bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3938: In vivo genome-wide CRISPR screen in pancreatic ductal adenocarcinoma defines HSPE1 as a potential oncogene by acting through G2/M cell cycle arrest
Authors: Boudreault Julien , Wang Ni , Yan Gang , Dai Meiou , Poulet Sophie , Daliah Girija , Lebrun Jean-Jacques 
Published: April 2023

Abstract
Superior knowledge of cancer biology has enabled unprecedented innovations in therapies targeting mutated driver genes. Despite the attempt of targeting cancer-inducing genes such as KRAS, the life expectancy of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) has poorly improved. We performed an unbiased genome wide in-vivo loss-of-function CRISPR screen to discover novel oncogenes and identified heat-shock protein HSPE1, whose function is still unknown in PDAC. By decreasing HSPE1 expression with shRNA and CRISPR technology, we detected a slowdown in cell growth of PDAC cancer cells. HSPE1 knock-out cells injected in mice displayed a drastic reduction in tumor volume. We exploited this vulnerability by disrupting HSPE1 function by using KHS101, a validated HSPD1-HSPE1 complex inhibitor. Several PDAC cell lines cultured in vitro were sensitive upon KHS101 treatment and in vivo administration of KHS101 reduced tumorigenesis. Compiling the negative fitness scores from DepMap database revealed a co-dependency between HSPE1 and PLK1, a protein involved in regulating G2/M checkpoint. Indeed, we detected a protein-level decrease of PLK1 in our experimental model of PDAC cells having either a drug-induced HSPE1 deficiency by KHS101 exposure or a HSPE1 gene-expression reduction by shRNA. We found that the cell cycle was disrupted through G2/M arrest in PDAC cells treated with KHS101. Our findings highlight a new role underlying PDAC tumorigenesis for HSPE1 and could unlock a new area of research towards precision medicine.
Citation Format: Julien Boudreault, Ni Wang, Gang Yan, Meiou Dai, Sophie Poulet, Girija Daliah, Jean-Jacques Lebrun. In vivo genome-wide CRISPR screen in pancreatic ductal adenocarcinoma defines HSPE1 as a potential oncogene by acting through G2/M cell cycle arrest. [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 3938.
Abstract 3961: Identification of lncRNAs as potential novel therapeutic targets in triple negative breast cancer
Authors: O'Malley Megan , Rana Zohaib , Sarkar Debina , Chia Jolyn , Diermeier Sarah 
Published: April 2023

Abstract
Triple negative breast cancer (TNBC) lacks targeted therapies. Recently, our laboratory and other groups described long non-coding RNAs (lncRNAs) as new drivers of TNBC progression, which represent an exciting new avenue for targeted treatments. LncRNAs are the most versatile and diverse class of non-coding RNAs with roles in the progression of TNBC development, including cell proliferation, differentiation, apoptosis, metastasis and drug resistance. LncRNAs have greater tissue-specific expression compared to proteins and can be targeted using nucleotide sequence-specific RNA therapeutics, leading to reduced systemic toxicities when used as a cancer target. Using a combined approach of computational analysis of patient data and CRISPR functional screening, we identified hundreds of lncRNAs as novel drivers of TNBC. We prioritized one lncRNA target (lncTNBC3) with high translational potential. LncTNBC3 knockdown lead to reduced TNBC cell proliferation in two different loss-of-function models. To gain initial insights into the mechanism via which lncTNBC3 functions, RNA sequencing was carried out on knockdown cells, revealing that lncTNBC3 impacts cell cycle and DNA repair pathways. Cell cycle analysis confirmed an increase in G2/M cell cycle arrest upon lncTNBC3 knockdown. In conclusion, we have identified a promising novel lncRNA target with a role in TNBC growth.
Citation Format: Megan O'Malley, Zohaib Rana, Debina Sarkar, Jolyn Chia, Sarah Diermeier. Identification of lncRNAs as potential novel therapeutic targets in triple negative 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 3961.
Abstract 4075: A modified FcγRI expressing-T cell, SolidT, enables antibody-mediated cytotoxicity to overcome the limitations of CAR-T cell therapy against solid tumors
Authors: Rasoulouniriana Diana , Santana-Magal Nadine , Gutwillig Amit , Farhat-Younis Leen , Shpilt Hana , Dotan Shahar , Pilpel Noam , Rider Peleg , Carmi Yaron 
Published: April 2023

Abstract
The pioneering design of chimeric antigen receptor T-cell (CAR-T) therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironment limit their efficacy in solid tumors. Recently, we characterized a novel subset of tumor-infiltrating CD4+ T-cells expressing the FcγRI receptor (Rasoulouniriana et al, 2019). Herein we detail the engineering of a novel receptor, based on the FcγRI structure, which is retrovirally transduced into PBMCs (both CD4 and CD8 T-cells). These cells, named SolidT cells, can target tumor cells using antibody intermediates. They show effective and specific cytotoxicity only when an appropriate antibody is added. Only target-bound antibodies activate these cells, while free antibodies are internalized without activation. Their cytotoxic activity is correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevents premature exhaustion. Furthermore, during ADCC these cells secrete attenuated cytokine levels compared to CAR-T, thereby enhancing their safety profile. These cells eradicate established melanoma tumors, infiltrate the tumor microenvironment and facilitate host immune cell recruitment in immunocompetent mice. In NSG mice, they infiltrate, persist, and eradicate tumors. As opposed to CAR therapies, which require changing the receptor across different types of cancer, our engineered T-cells remain the same throughout tumor types, while only the injected antibody changes. As such, can be adapted to treat a wide range of solid cancers without changing the manufacturing program. Overall, SolidT cells are capable of binding tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing a high density of tumor-associated antigens.
Citation Format: Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Hana Shpilt, Shahar Dotan, Noam Pilpel, Peleg Rider, Yaron Carmi. A modified FcγRI expressing-T cell, SolidT, enables antibody-mediated cytotoxicity to overcome the limitations of CAR-T cell therapy against solid tumors. [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 4075.
Abstract 4126: Anti-tumor immunity of M9657, a conditional CD137 immune agonist, is correlated with mesothelin expression on tumor cells
Authors: Xu Chunxiao , Zhou Xueyuan , Yalavarthi Sireesha , Schweickhardt Rene , Blaukat Andree , Helming Laura 
Published: April 2023

Abstract
Background: In clinical trials, systemic administration of first-generation CD137 agonist monotherapies was suspended due to either low anti-tumor efficacy or hepatotoxicity mediated by the epitope recognized on CD137 and Fc gamma receptor (FcγR) ligand-dependent clustering. M9657 is a bispecific conditional agonist that has been developed to bind simultaneously to mesothelin (MSLN) and CD137 to stimulate an anti-tumor immune response in the tumor microenvironment. M9657 was engineered in a tetravalent bispecific antibody (mAb2™) format with a human IgG1 backbone with LALA mutations, which abrogates binding to FcγRs but retains FcRn binding for IgG-like pharmacokinetics. M9657 is expected to have enhanced anti-tumor efficacy while avoiding systemic immune activation.
Methods: MSLN surface copy number was quantified in a series of cancer cell lines with a broad range of MSLN expression. CD8+ T cell-mediated tumor cell cytotoxicity and cytokine release from CD8+ T cells were investigated in a series of in vitro functional assays. The receptor occupancy (RO) of MSLN on the tumor cell surface and of CD137 on CD8+ T cells was determined by flow cytometry. MSLN in EMT-6 cells was knocked out using CRISPR and confirmed by immunohistochemistry. The anti-tumor efficacy of FS122m, a murine-reactive surrogate of M9657, was investigated in EMT-6 parental and MSLN knockout syngeneic tumor models.
Results: M9657 displayed MSLN-dependent cytokine release and tumor cell cytotoxicity. IFNγ release by CD8+ T cells correlated with MSLN copy number on tumor cells. MSLN copy number of 3000 was found to be the minimum required to trigger CD137 agonism. CD137 RO by M9657 on activated human CD8+ T cells and MSLN RO by M9657 on tumor cells increased with increasing concentrations of M9657. M9657 caused full agonism (EC100) when CD137 RO on activated human CD8+ T cells was approximately 30-38%. The mouse surrogate FS122m demonstrated potent dose-dependent anti-tumor efficacy in the EMT-6 tumor model, while no anti-tumor efficacy was observed in MSLN knockout tumors, which further confirmed that MSLN expression is required for M9657 anti-tumor immunity.
Conclusion: M9657 exhibits promising and potent MSLN-dependent conditional immune agonism, supporting its clinical investigation.
Citation Format: Chunxiao Xu, Xueyuan Zhou, Sireesha Yalavarthi, Rene Schweickhardt, Andree Blaukat, Laura Helming. Anti-tumor immunity of M9657, a conditional CD137 immune agonist, is correlated with mesothelin expression on tumor 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 4126.
Abstract 415: Metabolic reprogramming driven by IGF2BP3-COX6B2 axis promotes acquired resistance to EGFR-TKIs in non-small lung cancer
Authors: Lin Ziyou , Li Jingwei , Zhang Jian , Feng Weineng , Lu Jiaye , Ma Xiaofan , Ding Wen , Ouyang Shumin , Lu Jinjian , Yue Peibin , Wan Guohui , Liu Peiqing , Zhang Xiaolei 
Published: April 2023

Abstract
Acquired resistance represents a bottleneck to molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer, but its role in acquired resistance has not been fully understood. In this study, we discovered a novel mechanism of TKI resistance involved in IGF2BP3-dependent crosstalk between the epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis. We demonstrated the upregulated expression of RNA binding protein IGF2BP3 reduced the sensitivity of TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). Analysis of patient samples revealed a positive correlation between IGF2BP3 and COX6B2 and poor prognosis in lung cancer patients. We further confirmed that COX6B2 is a key downstream target in IGF2BP3-mediated acquired TKI-resistance. Mechanistically, IGF2BP3 bound to the 3’-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, IGF2BP3 significantly enhanced OXPHOS capacity in lung cancer through the IGF2BP3-COX6B2 axis by regulating nicotinamide metabolism, thus resulting in TKI resistance in lung cancer. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in remarkable growth inhibition in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, our findings suggest that metabolic reprogramming directed by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance, and targeting the metabolic pathway provides a new therapeutic strategy to overcome EGFR-TKI resistance in lung cancer.
Citation Format: Ziyou Lin, Jingwei Li, Jian Zhang, Weineng Feng, Jiaye Lu, Xiaofan Ma, Wen Ding, Shumin Ouyang, Jinjian Lu, Peibin Yue, Guohui Wan, Peiqing Liu, Xiaolei Zhang. Metabolic reprogramming driven by IGF2BP3-COX6B2 axis promotes acquired resistance to EGFR-TKIs in non-small 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 415.
Abstract 4156: Site specific tumor response to combination chemotherapy and immune checkpoint inhibitor in the syngeneic Pan02 pancreatic ductal adenocarcinoma model
Authors: Wong Andrew , Fadden Patrick , Clouse Cara , Wood Patrick , Brown-Augustine Marianna , Zhao Fei , Ser Elliot , Kolb Joseph , Hall Chassidy , Rainbolt Elizabeth 
Published: April 2023

Abstract
Syngeneic tumor models provide a platform to assess novel immune-oncology therapeutics in fully immuno-competent mice. A subcutaneous flank tumor implant provides a convenient and accessible location to monitor the tumor growth and response to therapy. However, the tumor microenvironment, and therefore, the responsiveness to immuno-oncology therapies, is greatly impacted by the location in which the tumor develops (Ho 2021, Oliver 2018). Given the potential of different immuno-suppressive features driven by the specific tumor location, we wanted to compare the tumor infiltrating leukocyte populations in the subcutaneous flank and orthotopic pancreatic Pan02 syngeneic models, as well as the response to standard of care therapies. Pan02 cells were either implanted orthotopically in the pancreas or subcutaneously in the flank and allowed to establish before dosing with either vehicle, oxaliplatin, anti-CTLA-4 or the combination of therapies. Established tumors from untreated orthotopic and flank models were sampled for flow cytometry to assess infiltration by a broad range of immune cell populations. Response to therapy was clearly dependent on tumor location with flank tumors being resistant to both monotherapy and combination therapy, while the orthotopic tumors responded modestly to monotherapy but displayed synergy with the combination therapy. The results suggest that for a given syngeneic tumor cell line with identical mutational load and antigenicity, we can generate unique tumor microenvironments dependent on implant location leading to different outcomes when testing novel immune-oncology therapies. These types of models can help define the context in which novel immune-oncology therapeutics can be expected to drive an effective immune response.
Citation Format: Andrew Wong, Patrick Fadden, Cara Clouse, Patrick Wood, Marianna Brown-Augustine, Fei Zhao, Elliot Ser, Joseph Kolb, Chassidy Hall, Elizabeth Rainbolt. Site specific tumor response to combination chemotherapy and immune checkpoint inhibitor in the syngeneic Pan02 pancreatic ductal adenocarcinoma model. [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 4156.
Abstract 4238: Specific oral microbiome is closely associated with oral potentially malignant disorders and oral squamous cell carcinoma
Authors: Kioi Mitomu , Isono Hiroshi , Nakajima Shintaro 
Published: April 2023

Abstract
Background: Bacterial and virus infection may cause pre-malignant and malignant disorder such as hepatocellular carcinoma and cervical cancer. Recent studies reported that oral bacterium is associated with gastric and colon cancer. However, it is not clear yet if the oral microbiome affects the development of pre-malignant disorder in oral cavity and oral cancer. Thus, this study aims to identify the periodontal pathogen candidates involved in the onset and progression of oral squamous cell carcinoma (OSCC).
Materials and Methods: Saliva was collected from 112 patients without oral mucosal diseases (OMDs) as control, 36 patients with oral potentially malignant disorders (OPMDs), and 104 patients with OSCC, and DNA was extracted in each sample. Periodontal examinations were performed on all patients. Endpoint-PCR was performed on seven species of oral pathogens using the extracted DNA. 16S ribosomal RNA (rRNA) was utilized for analysis of oral microbiome with 20 samples in each group. 4-nitroqquinoline-1-oxide (4-NQO)-induced tongue tumor model in mice was analyzed with or without endotoxin of one of the oral bacteria, Porphyromonas gingivalis (P. gingivalis).
Results: From the statistical analysis of the clinical parameters, periodontal disease tended to worsen in the OMPD and OSCC groups compared to the control group. The number of oral bacteria was significantly higher in the OSCC group than those in other groups. From PCR results, the detection rates of P. gingivalis, Aggregatibacter actinomycetemcomitans, and Treponema denticola were significantly higher in the OSCC group than those in the control group. From 16S rRNA analysis, the relative abundance of Prevotella buccae and intermedia was significantly higher in OSCC groups than in the control group. Furthermore, the relative abundance of P. gingivalis was higher in the OSCC group compared to other groups, regardless of age and the number of teeth. In mouse model, mice treated with P. gingivalis-derived endotoxin developed oral leukoplakia at earlier time points and tumors significantly higher lesions compared to control group.
Conclusion: These results suggest that specific periodontal pathogens are present in the oral cavity of OPMDs and OSCC patients and those changes in the bacterial flora due to their presence may contribute to the onset and progression of OMDs.
Citation Format: Mitomu Kioi, Hiroshi Isono, Shintaro Nakajima. Specific oral microbiome is closely associated with oral potentially malignant disorders and oral squamous cell carcinoma. [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 4238.
Abstract 4279: Method for identifying microsatellite instability high DNA abnormality samples
Authors: Perera Dilmi , Khakabi Sahand , Nip Ka Mun , Brahmbatt Sonal , Kense Adrian , Tam Kevin , Mulder David , McConechy Melissa , Huntsman David , Miller Ruth , Aguirre-Hernández Rosalía 
Published: April 2023

Abstract
Introduction: Tissue samples with high microsatellite instability (MSI-H) can be indicators of cancerous tumors that are sensitive to certain types of cancer treatments (e.g., immune modulation-checkpoint inhibitor treatment). MSI-H regions can be identified with Polymerase Chain Reaction (PCR) based assays and next-generation sequencing (NGS). However, these MS regions are susceptible to PCR and sequencing errors. We developed a computational method for detecting microsatellite instability high (MSI-H) tumors using next-generation sequencing (NGS) data to accurately identify true MSI-H samples from MS-Stable samples based on an analysis of these MS regions.
Methods: We developed a method for classifying a tissue sample as being microsatellite instability high (MSI-H) without using normal tissue from the same person which doubles the sequencing cost. Furthermore, the algorithm was designed for amplicon targeted assays where it is not always feasible to choose the most predictive MS sites. The machine learning classifier (ML) algorithm is a random forest algorithm with a training set of known MSI-H and MS-Stable samples to learn the relationship between the MSI status and the distribution of repeats in microsatellite regions of genomes using 21 MS loci. A negative control was used to normalize the ML features and therefore reduce the effects of PCR and sequencing errors in noisy MS sites.
Results: The MSI detection algorithm was validated in analytical and clinical samples achieving an accuracy greater than 98%. Analytical samples consist of commercial reference standard samples and well characterized FFPE treated cell-lines. Clinical samples consists of clinical FFPE tumor samples from cancer patients that were orthogonally validated using immunohistochemistry (expression of mismatch repair genes, i.e., MMRnormal vs MMRd) on tumor tissue and/or the Promega MSI PCR using matched tumor/normal. All experiments were performed in the Imagia Canexia Health CAP, CLIA, DAP certified laboratory using the Find It assay standard operating procedures for detecting genomic mutations in solid tumor tissue.
Conclusions: The MSI detection algorithm can accurately identify samples with MSI-H tumors. When used in a clinical setting, these patients can then be directed to treatments such as immune-checkpoint inhibitors.
Citation Format: Dilmi Perera, Sahand Khakabi, Ka Mun Nip, Sonal Brahmbatt, Adrian Kense, Kevin Tam, David Mulder, Melissa McConechy, David Huntsman, Ruth Miller, Rosalía Aguirre-Hernández. Method for identifying microsatellite instability high DNA abnormality samples. [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 4279.