectivity needed for immunotherapy of solid tumours, but only a few such glycopeptide epitopes have been targeted. Here, we used O-glycoproteomics data from multiple cell lines to identify a glycopeptide epitope in CD44v6, a cancer-associated CD44 isoform, and through a glycopeptide immunization strategy developed a cancer-specific monoclonal antibody, 4C8. 4C8 selectively binds to Tn-glycosylated CD44v6 in a site-specific manner with low nanomolar affinity. 4C8 was shown to be highly cancer selective by immunohistochemistry of sections from multiple healthy and cancerous tissues. 4C8 CAR T cells demonstrated target-specific cytotoxicity in vitro and significant tumor regression, and increased survival in vivo. Importantly, 4C8 CAR T cells selectively killed target cells in a mixed organotypic skin cancer model without affecting healthy CD44v6+ keratinocytes, indicating tolerability and safety. Targeting aberrantly glycosylated glycopeptide epitopes may provide the cancer selectivity needed for solid tumour immunotherapy.
Citation Format: Mikkel K.M. Aasted, Aaron C. Groen, John T. Keane, Sally Dabelsteen, Edwin Tan, Julia Schnabel, Fang Liu, Hyeon-Gyu S. Lewis, Constantine Theodoropulos, Avery D. Posey, Hans H. Wandall. Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrant O-glycosylated proteins. [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 5659.
Abstract 5693: Cancer cells subvert fibroblast function to promote a growth factor enriched tumor microenvironment in endocrine therapy resistant ER+ breast cancer
Authors: Griffiths Jason I. , Cosgrove Patrick A. , Castaneda Eric Medina , Nath Aritro , Chen Jinfeng , Adler Frederick R. , Chang Jeffrey T. , Khan Qamar J. , Bild Andrea H. 
Published: April 2023

Abstract
While endocrine therapy (ET) has considerably improved Stage II/III ER+ breast cancer survival rates, resistance emerges in 30-50% of patients. Recent advances have uncovered numerous cancer intrinsic and tumor-microenvironment mediated mechanisms contributing to ET resistance. However, the predominant mechanisms that prevent cure and ultimately lead to development of terminal metastatic cancer remain unknown. To reveal the leading causes of ET resistance in early-stage ER+ breast cancers, we used single-cell RNA sequencing to profile serial tumor biopsies from a larger cohort of patients. Patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor (ribociclib). We examined the evolution of tumor composition, cellular communication, and the phenotypic diversity of tumor-associated cancer and non-cancer cells throughout treatment. Our analyses reveal that ET-resistant tumors are fibroblast- and endothelial-enriched and consistently exhibit broad upregulation of growth factor signaling to cancer cells, with consistent activation of ERBB communication across patient tumors. Fibroblasts emerged as the primary source of these additional growth factor signals. Upregulation of fibroblast growth factor signaling (via NRG1/2, EGF and IGF) was commensurate with differentiation to a mesenchymal cancer-associated-fibroblast (myCAF) phenotype, which was itself stimulated by cancer cells through EGF and TGF signaling. In response to growth factor enrichment, cancer cells of ET-resistant tumors showed activation of MAPK signal transduction and downstream transcription factors promoting proliferation including FOS, JUN and TRIB1. These results indicate that ET resistance emerges in patient tumors when cancer cells subvert fibroblast function to promote a growth factor enriched tumor microenvironment permitting estrogen independent cancer proliferation.
Citation Format: Jason I. Griffiths, Patrick A. Cosgrove, Eric Medina Castaneda, Aritro Nath, Jinfeng Chen, Frederick R. Adler, Jeffrey T. Chang, Qamar J. Khan, Andrea H. Bild. Cancer cells subvert fibroblast function to promote a growth factor enriched tumor microenvironment in endocrine therapy resistant ER+ 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 5693.
Abstract 5793: Met confers radioresistance-associated aggressiveness through enhancing PLXDC2-mediated cancer stem cell plasticity
Authors: Chen Fanghui , Lang Liwei , Shay Chloe , Chen Georgia , Saba Nabil , Teng Yong 
Published: April 2023

Abstract
The development of radioresistance in head and neck squamous cell carcinoma (HNSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in the past decades. One of the clinical challenges is that radioresistance often promotes tumor aggressiveness. However, the underlying mechanisms and molecular determinants are largely unknown. We report here that radioresistance-associated HNSCC aggressiveness is effectively exacerbated by c-Met but can be suppressed by its genetic knockdown and pharmacological inactivation. Through unbiased RNAseq data, we further uncovered that the resulting upregulation of c-Met signaling increases the expression of PLXDC2. a critical gene associated with the tumor microenvironment. Mechanistically, PLXDC2 is upregulated in radioresistant HNSCC cells through c-Met mediated activation of ERK1/2-ELK1 signaling cascade. Most importantly, PLXDC2 modulates cancer cell plasticity by inducing epithelial-mesenchymal transition (EMT) and the emergence of cancer stem cell (CSC) subpopulation. Additionally, depletion of PLXDC2 overcomes c-Met-mediated radioresistance by reversing the EMT progress and blunting the self-renewal capacity of CSCs. Therapeutically, a combination of the c-Met selective inhibitor SU11274 with radiation remarkably induces tumor shrinkage and constrains tumor metastasis to lymph nodes in vivo. Our study is novel in being the first to explore the role and mechanism of the c-Met-PLXDC2 axis in radioresistance-associated HNSCC aggressiveness and the first to our knowledge to evaluate how to take advantage of blocking this signaling to overcome radioresistance in preclinical mouse models of HNSCC.
Citation Format: Fanghui Chen, Liwei Lang, Chloe Shay, Georgia Chen, Nabil Saba, Yong Teng. Met confers radioresistance-associated aggressiveness through enhancing PLXDC2-mediated cancer stem cell plasticity [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 5793.
Abstract 6703: Objective qualification of cell-free DNA by applying the cfDNA quality metric
Authors: Dorn Annika 
Published: April 2023

Abstract
Next Generation Sequencing (NGS) of cell-free DNA (cfDNA) has the potential to reveal new biomarkers for various conditions. Despite the establishment of low input library protocols, library preparation of cfDNA samples remains a challenge due to restricted amount of starting material and variable size distribution of cfDNA fragments. The yield and quality of cfDNA can vary and a lot of care is required to obtain appropriate cfDNA starting material for downstream applications. Further, cfDNA samples may contain high molecular weight (HMW) DNA that can negatively affect library yield and sequencing quality. Therefore, quality control of cfDNA starting material is essential to ensure the success of downstream experiments. The Agilent Tapestation system with the Cell-free DNA ScreenTape Assay is based on automated electrophoresis and thereby offers an objective and reliable qualification of cfDNA samples by applying the %cfDNA quality score. By comparing different samples with varying total DNA yield and HMW contamination, the additional level of information gained by the %cfDNA score is highlighted. While other QC methods might miss critical information on HMW DNA contamination, this could result in flawed yield estimations, ultimately threatening the successful outcome of downstream experiments. Therefore, accurate quantification of cfDNA starting material, taking also HMW DNA contamination into account is essential for NGS library preparation and generating reliable NGS results.
Citation Format: Annika Dorn. Objective qualification of cell-free DNA by applying the cfDNA quality metric [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 6703.
Abstract 6721: β3-adrenergic receptor correlates with tumor growth and progression in neuroblastoma
Authors: Boaretto Alessia , Bruno Gennaro , Nastasi Nicoletta , Favre Claudio , Calvani Maura 
Published: April 2023

Abstract
Neuroblastoma (NB) is a heterogeneous, often aggressive, extracranial tumor and the most common malignancy to be diagnosed in the first year of life. It has been already demonstrated that the specific antagonism of the β3-adrenergic receptor (β3-AR) on NB tumor cells affects tumor growth. To confirm the results obtained with the pharmacological approach on the crucial role played by the β3-AR receptor in influencing different pro-tumoral signaling pathways, here we investigated the effect of CRISPR/Cas9-mediated knock-out of β3-AR gene (ADRB3) on human NB cell line BE(2)-C in vitro and in vivo. Inoculation of BE(2)-C β3-AR−/- cells in athymic nude mice (NU(N-Cr)-Foxn1nu) showed a strong reduction of NB tumor growth compared to wild type cells, and in some cases β3-AR knock-out tumor cells failed in producing a tumor mass. RNA Sequencing on these tumor masses showed alterations of signaling pathways related to various tumor mechanisms, such as proliferation, cell motility and cell differentiation. Furthermore, we evaluated by flow cytometry the expression of β3-AR in circulating tumor cells (CTCs) from NB patients with different degrees of disease. Following depletion with anti-CD45 magnetic beads, tumor cells were identified through the expression of specific tumor markers, CD56 and GD2. Results showed that a high expression of β3-AR correlates with poor prognosis, characterized by metastatic or recurrent tumors, compared to patients with a favorable clinical outcome that instead show a low expression of β3-AR. Overall, our results demonstrate the β3-AR involvement in supporting NB tumor growth and suggest a possible role in regulating the metastatic potential of this tumor.
Citation Format: Alessia Boaretto, Gennaro Bruno, Nicoletta Nastasi, Claudio Favre, Maura Calvani. β3-adrenergic receptor correlates with tumor growth and progression in neuroblastoma. [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 6721.