bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 743: Using a novel NextGen linker system to generate a conditionally active biologic (CAB) anti-nectin4-ADC demonstrates improved efficacy in pancreatic PDX cancer models and improved tolerability and toxicity profile in non-human primates
Authors: Wang Jing , Chen Jian , Frey Gerhard , Liu Haizhen , Xing Charles , Woodard Kathryn , Chang Hwai , Boyle William J. , Short Jay M. 
Published: March 2024

Abstract
Antibody-drug conjugates (ADCs) are a promising treatment for various forms of cancer. The treatment efficacy is often limited by on-target/off-tumor toxicity caused by the antigen expression in healthy tissue and by unwanted payload release outside the tumor caused by cleavage of the linker via circulating proteases. Our conditionally active biologics (CAB) technology addresses the on-target/off-tumor toxicity and assists in reducing the off-target/off-tumor toxicity by reducing binding to the target under normal physiological conditions (1). To eliminate the remaining off-target/off-tumor toxicity, we developed a novel linker with superior serum stability, solubility, and tumor-specific payload release. Conjugation can be accomplished using regular IgG backbones without the need for sequence modification. Here we report the in vitro and in vivo characterization of a NextGen linker system to generate a CAB anti-Nectin4-ADC that combines the advantages of CAB antibody pH selectivity with the new linker technology. In vivo efficacy data demonstrated complete tumor regression in several cell line derived xenograft models as well as superior efficacy to an enfortumab vedotin analogue in a patient derived pancreatic cancer model. PK and tox data from a toxicology study in non-human primates will be presented. In addition, data demonstrating the influence of linker technology on specific cancer models will also be presented. In conclusion, the NextGen Nectin4 CAB ADC represents a potentially more effective treatment with increased safety in the clinic.
(1) Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ,and Short JM Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc Natl Acad Sci U S A 2021;118
Citation Format: Jing Wang, Jian Chen, Gerhard Frey, Haizhen Liu, Charles Xing, Kathryn Woodard, Hwai Chang, William J. Boyle, Jay M. Short. Using a novel NextGen linker system to generate a conditionally active biologic (CAB) anti-nectin4-ADC demonstrates improved efficacy in pancreatic PDX cancer models and improved tolerability and toxicity profile in non-human primates [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 743.
Abstract 7464: Tertiary lymphoid structures in pancreatic cancer: Biomarkers of immunogenic patients or direct contributors to anti-tumor immunity
Authors: Khanal Shrijan , Harder Olivia , Kirschstein Elijah , Mack Morgan , Ware Carl , Gough Michael , Young Kristina , Gunderson Andrew J. 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a cancer with low survival rates and currently no immunotherapy options. However, many tumors from PDAC patients can be heavily infiltrated with T and B cells associated with favorable survival outcomes indicating anti-tumor immunity is functional in certain patients. In some of these lymphocyte-inflamed PDAC tumors, spontaneous organization of tertiary lymphoid structures (TLS) is evident upon surgical resection and these patients have a clear survival advantage. TLS are predictive of immune checkpoint blockade response in some cancer types, yet PDAC patients, with or without TLS, are still insensitive to these strategies. To address this paradox, we evaluated surgically resected PDAC tumors from previously untreated patients and discovered that tumors with TLS (TLS+) recruited T and B cells with specific anti-tumor and memory phenotypes suggesting immunosurveillance of disease was enhanced. Furthermore, a subset of TLS+ patients contained germinal centers and improved humoral immune function corresponding to an increased neoantigen burden and long-term survival. When assessing gene expression differences between TLS+ and TLS- patients, operable inflammatory and immunosuppressive pathways emerged that could be therapeutically exploited to activate TLS neogenesis. To address these mechanistic questions, we have developed a method for inducing TLS formation in implantable mouse PDAC tumors in the orthotopic setting utilizing an antibody that agonizes the lymphotoxin beta receptor (LTBR) in mice bearing established PDAC tumors. These TLS are complexed with T cells, B cells, CXCL13+ cells, and PNAd+ HEV associated with reduced tumor growth, presence of lymphocyte-recruiting cancer associated fibroblasts and increases in anti-tumor T and B cell phenotypes. Interestingly, some mouse PDAC cell lines are resistant to TLS formation by LTBR agonism while others are susceptible offering a model to study patient heterogeneity. We will use this TLS+ PDAC mouse model to address how TLS may directly improve antigen-specific T cell and B cell immunity and elucidate the pathways that regulate TLS formation. These data will offer new strategies to overcome immunotherapy resistance in cancer patients.
Citation Format: Shrijan Khanal, Olivia Harder, Elijah Kirschstein, Morgan Mack, Carl Ware, Michael Gough, Kristina Young, Andrew J. Gunderson. Tertiary lymphoid structures in pancreatic cancer: Biomarkers of immunogenic patients or direct contributors to anti-tumor immunity [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 7464.
Abstract 7491: ctDNA liquid biopsy result among gynecologic cancer patients: Does it give additional information
Authors: Kim Min Kyu 
Published: March 2024

Abstract
Objectives: There are many target molecules for precisional cancer therapy Precision diagnosis-based target treatment is believed to be better survival approach compared than conventional treatment. Predictive markers are variant and vast. This study evaluated the initial experience of ctDNA liquid biopsy as a precision tumor marker for gynecologic cancer patients?
Methods: we retrospectively identified ovary/endometrial and cervical cancer patients who approved ctDNA test for various purpose. Two methods were used. Guardant 360 and Foundation One Liquid CDx.
Results: There were 31 cases. Median age was 60(46-84). Half of cases were ovarian cancer(17/31 55%).Cervix and endometrial cancer are 12(39%) and 2(6%).We found about ten percentages of actional genetic mutation patients(3/31).Two BRCA1 mutation(each patients have variant allele frequency(VAF) percentages are 50.4,49.6).One high bTMB(blood tumor mutational burden)was 21.There was no mutation in 6/31(19 %).
Conclusions: It seems additional supportive information may be acquired through well-established ctDNA liquid biopsy test among this population. Role of ctDNA liquid biopsy test for precision tumor marker should be investigated for future study.
Keywords: Liquid biopsy; Precision medicine; Tumor marker
Citation Format: Min Kyu Kim. ctDNA liquid biopsy result among gynecologic cancer patients: Does it give additional information [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 7491.
Abstract 7588: Discovery of NSP-5033: A novel and potent PARP7/12 dual inhibitor
Authors: Chen Qin , Huang Qionglin , Zhang Ke , Hao Yuli , Wang Zixuan , Li Bing 
Published: March 2024

Abstract
PARP7 is a mono-ADP-ribosyl transferase that catalyzes the transfer of single units of ADP-ribose onto substrate proteins to regulate their functions. One of its substrates is TANK binding kinases 1 (TBK1), whose MARylation by PARP7 inhibits its activation and thereby represses the type I IFN response to cytosolic nucleic acid. PARP7 is upregulated in many kinds of cancers and acts as a brake in cytosolic nucleic acid sensing, which leads to the suppression of type I IFN signaling and immune response. Therefore, PARP7 is a novel and promising target in cancer immunotherapy. Herein, we describe the discovery of a novel small molecule NSP-5033 as a dual PARP7/PARP12 inhibitor, which potently inhibits PARP7 and PARP12 enzymes with sub-nanomolar and low nanomolar activities, respectively. It displayed potent anti-proliferative activities against a number of cancer cell lines in vitro. NSP-5033 also increased the mRNA level of IFNβ and CXCL10 and stimulated STAT1 phosphorylation, suggesting that it restored the type I IFN response in tumor cells. With excellent ADME and pharmacokinetic properties, NSP-5033 demonstrated potent in vivo efficacy in human lung cancer xenografts with tumor regression and induced antitumor immunity in tumor-bearing immunocompetent mice. NSP-5033 has been nominated as a preclinival candidate for treatment of solid tumors and is undergoing IND-enabling studies.
Citation Format: Qin Chen, Qionglin Huang, Ke Zhang, Yuli Hao, Zixuan Wang, Bing Li. Discovery of NSP-5033: A novel and potent PARP7/12 dual inhibitor [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 7588.
Abstract 7589: The novel complex delivery system of C-phycocyanin-loaded klebsiella pneumoniabacterial ghost induces apoptosis and sensitizes non-small cell lung cancer cell lines to doxorubicin
Authors: Abdelaziz Basma Adel Elsayed , Mahmoud Hoda Eid , Sadek Omayma Mohamed , Sultan Ahmed Samir 
Published: March 2024

Abstract
Lung cancer is a significant cause of cancer-related deaths worldwide, with a high incidence rate, poor prognosis, aggressiveness, and a lack of effective treatment options. The present study has brought together two FDA-approved drugs with antineoplastic properties to create a complex that promises to revolutionize the treatment of Non-Small Cell Lung Cancer (NSCLC). By combining C-Phycocyanin extract (PCE), a pigment-protein complex synthesized by blue-green microalgae platensis, with the immunostimulatory doxorubicin (DOX) loaded Bacterial Ghosts (BGs), the present study aims to achieve enhanced dual-chemotherapy and remarkable inhibition of DOX-chemoresistance. The BG delivery system uses purified bacterial cell evacuation and safe confirmed Klebsiella pneumoniae BGs (KPBG) for safe and effective delivery, overcoming issues with resistance and poor delivery. The complex delivery system of KPBG-PCE/DOX was tested on two NSCLC cell lines, wild-P53, A549, and mutant-P53, NCI/H358, respectively. Our data showed that the loaded combined treatment significantly induced morphological changes with signs of apoptosis induction in the tested cell lines compared with the control. The WST-1 assay was used to evaluate cell proliferation. Data indicates that PCE and DOX have a synergistic effect at low concentrations when loaded on KPBGs for a constant count of BGs CFU/ml after 48 h of treatment. The viability inhibition and apoptosis induction of A549 and NCI/H358 cells were amplified in the combined treatment of 48 h compared to the control or either each drug alone. At the protein levels, our data showed activation of caspase-3, upregulation of BAX, and downregulation of Bcl-2, Bcl-XL, m-TOR, S6k, oncogenic β-catenin, and cyclin-D1 protein expression levels after treatment with (KPBG-PCE/DOX) for 48 h, indicating apoptotic induction and modulating oncogenic signaling pathways. In conclusion, the current study presents a promising outcome of a synergistic delivery system of KPBG-PCE/DOX that can inhibit lung cancer cell line proliferation, induce apoptosis, and increase cell sensitivity to DOX. The KPBG delivery system offers an appealing approach for a successful combination of targeted therapy for lung cancer.
Citation Format: Basma Adel Elsayed Abdelaziz, Hoda Eid Mahmoud, Omayma Mohamed Sadek, Ahmed Samir Sultan. The novel complex delivery system of C-phycocyanin-loaded klebsiella pneumoniabacterial ghost induces apoptosis and sensitizes non-small cell lung cancer cell lines to doxorubicin [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 7589.
Abstract 7595: PRMT5 inhibitor synergizes with PARP inhibitors in triple-negative breast cancer cells
Authors: Suresh Samyuktha , McPherson Lisa A. , Ford James M. 
Published: March 2024

Abstract
Background: Treating triple-negative breast cancer (TNBC) patients, an aggressive subtype of breast cancer, is an ongoing clinical challenge. Small-molecule inhibitors targeting the poly ADP-ribose polymerase (PARP) DNA repair enzymes, have been approved for treating only a subset of TNBC patients with a specific genetic landscape (BRCA1 mutation). However, TNBC patients with wildtype BRCA1 (BRCA1WT) are still lacking targeted therapy and chemotherapy remains their main treatment strategy. High expression of protein arginine methyltransferase 5 (PRMT5) is linked to poor prognosis in breast cancer and PRMT5 alone or via its interacting proteins plays an oncogenic role in breast cancer. Recent evidence suggests that PRMT5 is a key player in regulating the repair of DNA double strand breaks (DSBs) either through homologous recombination (HR) or non-homologous end joining (NHEJ) depending on the PRMT5 expression level within the cell. This dependency of cancer cells on PRMT5 expression levels in deciding the repair pathway of choice can be exploited for developing therapies. We hypothesize that in BRCA1 wildtype TNBC cells, inhibiting PRMT5 activity will force the cells to rely on NHEJ rather than HR to repair DNA DSBs, and introducing PARP inhibitors in this setting will inactivate NHEJ as well, causing synthetic lethality and cell death. In this study, we evaluated the pre-clinical benefit of combining PARP inhibitors with a PRMT5 inhibitor in TNBC cells.
Methods: Human TNBC cell lines with wildtype BRCA1 (MDA-MB-468, HCC1806) and mutant BRCA1 (MDA-MB-436, SUM149-PT) were treated with varying doses of two PARP inhibitors (Olaparib, Talazoparib) and a PRMT5 inhibitor (GSK3326595) as single agents or in combination. MTT-based cell viability assay was used to determine cytotoxicity of the treatments. mRNA expression was determined by RT-qPCR after drug treatment.
Results and Conclusion: We report that PRMT5 inhibition synergizes with both Olaparib and Talazoparib, to potentiate cell death in two BRCA1WT but not in BRCA1mut TNBC cell lines. Furthermore, we show that inhibiting PRMT5 in BRCA1WT cells upregulates the mRNA expression of RAD50, a DNA damage sensing gene in the HR pathway. Our ongoing study is to delineate the molecular mechanism of action for the observed synergy and whether PRMT5 inhibition can overcome resistance to PARP inhibitors. Through this study, we will identify a novel treatment strategy for the majority of TNBC patients (BRCA1WT) who currently lack targeted therapies.
Citation Format: Samyuktha Suresh, Lisa A. McPherson, James M. Ford. PRMT5 inhibitor synergizes with PARP inhibitors in triple-negative breast cancer 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 7595.
Abstract 7602: Discovery of GH1581, a potent and selective WRN inhibitor as a cancer therapy
Authors: Li Jiapeng , Zhang Guiping , Li Jie Jack 
Published: March 2024

Abstract
Defects in DNA mismatch repair (MMR) proteins could induce damage of genome, resulting microsatellite instability (MSI). MSI is highly correlated with the occurrence of several types of cancers, mainly in colon, gastric, endometrial, and ovarian cancers. Despite advances in the treatment of MSI-high cancers, tumor evolution and drug resistance remain the leading causes of treatment failure and death in cancer patients. About 50% MSI cancers have no response to immune checkpoint inhibitors. There is still unmet needs to be fulfilled for MSI-high patients. WRN is a RecQ family helicase involves in genome stability maintenance, DNA repair, replication, transcription, and telomere maintenance. Recent studies have identified WRN as a synthetic lethal target of MSI-high cancers. Employing structure-based drug design strategy, we have discovered a potent and selective WRN inhibitor, GH1581. In vitro, GH1581 displayed specific &lt; 10 nM potency in ADP-Glo assay and &lt; 10 nM potency in cell proliferation assay using MSI cancer cell lines. In vivo, GH1581 demonstrated favorable pharmacokinetic properties in different species. In SW48 xenograft model, it inhibited the tumor growth with 100% TGI at QD dosing of 10 mg/kg without severe adverse effect on body weight. In summary, we discovered GH1581 as a novel inhibitor of WRN with high in vitro and in vivo efficacy.
Citation Format: Jiapeng Li, Guiping Zhang, Jie Jack Li. Discovery of GH1581, a potent and selective WRN inhibitor as a cancer therapy [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 7602.
Abstract 7636: Quantitative analysis of colorectal adenocarcinoma images obtained by single-shot 17-plex staining followed by imaging with the Orion™ spatial biology platform
Authors: Lo Edward , George Tad , Larkin Selena 
Published: March 2024

Abstract
Background To understand the tumor microenvironment (TME), high resolution imaging of multiple biomarkers with whole slide context can be used as a basis for downstream biomarker quantitation and predicting patient outcomes1. Here we investigate a sample of invasive colorectal adenocarcinoma using whole slide, single-step high-plex staining and imaging at single-cell resolution followed by quantitative analysis.
Methods The slide was stained in one round with a 17-plex immune-oncology panel then imaged in one round with the Orion™ spatial biology platform. Quantitative analysis was performed on the resulting TIFF file using the following pipeline:- Manually annotate regions of interest (ROI) on the tissue- Segment whole slide images into cells with UnMICST and S3segmenter - Import mask and clean data in QuPath - Generate primary feature data table with QuPath - Classify cells into populations in QuPath - Generate spatial biomarkers - Compare cell populations and their spatial interactions in the different ROIs.
Results Data revealed a distinction between normal colonic epithelium, well-differentiated adenocarcinoma with immune cell collection, and an infiltrating border of the carcinoma. Differences in immune cell content and spatial organization were measured, and the infiltrating border found to contrast with other tumor regions by showing a lower proliferative fraction (Ki-67, nuclear) and differences in E-cadherin and cytokeratin expression patterns.
Conclusions These data highlight the importance of sufficient plex, resolution and whole slide context to derive reliable spatial biomarkers of potential prognostic value. Further, hours vs. days speed for whole-section multiplexed biomarker quantitation, along with same-section conventional chromogenic analysis, makes this approach suited to multi-patient clinical studies.
1 JR Lin et al., High-plex immunofluorescence imaging and traditional histology of the same tissue section for discovering image-based biomarkers, Nat Cancer, 4, 1036-1052 (2023).
Citation Format: Edward Lo, Tad George, Selena Larkin. Quantitative analysis of colorectal adenocarcinoma images obtained by single-shot 17-plex staining followed by imaging with the Orion™ spatial biology platform [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 7636.
Abstract 779: Functional role of TGF-beta receptor type-2 in breast cancer progression and survival
Authors: Srivastava Meera , Bera Alakesh , Pollard Harvey B. , Hu Hai , Shriver Craig D. 
Published: March 2024

Abstract
Background and Rational: Transforming growth factor β (TGFβ) signaling is pivotal in cellular proliferation and can exhibit either tumor-suppressive or promoting effects depending on cellular context and genetic alterations. TGFβ receptor type-2 (TGFβR2), the ligand-binding receptor, is implicated in various cancers. This study explores the functional role of TGFβR2 in breast cancer (BrCa) progression. Materials and
Method: Genomic alterations in TGFβR2 were assessed in TCGA samples. TGFβR2 mRNA and protein expression were examined in a panel of BrCa cell lines, including MCF7, MCF12A, MDA-MB-231, and MDA-MB-468. Additionally, serum samples from BrCa patients, meticulously categorized into subtypes such as triple-negative (TN), human epidermal growth factor receptor 2-positive (Her2+), Luminal A (LA), Luminal B1 (LB1), and Luminal B2 (LB2), were analyzed. BrCa cell lines were treated with TGFβ ligand to investigate receptor expression modulation.
Results: Analysis of genomic alterations in TGFβR2 from The Cancer Genome Atlas (TCGA, n=1084, BrCa samples) revealed TGFβ copy number amplification in 25% of samples, while less than 1% showed TGFβR2 amplification. Elevated TGFβR2 levels were identified in aggressive triple-negative MDA-MB-231 cells compared to other tested cell lines. Serum samples from BrCa patients (n=240) demonstrated higher TGFβR2 levels, particularly in Luminal B1 subtype and African American patients. Treatment of BrCa cell lines with TGFβ ligand induced TGFβR2 expression, suggesting ligand-induced receptor upregulation.
Discussion: The findings suggest TGFβR2 as a potential biomarker for BrCa, with higher levels associated with aggressiveness and racial disparities. Ligand-induced receptor upregulation implies a potential oncogenic role. These results contribute to understanding TGFβR2's functional significance and its implications in breast cancer progression, offering insights into potential biomarkers and therapeutic targets.
Citation Format: Meera Srivastava, Alakesh Bera, Harvey B. Pollard, Hai Hu, Craig D. Shriver. Functional role of TGF-beta receptor type-2 in breast cancer progression and survival [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 779.