bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB178: Cell free RNA for prediction of PDAC in de novo symptomatic patients presenting for EUS-FNA
Authors: Moore Travis , Spiliotopolous Elias , Callahan Rowan , Kirschbaum Ward , Kim Hyun Ji , Keith Dove , Grossberg Aaron , Spellman Paul T. , Mills Gordon , Sears Rosalie C. , Morgan Terry , Ngo Thuy 
Published: April 2023

Abstract
Endoscopic ultrasound (EUS), the primary procedure for the diagnosis of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer, is invasive. We aim to develop a liquid biopsy approach using plasma cell-free messenger RNA to stratify patients prior to EUS and assist in the precision diagnosis of PDAC. We found a set of plasma cell-free messenger RNA biomarkers and a set of robust reference genes to classify PDAC patients from intermediary pancreatic pathologies such as: benign cases, pancreatitis, and intraductal papillary mucinous neoplasm (IPMN) with reproducible results validated in separate cohorts. Our results demonstrate a non-invasive liquid biopsy approach for stratifying patient groups before invasive and definitive EUS screening.
Citation Format: Travis Moore, Elias Spiliotopolous, Rowan Callahan, Ward Kirschbaum, Hyun Ji Kim, Dove Keith, Aaron Grossberg, Paul T. Spellman, Gordon Mills, Rosalie C. Sears, Terry Morgan, Thuy Ngo. Cell free RNA for prediction of PDAC in de novo symptomatic patients presenting for EUS-FNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB178.
Abstract LB212: BCG022: A novel bispecific antibody-drug conjugate targeting HER3 and MET
Authors: Li Zhuolin , Shang Chengzhang , Guan Xuewa , Han Zhenyan , An Gao , Zhang Ellen , Lin Qingcong , Yang Yi 
Published: April 2023

Abstract
HER3 is a unique EGFR family member that plays a role in both tumor progression and drug resistance. Its expression can act as a bypass mechanism for EGFR and HER2-targeted therapies, resulting in therapeutic resistance. MET has also been reported as a bypass resistance mechanism to EGFR-TKI treatment. HER3 and MET are co-expressed at high prevalence in multiple tumor types, including gastric, colorectal, breast, and non-small-cell lung cancer (NSCLC). In addition, HER3 and MET are frequently overexpressed in liver metastases from patients with colorectal cancer, indicating that targeting both proteins may provide clinical benefit. We generated fully human bispecific antibodies (bsAbs) targeting HER3 and MET with cross-species reactivity, using RenLite® mice, which contain the full human heavy chain variable domain with a common human kappa light chain to facilitate future bispecific antibody assembly. These 1+1 bsAbs have demonstrated enhanced internalization compared to the parental monoclonal antibodies in multiple cancer cell lines. These bsAbs were then conjugated with Monomethyl auristatin E (MMAE) to generate HER3 and MET-targeting bispecific ADC (BCG022) candidates. In vivo drug efficacies are being screened using cell-derived hepatocellular carcinoma (HCC) and gastric carcinoma xenografts, as well as patient-derived gastric and pancreatic xenograft models. Collectively, these results suggest that BCG022 has the potential to be a novel therapeutic option for HER3 and MET co-expressing tumors.
Citation Format: Zhuolin Li, Chengzhang Shang, Xuewa Guan, Zhenyan Han, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. BCG022: A novel bispecific antibody-drug conjugate targeting HER3 and MET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB212.
Abstract LB214: A first-in-class bispecific antibody-drug conjugate (DM002) targeting HER3 and the juxtamembrane domain of MUC1
Authors: Zhang Yifu , Shang Chenzhang , Wang Nannan , An Gao , Zhang Ellen , Lin Qingcong , Yang Yi 
Published: April 2023

Abstract
Despite the entry of new anti-cancer drugs into the market, there were more than 10 million deaths from cancer globally in 2021, with cancers of the lung, stomach, breast, and pancreas contributing to the most cancer-related deaths in China and the USA. Accordingly, there is an urgent need for improved therapeutic interventions. Antibody-drug conjugates (ADC) are novel drugs that exploit the specificity of a monoclonal antibody for target antigens expressed on cancer cells in order to achieve targeted delivery of a potent cytotoxic payload. More recently, bispecific ADCs (BsADC) targeting two tumor-associated antigens (TAA) have been developed to further amplify tumor cell specificity while minimizing toxicity to normal tissue, thus allowing for broader therapeutic windows. HER3 and MUC1 are two TAAs that are commonly expressed/co-expressed on multiple tumor types, including lung, gastric, breast and pancreatic cancer; however, neither antigen has been successfully targeted by effective drugs: of the candidates targeting HER3 antigen being evaluated in human clinical studies, most are well-tolerated, but with limited efficacy. On the other hand, high levels of MUC1 in diseased tissues can undergo auto-proteolysis, so that drugs targeting the MUC1-N region will be neutralized before reaching the tumor tissues, thereby limiting the recognition of tumor cells. To overcome these challenges, we generated fully human bispecific antibody candidates with human-monkey cross-species reactivity that target HER3 and the juxtamembrane domain of MUC1. These bsAbs exhibit higher endocytic activity in HER3-low tumor cell lines compared with other currently available HER3 mAb. These bsAbs were subsequently conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker to obtain first-in-class BsADC candidates, DM002. DM002 candidates showed robust anti-tumor activity in multiple CDX and PDX models of lung, breast, gastric and pancreatic cancer; most notably, DM002 candidates outperformed benchmark ADCs in BP0508 lung PDX models. Together, these data indicate that DM002 will be a promising therapeutic drug for patients with HER3 and MUC1 co-expressing tumors.
Citation Format: Yifu Zhang, Chenzhang Shang, Nannan Wang, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. A first-in-class bispecific antibody-drug conjugate (DM002) targeting HER3 and the juxtamembrane domain of MUC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB214.
Abstract LB233: Preclinical analysis identifies predictive biomarker and potential pathways of resistance to lurbinectedin treatment in small cell lung cancer
Authors: Chakraborty Subhamoy , Coleman Charles , Demircioglu Deniz , Hasson Dan , Sen Triparna 
Published: April 2023

Abstract
Background: Small cell lung cancer (SCLC) is an exceptionally aggressive disease with limited treatment options that typically result in transient responses. SCLC is responsible for approximately 250,000 deaths globally per year. Major hurdles to improving SCLC treatment include the development of rapid chemo-resistance and limited second-line therapies. Lurbinectedin is FDA approved as a second-line treatment for SCLC but shows a response in a subset of patients. Therefore, improved mechanistic understanding and identifying predictive biomarkers of lurbinectedin treatment is a major unmet clinical need.
Methods: We treated SCLC cell lines and patient-derived xenograft (PDX) models from all major SCLC subtypes with lurbinectedin. Lurbinectedin-mediated changes in signaling pathways were studied by bulk RNA sequencing, western blot, and flow cytometry. Anti-tumor efficacy and toxicity studies were performed in vivo.
Result: All human and PDX-derived SCLC cell lines showed sensitivity to lurbinectedin at a nano-molar concentration ranging from 1.905 to 30 nM. Bulk RNA-seq analysis showed lurbinectedin induced changes in neuroendocrine phenotype, DNA damage response and tumor progression markers in vitro. Single agent treatment of lurbinectedin showed remarkable anti-tumor efficacy in an ASCL1-driven PDX model. RNA sequencing analysis identified modulation of genes in multiple signaling pathways including PI3K-AKT, apoptosis and EMT to be significantly associated with the lurbinectedin response in PDX models.
Conclusion: There is an immediate need to understand the subsets of SCLC that would be most sensitive to lurbinectedin and identify predictive biomarkers. We demonstrate MYC as a predictive biomarker for lurbinectedin response. We are the first to show that single agent lurbinectedin shows remarkable anti-tumor efficacy in a ASCL1-driven PDX models of SCLC. Furthermore, our pre and post-lurbinectedin treatment transcriptomic analysis identify the pathways that may contribute to primary or acquired resistance to lurbinectedin in SCLC. Finally, we identity candidate targets that would guide the design of future combination clinical trials with lurbinectedin in SCLC.
Citation Format: Subhamoy Chakraborty, Charles Coleman, Deniz Demircioglu, Dan Hasson, Triparna Sen. Preclinical analysis identifies predictive biomarker and potential pathways of resistance to lurbinectedin treatment in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB233.
Abstract LB238: Image-based phenotypic profiling of a chemogenomic screening library identifies nobel targets of known inhibitors
Authors: Tanabe Kenji 
Published: April 2023

Abstract
The gene encoding epidermal growth factor receptor (EGFR) is a major driver gene in cancer. Many drugs targeting EGFR-associated molecules have been developed, yet many have failed in clinical trials due to a lack of efficacy and/or unexpected side effects. In this study, I used image-based phenotypic profiling to screen a pharmacologically active compound library with the aim of identifying new druggable targets in the EGFR pathway. As anticipated, the phenotypic screen identified compounds that produce phenotypes resulting from targeting a known specific molecule or pathway. The assay also showed that compounds with diverse known mechanisms of action produced similar, EGFR-related cellular phenotypes. Biochemical assays revealed that those compounds share a previously unappreciated common target/pathway, showing that the image-based assay can identify new target molecules that are independent of the compound’s known target.
Citation Format: Kenji Tanabe. Image-based phenotypic profiling of a chemogenomic screening library identifies nobel targets of known inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB238.
Abstract LB255: Benchmarking NGS integration site analysis methods in support of long-term safety monitoring of gene therapy products
Authors: Otto Jeffrey M. , Fan Yongjun , Bao Guanhui , Corney David , Niu Ben , Yu Qiu , Khan Baursha , Turner Laure , Mozdzierz Chris , Latif Haythem , Zhou Ginger 
Published: April 2023

Abstract
The FDA Guidance to Industry on Long Term Follow-Up (LTFU) After Administration of Human Gene Therapy Products states the importance of longitudinal testing of gene products introduced into human subjects. Depending on the delivery mechanism, the therapeutic gene product may or may not integrate into the genome. Of particular interest are gene-product integrations near proto-oncogenes which might lead to malignancies. The FDA LTFU guidance states that recipients of an integrating gene therapy modality should be tracked for 15 years, while those receiving a non-integrating therapy modality should be tracked for 5 years. Therefore, advanced analytical methods are needed to identify, quantify, and track integration events across the genome. Here, we provide a comprehensive evaluation of methods leveraging next-generation sequencing approaches for genome-wide analysis of lentiviral integration events. Our analysis employed well-characterized standards consisting of varying copy number and known integration sites. ​
The approaches we characterized can be bucketed into two major groups: PCR amplification approaches and target capture-based approaches. All methods detected true positives with strong correlation to theoretical integration site dosage levels down to 1% allele frequency. Comparatively, PCR amplification-based approaches have lower data requirement per sample suggesting higher sensitivity, greater molecular capture, and lower limit of detection compared with target enrichment-based approaches. Target enrichment-based approaches can afford the flexibility to capture the integrated vector, which is of interest for characterizing partial integration events. While all methodologies performed well in our study, the choice of assay (or assays) for testing will depend on numerous factors including but not limited to the viral vector system and construct and starting material availability.
Citation Format: Jeffrey M. Otto, Yongjun Fan, Guanhui Bao, David Corney, Ben Niu, Qiu Yu, Baursha Khan, Laure Turner, Chris Mozdzierz, Haythem Latif, Ginger Zhou. Benchmarking NGS integration site analysis methods in support of long-term safety monitoring of gene therapy products [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB255.
Abstract LB274: Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance
Authors: Dou Xuefeng , Campisi Judith , Sun Yu 
Published: April 2023

Abstract
Cellular senescence is a permanent state of cell cycle arrest and occurs in proliferating cells subjected to various stresses. Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence, PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured ‘Warburg effect’, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Nevertheless, specific targeting PDK4 curtails the adverse effects of senescent cells in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Of note, increased levels of lactate in circulating blood after chemotherapy predicts lower survival in cancer clinics. PDK4 upregulation and ensuing lactate production are thus among key features of senescence, in addition to the established cell-autonomous and non-cell-autonomous hallmarks of senescent cells, providing a novel therapeutic target for future clinical oncology. Together, our study substantiates the hypercatabolic capacity of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies, including but not limited to cancer.
Citation Format: Xuefeng Dou, Judith Campisi, Yu Sun. Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB274.
Abstract LB303: Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer
Authors: Zaheer Javeria , Shanmugiah Joycie , Kim Hyeongi , Kim Jin Su 
Published: April 2023

Abstract
The deposition of the extracellular matrix (ECM) is associated with poor prognosis and therapy response in gastric cancer. An elevated extracellular matrix (ECM) and interstitial fluid pressure in gastric cancer limits the targeting of HER2-expressing gastric cancer cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here we used Losartan (LOS), which is an antihypertensive drug, to downregulate ECM and interstitial fluid pressure in gastric cancer mice model. After 40 mg/kg of LOS treatment, a 2-fold higher Alexa-647-TRZ uptake significantly enhanced 64Cu-TRZ uptake by positron emission tomography (PET) imaging, LOS treatment decreased the tumor volume, and enhanced the survival rate. LOS-treated samples showed reduced SERPINE1 mRNA expression compared with the controls, as determined by qRT-PCR. Downregulated mRNA expression of TGFβ-1, and upregulated mRNA expression of MMP-2 in LOS-treated samples were observed. The corresponding protein expression of SERPINE1 was confirmed using western blotting. We also confirmed that silencing of SERPINE1 increased MMP2 activity. We revealed that the enhanced therapeutic effect of 64Cu-TRZ via LOS was due to the downregulation of SERPINE1, which degrades the ECM through MMP2. Our novel combinational therapy of using 64Cu-TRZ with LOS is highly effective for treatment of gastric cancer.
Citation Format: Javeria Zaheer, Joycie Shanmugiah, Hyeongi Kim, Jin Su Kim. Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB303.
Abstract LB340: Spur cell-delivered peptide antigen generates T cell immunity to eradicate mouse KRASG12D spontaneous lung cancer
Authors: Qu Shuang , Wang Jiafan , Jia Meng , Liang Hongwei , Liu Yuan , Zen Ke 
Published: April 2023

Abstract
Red blood cells (RBCs) have been widely used in delivering various drugs including cancer antigens. However, due to their inherent biocompatibility and low immunogenicity, RBC-based tumor antigen delivery often fails to initiate anti-tumor immunity and results in lower clinical efficacy of cancer vaccines. Here we report that tumor antigen-encapsulated RBCs can be rapidly transformed to spur cells which have much higher immunogenicity. Compared to normal RBCs, spur cells display a defused surface CD47 pattern with a lower affinity to SIRPα, and thus can be rapidly engulfed by activated macrophages and dendritic cells. The tumor antigen-loaded spur cells elicit high antigen responses both in vitro and in vivo. In combination with the SHP-1 inhibitor, spur cell-delivered KRASG12D antigenic peptides markedly suppress tumor growth in KRASG12D spontaneous mouse lung cancer model. In addition, a specific T cell population targeting the KRASG12D mutated peptide antigen is detected in cancer-survival mice. Our study thus has developed spur cell-delivered cancer neoantigen as an effective cancer vaccine.
Citation Format: Shuang Qu, Jiafan Wang, Meng Jia, Hongwei Liang, Yuan Liu, Ke Zen. Spur cell-delivered peptide antigen generates T cell immunity to eradicate mouse KRASG12D spontaneous lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB340.
Abstract LB351: A novel mouse model to interrogate the functional relationship between protein synthesis and antigen presentation in cancer
Authors: Jaeger Alex M. , Weeden Andrew , Ali Anika 
Published: April 2023

Abstract
Antigen presentation is a fundamental component of cancer immunity. Cytotoxic CD8+ T cells, the primary mediators of cell killing, recognize peptide antigens presented in the context of Major Histocompatibility Complex Class I (MHC-I). MHC-I presents an astoundingly diverse array of peptides, collectively known as the immunopeptidome. The biosynthesis of the immunopeptidome, which integrates gene expression, protein synthesis, and proteolytic processing, is not well understood. Additionally, most studies interrogating the immunopeptidome use cultured cells in vitro, which lack physiologically relevant stimuli. In contrast, in vivo studies utilize bulk tumor or tissue lysates, in which heterogeneous cell mixtures obscure the ability to understand cell type or disease specific patterns of antigen presentation. The technical limitations have hampered our understanding of the cancer immunopeptidome in physiologically relevant tumor microenvironments in vivo. Here we present a novel genetically engineered mouse model (GEMM) of cancer, that includes KrasLox-Stop-Lox-G12D; p53fl/fl; a Cre conditionally tagged MHC-I (KbStrep), and a Cre conditionally tagged ribosome (Rpl22HA/HA), termed the “KP/RiboMHC” mouse model. The KP/RiboMHC model enables simultaneous purification of ribosomes and peptide MHC complexes to functionally interrogate translational dynamics and antigen presentation in vivo. We developed optimized workflows to perform simultaneous ribosome profiling and immunopeptidomics from lung and pancreas cancer cell lines in vitro and specifically from malignant cells in vivo. Thus, the KP/RiboMHC model provides an unprecedented opportunity to ask fundamental questions regarding the influence of physiological stimuli in the tumor microenvironment on the biosynthesis of the immunopeptidome. Insights gained using this mouse will pave the way forward for the development of context specific, peptide-centric cancer immunotherapies.
Citation Format: Alex M. Jaeger, Andrew Weeden, Anika Ali. A novel mouse model to interrogate the functional relationship between protein synthesis and antigen presentation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB351.