tbuckley/cabot-search huggingface dataset:
Abstract 5676: Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples
Authors: Qixuan Wang, Juan Wang, Radhika Mathur, Mark W. Youngblood, Qiushi Jin, Ye Hou, Lena A. Stasiak, Yu Luan, Joseph F. Costello, Feng Yue
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) represents the most prevalent malignant primary brain tumor with highly unfavorable prognosis. Currently, most genomic studies are conducted at a single site of a tumor, which do not reflect the complete genetic or epigenetic information across the whole tumor. Furthermore, the intra-tumoral heterogeneity (ITH) of 3D genome organization has also not been studied yet. To address these gaps, we performed Hi-C experiments in 21 samples obtained from 9 GBM patients, with 15 of them being spatially mapped based on their 3D coordinates from the same patients. We identified extensive inter-tumoral and intra-tumoral heterogeneity in genome compartmentalization and chromatin interactions. Notably, in a patient with 9 spatially mapped samples from both temporal and frontal regions, we accumulated over 6 billion reads and defined high-resolution region-specific chromatin interactions, regulatory networks, and key regulators within the same patient. We detected structural variation (SV) and enhancer hijacking across all the samples, and identified recurrent events that affect known cancer-related genes such as CDKN2A/B. Finally, we introduce the concept of 'enhancer amputation', defined as the loss of enhancers due to SVs which lead to decreased expression of their original target genes. To our knowledge, this study represents the first large-scale exploration of the 3D genome in primary GBM patients and the first investigation of 3D genome organization in multiple regions of the same tumor. Our findings provide unprecedented insights into the ITH of GBM at the 3D genomic level, opening new avenues for understanding and potentially targeting this devastating disease. Citation Format: Qixuan Wang, Juan Wang, Radhika Mathur, Mark W. Youngblood, Qiushi Jin, Ye Hou, Lena A. Stasiak, Yu Luan, Joseph F. Costello, Feng Yue. Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples [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 5676.
Abstract 7567: In-depth mass cytometry analysis reveals different immune cell composition of unique molecular subtypes in extensive stage small-cell lung cancer
Authors: Yuekang Li, Jingjing Qu, Binggen Wu, Qian Shen, Wenjia Sun, Lijun Chen, Bo Wang, Lixiong Ying, Jianya Zhou, Jianying Zhou
Journal: Cancer Research (2024)

Abstract Background: A novel molecular subtype classification was fashionable for small cell lung cancer (SCLC). However, the distribution of SCLC molecular subtype classification in Chinese patients were unknown, especially extensive stage (ES)-SCLC. It should validate and define their associated microenvironments across subtypes in ES-SCLC. Method: We used immunohistochemical (IHC) to evaluate SCLC markers of the subtypes including ASCL1, NEUROD1, POU2F3, SCLC-A/N/P in 135 ES-SCLC tumors. Peripheral blood of 24 ES-SCLC patients was test by mass cytometry using time-of-flight (CyTOF) to evaluate the differences in immune subsets regard to the subtype tumor microenvironment (TME). Validation was performed using flow cytometry and multiplex IF. Results: ASCL1, NEUROD1, POU2F3, and Inflamed were account for 60.7%, 28.9%, 7.4%, and 18.5% of SCLC tumors, respectively. Significant intratumoral heterogeneity was observed with 15.6% of the tumors being both positive for SCLC-A and -N subtype markers, respectively. The SCLC-I type possessed more CD8+ T-cells infiltration and had higher frequency an ‘inflamed’ immunophenotyped. CyTOF data showed greater CD161+CD127+CD8+T cells proportion in SCLC-I than SCLC-N subtypes before and after anti-immunotherapy. Furthermore, we validated that lung tissue of SCLC-I were infiltrated more CD161+CD127+CD8+T cells compared to SCLC-N subpopulation(P=0.0281). Flow cytometry further showed the stronger immune activation of CD161+CD127+CD8+T cells in SCLC-I types induced higher expression of GZMB and GNLY and lower-expression of T-cell exhaustion markers PD-1,TIGIT and LAG3 in comparison with SCLC-N types. We further confirmed that the high level of CD161+CD127+CD8+T associated with a favorable treatment response and prolonged overall survival. Conclusion: The present study validated the molecular subtypes in ES-SCLC patients. Furthermore, SCLC-I subtype has longer PFS and OS than SCLC-A, -N and -P patients. Our research not only provides an insight into the immune landscape of ES-SCLC but also sheds light on a special subset of CD161+CD127+CD8+T cells with prognostic and therapeutic significance. Citation Format: Yuekang Li, Jingjing Qu, Binggen Wu, Qian Shen, Wenjia Sun, Lijun Chen, Bo Wang, Lixiong Ying, Jianya Zhou, Jianying Zhou. In-depth mass cytometry analysis reveals different immune cell composition of unique molecular subtypes in extensive stage small-cell lung cancer [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 7567.
Abstract 4077: T cell targeting with PD-1-selective immune cell engagers based on GlycoConnect™ (GC™-ICEs) show excellent efficacy and tolerability
Authors: Remon van Geel, Mick Verhagen, Elias Post, Willem Vugs, Sorraya Popal, Sander van Berkel, Floris van Delft
Journal: Cancer Research (2024)

Abstract Engagement of T cell cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-immunocytokines, based on molecular architectures generated by a variant of DNA recombinant technologies, have recently entered the clinic. Earlier we have demonstrated how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan1, can be applied for attachment of various cytokines, including RLI or IL-15, without prior antibody engineering. The immunostimulatory activity of these GlycoConnect™ immune cell engagers (GC™-ICEs) can be modulated by tailoring linker design and payload stoichiometry. In this presentation, we demonstrate the GC™-ICE with either IL-15 or RLI can be applied to selective targeting of T cells, based on PD-1-selective binding and activation, using either protease-sensitive or non-cleavable linkers. We will show how such T cell targeting can be achieved leading to significant tumor volume reductions in syngeneic mouse models. Moreover, we have found that the GC-ICE™ can be applied without inducing systemic immune activation, thereby displaying a promising therapeutic index. In vitro and in vivo studies will be presented to showcase the biological activity of these GC™-ICEs in comparison to conventional immunocytokines obtained via genetic engineering.1Wijdeven et al., Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. mAbs 2022, 14, DOI: 10.1080/19420862.2022.2078466. Citation Format: Remon van Geel, Mick Verhagen, Elias Post, Willem Vugs, Sorraya Popal, Sander van Berkel, Floris van Delft. T cell targeting with PD-1-selective immune cell engagers based on GlycoConnect™ (GC™-ICEs) show excellent efficacy and tolerability [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 4077.
Abstract 5709: PF-07104091, a first-in-class CDK2-selective inhibitor for the treatment of HR+/HER2- breast cancer and CCNE1high ovarian cancer
Authors: Chen Shen, Ming Qiu, Nanni Huser, Bernadette Pascual, Qin Zhang, Todd VanArsdale, Anwar Murtaza, Jonathan Almaden, berly Kim, Lars Anders, Koleen Eisele
Journal: Cancer Research (2024)

Abstract The selective inhibition of Cyclin\CDK complexes controlling cell cycle progression has been established as cancer therapy by selective CDK4/6 inhibitors in HR+/HER2- breast cancer. Expanding control of the cell cycle through selective inhibition of CDK2 offers novel therapeutic opportunities in cancer, including targeting CCNE1 amplified tumors and countering resistance to CDK4\6 inhibitors in ER+ breast cancer. PF-07104091 is a first-in-class CDK2-selective inhibitor under clinical investigation in patients with HR+/HER2- breast cancer and ovarian cancer. Preclinical studies using PF-07104091 establish the therapeutic impact of CDK2 inhibition in both diseases and highlight distinct mechanistic roles for CDK2 in control of cancer cell proliferation. In models of CCNE1 amplified ovarian cancer, CDK2 plays the dominant role in control of RB1 phosphorylation and the G1 checkpoint. CDK2 inhibition with PF-07104091 induces G1 growth arrest and controls tumor xenograft growth as single agent therapy. In ER+ breast models CDK2 plays a supportive role in the control of RB1 phosphorylation cooperating with CDK4\6. Whole genome CRISPR KO and CRISPR activation screens in conjunction with CDK4\6 inhibition establish CDK2 KO as a primary sensitizer to CDK4\6 inhibition, and support Cyclin E\CDK2 complexes as the driver of resistance to CDK4\6 inhibitors in ER+ breast models. PF-07104091 combined with CDK4\6 inhibitor Palbociclib or CDK4-selective inhibitor PF-0060 synergistically controls proliferation of ER+ BC cells in vitro and induces tumor regression in ER+ BC xenograft models, including PDX models with acquired resistance to CDK4\6 inhibitors and endocrine therapy. Citation Format: Chen Shen, Ming Qiu, Nanni Huser, Bernadette Pascual, Qin Zhang, Todd VanArsdale, Anwar Murtaza, Jonathan Almaden, berly Kim, Lars Anders, Koleen Eisele. PF-07104091, a first-in-class CDK2-selective inhibitor for the treatment of HR+/HER2- breast cancer and CCNE1high ovarian cancer [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 5709.
Abstract 876: <i>spatialGE</i>: Empowering researchers to study the tumor microenvironment leveraging spatial transcriptomics
Authors: Oscar Ospina, Roberto Manjarres-Betancur, Guillermo Gonzalez-Calderon, Alex C. Soupir, Inna Smalley, Kenneth Tsai, Joseph Markowitz, Anders Berglund, Xiaoqing Yu, Brooke L. Fridley
Journal: Cancer Research (2024)

Abstract The use of single-cell RNA-seq (scRNA-seq) to understand the complexity of the tumor microenvironment (TME) has been pivotal in advancing cancer research and treatment strategies. Nevertheless, locating the individual TME components in their spatial contexts is essential to understanding the complexity of the TME, tumorigenesis, metastasis, and drug response. The recent popularity of spatially resolved transcriptomics (SRT) allows researchers to describe the TME and their spatial neighborhoods; however, SRT data analysis can be challenging for non-data scientists. Thus, we have developed spatialGE, a point-and-click web application designed to empower researchers in the analysis of SRT data. Our application offers a suite of functionalities, including the visualization of spatial gene expression activity maps, quantification of the spatial heterogeneity, testing of pathway-level spatial aggregation, tissue domain/niche detection, detection of spatial gradients in expression patterns, and differential expression analysis. Furthermore, spatialGE allows direct comparative analysis of gene expression with the morphology in tissue images, as well as methods for cell/domain phenotyping. Data input has been streamlined and made flexible to receive outputs from multiple SRT platforms. Analyses and results are stored within user-defined projects to facilitate accessibility at any time. We demonstrate the usefulness of spatialGE through its application to leptomeningeal metastatic melanoma (LMM) tissues assayed with the Visium platform. The gene expression tissue domain detection and gradient analysis in spatialGE indicated that SERPINA3 expression is higher in tumor regions closer to stroma. This finding led to cell culture experiments indicating that knocking down SERPINA3 results in the sensitization of tumors to MAPK-targeting therapy. These results highlight the utility of spatialGE for exploring SRT data and the empowerment of cancer researchers to explore the spatial architecture of the TME. Citation Format: Oscar Ospina, Roberto Manjarres-Betancur, Guillermo Gonzalez-Calderon, Alex C. Soupir, Inna Smalley, Kenneth Tsai, Joseph Markowitz, Anders Berglund, Xiaoqing Yu, Brooke L. Fridley. spatialGE: Empowering researchers to study the tumor microenvironment leveraging spatial transcriptomics [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 876.
Abstract 89: Comprehensive cell based bioassay approaches for characterization, and clinical development of therapeutic agonistic antibodies for cancer immunotherapy and autoimmune diseases
Authors: Venkatesh Chari, Jennifer Lin-Jones, Luhan Yang, Jane E. Lamerdin, Gaurav Agrawal
Journal: Cancer Research (2024)

Abstract Agonistic antibodies are emerging as promising therapeutics for targeting immune checkpoints, particularly those within the TNF Receptor Superfamily, as they play a crucial role in regulating immune cell function, especially in the context of cancer treatment. In addition, there is also a growing focus on the potential of agonistic antibodies to selectively activate co-inhibitory checkpoint receptors. This offers a promising avenue for suppressing inflammation in autoimmune diseases and restoring tolerance in graft-vs-host disease (GvHD) while avoiding the complications of global immunosuppression. While a substantial number of clinical trials are currently underway for oncology and autoimmune indications, there is a notable scarcity of commercially available assays to support the clinical development of this class of therapeutics, impacting their time-to-clinic. Existing assays frequently fail to accurately assess the agonistic activity of antibodies as they are unable to replicate the necessary physiologically relevant conditions. In this context, we present several case studies that highlight the pivotal role of cell-based bioassay approaches developed by Eurofins DiscoverX in driving the characterization and clinical development of agonistic antibody therapeutics targeting various checkpoint receptors. Additionally, we discuss our data demonstrating the indispensable role of FcyR-mediated antibody clustering in establishing the otherwise elusive agonistic activity of antibodies. Citation Format: Venkatesh Chari, Jennifer Lin-Jones, Luhan Yang, Jane E. Lamerdin, Gaurav Agrawal. Comprehensive cell based bioassay approaches for characterization, and clinical development of therapeutic agonistic antibodies for cancer immunotherapy and autoimmune diseases [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 89.
Abstract 7569: Characterizing pathways for metastasis of retinoblastoma in forebrain organoids
Authors: Yulia Shtanko, Sara Rodriguez, Benjamin Schachner, Emily Adis, Samantha McLaughlin, Sebastian Borges, James Dollar, Ashley Zuniga, Gabriela Quintana, Sofia Lopez, Dawn Owens, Chloe Moulin, Steffanie Braun, Gulum Yenisehirli, Daniel Pelaez, J. William Harbour, Stefan Kurtenbach
Journal: Cancer Research (2024)

Abstract Retinoblastoma (Rb) is a childhood cancer of the eye, which usually presents in children under the age of five. When detected early, Rb has favorable prognosis in developed countries, but metastasis into the central nervous system (CNS) through the optic nerve correlate with a high mortality rate. Even if detected early, the available harsh and unspecific treatments can cause serious side effects, and enucleations are still performed frequently. There is still uncertainty regarding the mechanism for metastasis into the central nervous system. We performed bioinformatic analysis of single cell sequencing data for retinoblastoma, retinal tissues, optic nerve, and brain, to identify potential pathways and cell-cell communications fostering Rb invasion into the optic nerve and brain. Our analysis revealed several potential metastatic drivers, including immune modulation involving MIF, secreted by the Rb cells, as well as cell-adhesion pathways promoting a change in cellular phenotype. Given that animal models do not faithfully recapitulate human Rb initiation and progression, we developed a novel human iPSC-derived forebrain organoid model to investigate mechanisms of Rb CNS metastasis. Microinjections of GFP-labelled Rb cells allow to track growth and spread. In this fully human model including microglial cells, we can, for the first time, study the Rb forebrain interactions and pathways involved. RNA-seq analysis of Rb cells growing in forebrain organoids shows increased activity in neuron projection development and neuron migration, overlapping with the observed phenotype switch of invading Rb. Together, we present a novel iPSC-derived human forebrain model to monitor growth and spread of metastatic Rb, and describe new pathways involved in invading and metastasizing Rb. Citation Format: Yulia Shtanko, Sara Rodriguez, Benjamin Schachner, Emily Adis, Samantha McLaughlin, Sebastian Borges, James Dollar, Ashley Zuniga, Gabriela Quintana, Sofia Lopez, Dawn Owens, Chloe Moulin, Steffanie Braun, Gulum Yenisehirli, Daniel Pelaez, J. William Harbour, Stefan Kurtenbach. Characterizing pathways for metastasis of retinoblastoma in forebrain organoids [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 7569.
Abstract 3383: Growth suppression and selective disruption of actin by alpha-santalol in human melanoma SK-MEL2 cells
Authors: Ajay Bommareddy, Ritesh Chandrasekaran, Michael Lu, Delilah Penate
Journal: Cancer Research (2024)

Abstract Alpha-santalol, a major component of sandalwood oil has been shown to have chemopreventive and anti-tumor effects in different pre-clinical cancer models. The present study was undertaken to determine the in vitro efficacy of alpha-santalol on SK-MEL2 human melanoma cells and an immortalized human keratinocyte cell line (HACaT). In this study, we employed MTT assay, Trypan blue assay, wound healing assay, and confocal microscopy for imaging phalloidin/DAPI stained cells to investigate the cytotoxicity, cell viability, migratory potential respectively of the cells treated with different concentrations of alpha-santalol and DMSO for given time periods. Results showed that alpha-santalol treatment significantly decreased SK-MEL2 cell viability, wound healing, while only affecting HACaT cells at higher concentrations. Alpha-santalol treatment also disrupted actin cytoskeleton in SK-MEL2 cells, whereas HACaT cells were more resistant to this effect. In conclusion, the present study reveals selective growth inhibitory and anti-migratory effects of alpha-santalol in human melanoma cells and warrants future studies to systemically explore the mechanistic details involved in its growth inhibitory and antimigratory effects. Citation Format: Ajay Bommareddy, Ritesh Chandrasekaran, Michael Lu, Delilah Penate. Growth suppression and selective disruption of actin by alpha-santalol in human melanoma SK-MEL2 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 3383.
Abstract 3698: Characterization of circulating rare events in non-small cell lung cancer
Authors: Jiyoun Seo, Stephanie N. Shishido, Jeremy Mason, Carmen Ruiz Velasco, Jaden Mullin, Rishvanth Prabakar, James Hicks, Peter Kuhn
Journal: Cancer Research (2024)

Abstract Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer, accounting for about 80 - 85% of all diagnoses. Unfortunately, 75% of NSCLC diagnoses are made when cancer has already spread and the prognosis is poor. Therefore, biomarker investigation that might allow for early detection of NSCLC is critical to improving patient outcomes. The purpose of this study is to demonstrate the feasibility of liquid biopsy to detect and identify circulating rare events, such as circulating tumor cells (CTCs), associated with NSCLC. Here we apply our non-enrichment-based High Definition Single Cell Assay (HDSCA) workflow which utilizes an immunofluorescence staining technique and an unsupervised rare event detection algorithm to identify the circulating rare cells and acellular events in samples collected from 206 NSCLC patients and 60 healthy individuals. We detected a heterogeneous population of circulating rare events in NSCLC, including epithelial, mesenchymal, and endothelial cells, as well as acellular events such as oncosomes. Cancer-associated circulating rare events with statistically significant prevalence in NSCLC compared to healthy individuals were observed. Molecular characterization using multiplexed targeted proteomics based on imaging mass cytometry and genomic analysis by single-cell copy number profiling confirmed the phenotypic heterogeneity and genomic profiles of the detected circulating rare events. In this study, our results demonstrate the use of the extended capabilities of liquid biopsy to identify a comprehensive overview of circulating rare events that can provide clinically valuable biomarkers in NSCLC. Citation Format: Jiyoun Seo, Stephanie N. Shishido, Jeremy Mason, Carmen Ruiz Velasco, Jaden Mullin, Rishvanth Prabakar, James Hicks, Peter Kuhn. Characterization of circulating rare events in non-small cell lung cancer [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 3698.