bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB216: Pre-clinical characterization of NGM831, an ILT3 antagonist antibody for the treatment of solid tumors
Authors: Chen Peirong , Crawley Suzanne C. , Lin Vicky Y. , Kapoor Varun , Paavola Kevin J. , Chen Hung-I , Lichtman Joshua S. , Li Betty , Mondal Kalyani , Kutach Alan K. , Wang Yan , Kaplan Daniel D. , Roda Julie M. 
Published: June 2022

Abstract
Suppressive myeloid cells inhibit antitumor immunity by preventing T cell responses. Immunoglobulin-like transcript 3 (ILT3, also known as LILRB4) is highly expressed on tumor-associated myeloid cells and promotes their suppressive phenotype. Our team recently identified fibronectin as a functional ligand for ILT3. The fibronectin-ILT3 interaction serves as a “stromal checkpoint” through which the extracellular matrix actively promotes myeloid cell suppression in the tumor microenvironment. We now report the pre-clinical characterization of NGM831, a humanized IgG1 (N297G) antibody that binds to ILT3 of human and cynomolgus monkey origin with high specificity and sub-nM affinity and blocks the interaction of ILT3 with both its reported ligands, fibronectin and ApoE. In a gene expression profiling experiment, treatment of tolerogenic dendritic cells with NGM831 in the presence of fibronectin decreased their expression of inhibitory and scavenger receptors (CD163, MRC1, MARCO, STAB1, LILRB2) and markers of dendritic cell immaturity (CD14, CD209, FOLR2) and increased their expression of genes involved in antigen presentation (TNFSF14, DCSTAMP, CD82, OLR1) and TH1 polarization (SPP1, TBX21), suggesting that these cells had been remodeled to a more stimulatory phenotype. Consistent with these observations, treatment of tolerogenic dendritic cells with NGM831 increased their production of pro-inflammatory cytokines in response to FcɣR ligation, restored their responsiveness to maturation stimuli such as lipopolysaccharide (LPS) and CD40 ligand (CD40L), and increased their production of chemokines that could induce the migration of other immune cells to sites of inflammation. In addition, NGM831 acted synergistically with pembrolizumab to increase the ability of dendritic cells to stimulate allogeneic T cells in mixed lymphocyte reactions. Taken together, these results demonstrate that NGM831 can block fibronectin-mediated immunosuppression and promote myeloid cell reprogramming. These data support the clinical development of the ILT3 antagonist antibody NGM831 alone and in combination with immune checkpoint blockade. NGM831 is expected to enter clinical trials for the treatment of advanced solid tumors in early 2022.
Citation Format: Peirong Chen, Suzanne C. Crawley, Vicky Y. Lin, Varun Kapoor, Kevin J. Paavola, Hung-I Chen, Joshua S. Lichtman, Betty Li, Kalyani Mondal, Alan K. Kutach, Yan Wang, Daniel D. Kaplan, Julie M. Roda. Pre-clinical characterization of NGM831, an ILT3 antagonist antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB216.
Abstract LB218: A safe and highly potent anti-PD-1-IL-2c fusion that decouples efficacy and toxicity of IL-2 therapy
Authors: Ye Fan , Huang Jianing , Huang Zoey , Chen Sandra , Liao Eric , Li Ella , Quach Allison , Jiang Jenny , Lin Hanna , Hua Michael , Yung Savannah , Cheng Lili , Zhong Ziyang 
Published: June 2022

Abstract
Interleukin 2 (IL-2) is a pivotal immune agonist for tumor immunotherapy that has produced impressive clinical efficacy in a number of cancer types. Nevertheless, its pleiotropic effect has led to prohibitory side effects and immune restraint. In contrast, the PD-1 blockade-based cancer immunotherapy has a good safety profile by targeting and sustaining the activity of tumor-antigen specific T cells within cancer tissues. To take full advantage of complementary antitumor activity of PD-1 monoclonal antibody (mAb) and IL-2 as well as supreme intratumoral T-cell-targeting property of PD-1, a bifunctional fusion protein composed of PD-1 mAb and IL-2 mutein (αPD-1-IL-2c) is designed. IL-2c is a chimeric molecule that contains a fragment from IL-15 and does not bind to IL-2 receptor alpha (IL-2Rα). αPD-1-IL-2c stimulated greater pSTAT5 activation and proliferation in PD-1+ T cells than PD-1- T cells. αPD-1-IL-2c also induced a much stronger anti-tumor immune response compared to PD-1 mAb, IL-2c, or PD-1 mAb in combination with IL-2c in multiple syngeneic models such as B16F10, CT26, and MC38. In CT26 and MC38 models, αPD-1-IL-2c achieved complete response starting from 0.3 mg/kg dosing. In B16F10 model, αPD-1-IL-2c showed greater than 70% tumor growth inhibition (TGI). Global gene expression profiling studies showed that PD-1-IL-2c treatment significantly elevated expression levels of Cd3d, Cd3e, Cd8a, Il2rα, Cxcr3, Cxcr6, Zap70, Lck, and Pdcd1 in tumor tissues compared to treatment with PD-1 mAbs or IL-2c, indicating a specific expansion and activation of T cell in the tumor microenvironment (TME). The safety profile of αPD-1-IL-2c was assessed and compared to WT IL-2 and a leading “No-α” αPD-1-IL-2 fusion protein (αPD-1-IL-2x). WT IL-2 and αPD-1-IL-2x induced significant body weight loss and severe splenomegaly when dosed at 1.25 mg/kg. In contrast, αPD-1-IL-2c dosed at 10 mg/kg did not cause appreciable body weight loss and only led to minimal splenomegaly. In summary, we have developed a safe and highly potent αPD-1-IL-2 mutein that achieves full PD-1 blockade and TME-specific T cell activation and expansion without appreciable toxicity.
Citation Format: Fan Ye, Jianing Huang, Zoey Huang, Sandra Chen, Eric Liao, Ella Li, Allison Quach, Jenny Jiang, Hanna Lin, Michael Hua, Savannah Yung, Lili Cheng, Ziyang Zhong. A safe and highly potent anti-PD-1-IL-2c fusion that decouples efficacy and toxicity of IL-2 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB218.
Abstract LB503: Using JBrowse 2 plugins to visualize cancer genomic data
Authors: Haw Robin Andrew , Diesh Colin , Bridge Caroline , Buels Rob , Stevens Garrett , Xie Peter , Martinez Teresa , Hershberg Elliot , Zhang Junjun , Dider Shihab , Cain Scott , Stein Lincoln , Holmes Ian 
Published: June 2022

Abstract
Genome browsers are essential tools for integrating, exploring, and visualizing data from large cancer genomics datasets. JBrowse 2 is a JavaScript genome browser with novel features for visualizing structural variants, syntenic alignments, and multiple types of genomic data. Although JBrowse 2 is available as a web-based or desktop application, the capabilities and features are not fixed and can be expanded through a comprehensive plugin system. To help address users' needs, we launched the new JBrowse 2 Plugin Store (https://jbrowse.org/jb2/plugin_store/). The overarching goals of the Plugin Store are to showcase the crucial features plugins add to JBrowse 2, to enable researchers to search for plugins they need, and for developers to highlight their plugins. The plugin system spans all aspects of the JBrowse 2 application and enables new track types (e.g. Manhattan plots, Hi-C data, ideograms), data adapters (e.g. API endpoint adapters for NCI Genomic Data Commons and the International Cancer Genome Consortium), and views (e.g. dot plots and multiple sequence alignments). Here, we present the capabilities of JBrowse 2 plugins and describe usage scenarios for cancer biologists and bioinformaticians, and software developers.
Citation Format: Robin Andrew Haw, Colin Diesh, Caroline Bridge, Rob Buels, Garrett Stevens, Peter Xie, Teresa Martinez, Elliot Hershberg, Junjun Zhang, Shihab Dider, Scott Cain, Lincoln Stein, Ian Holmes. Using JBrowse 2 plugins to visualize cancer genomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB503.
Abstract LB507: Towards elucidating the role of RNA modifications in cancer by improving the quantitative accuracy of mass spectrometric profiling of RNA modifications
Authors: Chiu Norman H. , Simpson Jennifer H. , Fleming Renata L. , Teng Jian , Tannous Bakhos A. 
Published: June 2022

Abstract
The molecular structure of both coding and non-coding RNA is frequently altered by the enzymatic activity of either writer or eraser of RNA modifications. Since the RNA functions are dependent on its molecular structure, cellular activities that involve specific RNA molecule(s) can potentially be regulated by the reversible nature of RNA modifications. There are more than 140 known RNA modifications. Mass spectrometry is a proven technique for the identification of RNA modifications. However, due to the lack of ribonucleoside standards and biases in normalizing the level of RNA modifications, it remains a challenge to perform the quantitative analysis of multiple RNA modifications that may co-exist in a biological sample. Our group has recently developed a method for standard-free quantitative epitranscriptomic profiling (SqEP) that allows us using mass spectrometry to accurately determine the abundancy of each detectable RNA modification without using any ribonucleoside standards to calibrate the detection signals. Thus, the SqEP method can be used for the untargeted analysis of RNA modifications. It also allows us to directly compare the level of different RNA modifications that are detectable in an individual cell line. This is an important feature for studying the relationships between various RNA modifications. Using glioblastoma (GBM) as our model, the results from using the SqEP method to determine the level of specific RNA modifications in patient-derived GBM cell lines were shown to be more accurate than the existing methods, and complied with the gene expression data from GBM patients that are available in the Cancer Genome Atlas (TCGA) program.
Citation Format: Norman H. Chiu, Jennifer H. Simpson, Renata L. Fleming, Jian Teng, Bakhos A. Tannous. Towards elucidating the role of RNA modifications in cancer by improving the quantitative accuracy of mass spectrometric profiling of RNA modifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB507.
Abstract LB527: A novel dimeric small molecule-radio conjugate targeting fibroblast activation protein with high and prolonged tumor uptake
Authors: Cazzamalli Samuele , Galbiati Andrea , Zana Aureliano , Bocci Matilde , Millul Jacopo , Mock Jacqueline , Elsayed Abdullah , Neri Dario 
Published: June 2022

Abstract
Imaging procedures based on small molecule-radio conjugates targeting Fibroblast Activation Protein (FAP) are taking the spotlight in clinical practice for the diagnosis of a wide variety of cancer lesions. However, therapeutic applications of FAP-targeting radioligand therapeutics are limited by their short residence time in tumor lesions. We have recently described the discovery of OncoFAP, a novel ultra-high affinity ligand of FAP which has been already validated for PET imaging applications in more than twenty patients with solid tumors. In this abstract, we describe the development and in vivo characterization of BiOncoFAP, a dimeric FAP targeting small molecule based on OncoFAP. In particular, OncoFAP and BiOncoFAP displayed a superimposable affinity for recombinant human FAP (KD = 970 pM and 993 pM, respectively, measured by Fluorescence Polarization). Moreover, the two ligands exhibited a clear selectivity for the target, without significantly interacting with a wide panel of non-target proteins. BiOncoFAP was coupled to a DOTAGA chelator, suitable for radiolabeling with [177Lu]Lu for therapeutic applications. Cold [natLu]Lu-BiOncoFAP-DOTAGA showed an excellent stability in both mouse and human serum, with half-life longer than 5 days, supporting in vivo investigations. In a head-to-head in vivo biodistribution comparative study against [177Lu]Lu-OncoFAP-DOTAGA, [177Lu]Lu-BiOncoFAP-DOTAGA exhibited a more stable and prolonged residence time in FAP-positive tumors implanted in immunodeficient mice (~20% ID/g and ~200-to-1 tumor-to-blood ratio, 24 h after systemic administration). Notably, [177Lu]Lu-BiOncoFAP-DOTAGA did not significantly accumulate in healthy organs, thus showing an outstanding tumor-to-organ ratio (e.g., 12-to-1 tumor-to-kidney and 34-to-1 tumor-to-liver ratio, at the 24 h time point). These findings heighten BiOncoFAP as promising candidate for the development of anti-cancer radioligand therapeutics towards FAP-expressing tumor lesions.
Citation Format: Samuele Cazzamalli, Andrea Galbiati, Aureliano Zana, Matilde Bocci, Jacopo Millul, Jacqueline Mock, Abdullah Elsayed, Dario Neri. A novel dimeric small molecule-radio conjugate targeting fibroblast activation protein with high and prolonged tumor uptake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB527.
Abstract LB530: A potent and selective small molecule antagonist of PD-L1 ABSK043 demonstrates significant anti-tumor efficacy in combination with other agents in preclinical models
Authors: Ying Haiyan , Zhang Yongxian , Yang Fei , Xin Wenqun , Song Jiaqi , Chen Zhui 
Published: June 2022

Abstract
Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for various cancers. Unlike antibodies, small molecule inhibitors may offer potential advantages in oral dosing, adjustable control of drug exposure, improved tumor penetration and many other aspects. Therefore, small molecule antagonist which can efficiently abolish interaction of PD-1 and PD-L1 may render a novel alternative treatment approach with potentially improved clinical benefits. ABSK043, an oral small molecule inhibitor of PD-L1 discovered by us, has entered into clinical Phase I in 2021. Preclinically, ABSK043 has shown significant tumor growth inhibition as a single agent in multiple models. To explore potential synergy of ABSK043 with other therapeutic agents, in vivo combination experiments were conducted.
In this work, we present in vivo combination results for ABSK043 with several therapeutic agents such as a VEGFR inhibitor axitinib, or carboplatin, a key component of the widely used CRC standard-of care chemotherapy treatment regimen, as well as other immune-oncology agents. These combinations demonstrated strong in vivo synergy in tumor mouse syngeneic models. Taken together, these data for the first time demonstrated combination synergy of a small molecule PD-L1 inhibitor with other agents and pave the road for potential clinical evaluation of combination treatment of ABSK043 with these agents in patients.
Citation Format: Haiyan Ying, Yongxian Zhang, Fei Yang, Wenqun Xin, Jiaqi Song, Zhui Chen. A potent and selective small molecule antagonist of PD-L1 ABSK043 demonstrates significant anti-tumor efficacy in combination with other agents in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB530.
Abstract LB537: CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation
Authors: Guo Deyin , Xing Fan , Xiao Jingshu , liang Jiaming 
Published: June 2022

Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Although oncolytic virus (OV) therapy has been proposed as a potential approach to treat GBM, the resistance is frequently observed because GBM cells are usually nonpermissive to OV. Here, we describe a dual-step drug screen for identifying chemical enhancers of oncolytic virus in GBM. An inhibitor of the cyclin-dependent kinases 4/6 (CDK4/6) was identified as the top enhancer from 1416 FDA-approved drugs, selectively increasing potency of the two OV strains, including VSVΔ51 and Zika virus. Mechanistically, CDK4/6 inhibition promoted the autophagic degradation of MAVS, resulting in impaired antiviral responses and enhanced tumor-selective replication of VSVΔ51 in vitro and in vivo. CDK4/6 inhibition cooperated with VSVΔ51 to induce severe DNA damage stress, leading to the amplification of oncolysis. In GBM xenograft models, combination treatment of CDK4/6 inhibitor and VSVΔ51 significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice. Further investigation revealed that CDK4/6 inhibitor and VSVΔ51 synergistically induced the immunogenic cell death and boosted the anti-tumor immunity. Together, our study features a promising approach of treating aggressive GBM through the combination of CDK4/6 inhibitor with OV.
Citation Format: Deyin Guo, Fan Xing, Jingshu Xiao, Jiaming liang. CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB537.
Abstract LB542: Overexpression of the short isoform of Brd4 in ovarian carcinoma leads to highly aggressive tumor phenotype
Authors: Drumond-Bock Ana Luiza , Wang Luyao , Wang Lin , Cybula Magdalena , Rostworowska Maria , Bieniasz Magdalena 
Published: June 2022

Abstract
High-grade serous ovarian carcinoma (HGSOC) is one of the deadliest types of cancer in the US. Occurrence of sporadic HGSOC is associated with high genomic instability, which causes amplification and deletion of several different genes. BRD4 is one of the most frequently amplified genes in ovarian carcinoma patients. BRD4 amplification leads to overexpression of BRD4 proteins including long and short BRD4 isoforms (BRD4-L and BRD4-S, respectively), and is associated with poor patient prognosis. Recently, it has been shown that the short isoform BRD4-S contributes to oncogenic properties of several tumor types; however, little is known about its role in ovarian cancer. Therefore, in order to interrogate the function of different BRD4 isoforms in HGSOC, we generated ovarian cancer cell lines stably overexpressing BRD4 isoforms (BRD4-L and BRD-S). Our data revealed that overexpression of BRD4-S in ovarian carcinoma cell lines induces a highly aggressive tumor phenotype in vitro and in vivo. Ovcar4-BRD4-S cells showed significantly higher cell proliferation rate and increased anchorage-independent growth when compared with parental cell lines. In addition, Ovcar4-BRD4-S presents a high level of DNA damage reflected by increased pH2AX foci. We also observed a disruption of cell cycle in Ovcar4-BRD4-S cells associated with a higher number of cells arrested in G2/M phase and increased population of polyploid cells. In vivo experiments demonstrated that BRD4-S expressing tumors grow significantly faster than parental tumors. BRD4-S overexpressing tumors are also very resistant to DNA-damage agents including standard of care platinum drugs. Finally, our preliminary drug screening demonstrated that Ovcar4-BRD4-S cells are highly sensitive to Wee1 inhibitor MK-1775. Furthermore, the combination of MK-1775 with paclitaxel synergistically increased the antitumor effect. In summary, our studies indicate that amplification of the BRD4 gene in HGSOC patients might lead to an increase in splicing of BRD4-S transcript, which in consequence promotes highly aggressive and platinum-resistant tumors. Precision therapies targeting BRD4 amplified tumors, such as Wee1 inhibitors in combination with paclitaxel hold great promise to improve ovarian cancer treatment and reduce chemotherapy resistance, which is a critical problem for eradication of this aggressive tumor.
Citation Format: Ana Luiza Drumond-Bock, Luyao Wang, Lin Wang, Magdalena Cybula, Maria Rostworowska, Magdalena Bieniasz. Overexpression of the short isoform of Brd4 in ovarian carcinoma leads to highly aggressive tumor phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB542.
Abstract LB544: Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs
Authors: Lee You Won , Choi Hun Mi , Oh Seung Yeon , Lee Eun Ji , Pyo Kyoung-Ho , Kim Jae Hwan , Byeon Youngseon , Heo Seong Gu , Lim Sun Min , Hong Min Hee , Kim Chang Gon , Kim Hye Ryun , Yun Mi Ran , Cho Byoung Chul 
Published: June 2022

Abstract
Introduction: Acquired resistance to ALK-tyrosine kinase inhibitors (ALK-TKIs) treatment, particularly target-off resistance, remains a clinical challenge for ALK-rearranged non-small cell lung cancer (NSCLC). To explore novel vulnerabilities of ALK TKI-resistant cancer cells, we focused on their distinct metabolic pathways for growth and survival.
Experimental Design: To investigate metabolic pathways in resistance mechanisms, we generated ALK-TKIs -acquired-resistant in vitro/vivo models. We screened metabolite mechanisms using metabolite assay kit, Seahorse Extracellular Flux Analyzer, real-time PCR, western blot, RNA-seq in resistant models.
Results: Through an integrated transcriptomic and metabolic assay screening approach, we identified the enhanced reliance on glutamine metabolism in target-off ALK-TKIs-resistant cells. Specifically, resistant cells were characterized by upregulation of glutaminase 1 (GLS1), a mitochondrial enzyme hydrolyzing glutamine into glutamate, simultaneously with downregulation of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this metabolic state intensively accelerates glutaminolysis and subsequent mitochondrial glutamine-derived aspartate synthesis, resulting in TKI resistance by reinforcing antioxidant capacity with increase of NADPH and glutathione. Mechanistically, GLS1 inhibition elicited a marked reduction of cell growth with increase of reactive oxygen species (ROS) in resistant cells, which was restored by supplementation of exogenous aspartate. The antitumor activity of GLS1 inhibition against resistant tumor cells was further validated in in vivo experiments, patient-derived xenograft (PDX) and EML4-ALK transgenic mice. More importantly, glutaminase inhibitor CB-839 enhanced the therapeutic efficacy of anti-PD-L1 treatment in immune checkpoint blockade (ICB)-resistant EML4-ALK transgenic mice.
Conclusion: Our findings highlight a new metabolic vulnerability of ALK-TKIs resistant tumors and provide a rationale for targeting GLS1 as a potential treatment option to overcome ALK-TKIs resistance.
Citation Format: You Won Lee, Hun Mi Choi, Seung Yeon Oh, Eun Ji Lee, Kyoung-Ho Pyo, Jae Hwan Kim, Youngseon Byeon, Seong Gu Heo, Sun Min Lim, Min Hee Hong, Chang Gon Kim, Hye Ryun Kim, Mi Ran Yun, Byoung Chul Cho. Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB544.