tbuckley/cabot-search huggingface dataset:
Abstract 4047: Unraveling synergistic therapeutic strategies involving FAK inhibition and immunotherapy using anti-PD1 antibody in KRAS and LKB1-driven lung cancer
Authors: Junghui Koo, Carol Tucker-Burden, Melissa Roy, Chunzi Huang, Wei Zhou, Melissa Gilbert-Ross, Haian Fu, Suresh S. Ramalingam, Adam I. Marcus
Journal: Cancer Research (2024)

Abstract Lung cancer presents a global health challenge demanding innovative preclinical models forresearch and therapeutic advancement. Genetically engineered mouse models (GEMMs) have seenremarkable growth in complexity and application over the past two decades. Our work leveragesthese models and is specifically designed to address the pressing need for effectiveimmunochemotherapies in the context of KRAS and LKB1 (KL) mutant lung adenocarcinoma,which shows resistance to most immunotherapies. Our study centers around a preclinicalsyngeneic orthotopic mouse model we developed using mouse lung and metastatic tumor cell linesderived from KL-GEMM. This model, optimized to mimic human lung cancer closely, providesan ideal platform for exploring the intricate interplay between the immune system and tumorprogression. Furthermore, we have previously shown the LKB1 mutant cell lines and tumormodels are uniquely sensitive to FAK inhibitors, and therefore we wanted to test whether thecombination of a FAK inhibitor with anti-PD1 therapy can improve sensitivity. The combinatoryadministration of FAK inhibitor (VS-6063) with anti-PD1 mAb synergistically increased anti-tumor response and survival outcome compared with single-agent therapy in the KL-mediatedsyngeneic orthotopic lung cancer model. By using GEMM-derived syngeneic cell lines, we haveevaluated the potential for creating innovative immunochemotherapies, customized for KL co-mutant lung adenocarcinomas with promising clinical potential. Furthermore, using this modelenables a deeper understanding of the KL mutant disease's pathogenesis, the impact of sex-biasedcancer development, and the assessment of novel immunochemotherapy treatment strategies in theKL genetic sub-type of lung adenocarcinoma. Citation Format: Junghui Koo, Carol Tucker-Burden, Melissa Roy, Chunzi Huang, Wei Zhou, Melissa Gilbert-Ross, Haian Fu, Suresh S. Ramalingam, Adam I. Marcus. Unraveling synergistic therapeutic strategies involving FAK inhibition and immunotherapy using anti-PD1 antibody in KRAS and LKB1-driven 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 4047.
Abstract 2342: BARTsc: A transcription factor analysis suite for single-cell omics data
Authors: Hongpan Zhang, Jingyi Wang, Zhenjia Wang, Chongzhi Zang
Journal: Cancer Research (2024)

Abstract In Eukaryotic cells, the expression of a small set of transcription factors (TFs) is usually sufficient to set up a cell-type-specific gene expression program. The underlying complicated epigenetic mechanisms that explain how cells change their states in response to intra- and extra-cellular signals in different scenarios remain to be fully understood. Importantly, epigenetic regulation of gene expression has been considered a central regulatory mechanism of cell fate determination and cellular plasticity. Insights into it will also profoundly impact our understanding of misregulation of gene expression in diseases such as cancer. However, the functional TFs of many cell types remain unclear, which greatly hinders the study of epigenetic regulatory mechanisms. The rapid development of single-cell technology is a promising opportunity that enables us to infer functional TFs for different cell types. Some computational methods have been published in this area. However, existing methods have various pitfalls. For instance, some methods use transcription factor binding motifs (TFBMs) as the reference of TF binding, overlooking widespread non-specific binding. Some other methods hold strict criteria for training data and thus can only predict a small number of TFs. To overcome these issues, we propose to leverage publicly available high-quality ChIP-seq data to predict TFs functional in single-cell omics data. Here, we present BARTsc, a comprehensive suite for a series of TF analysis functionalities, including inference of signature TFs of given cell types/clusters, cross-cell-type/cluster TF activity comparative analysis, and TF clustering based on their cross cell-type distributions. The input of BARTsc can be either scRNA-seq, scATAC-seq, or scMultiome data. We demonstrate that BARTsc outperforms several existing tools in both sensitivity and specificity in identifying key cell type regulators in single-cell datasets of well-studied systems. Applying BARTsc to a scRNA-seq dataset for cancer-associated fibroblasts (CAFs), we identified distinct regulatory activities of some TFs in different subtypes of CAFs, but the TF genes are universally expressed in these subtypes. In addition, by time course BARTsc analysis, we identified a list of TFs that may either promote or suppress CAF differentiation, offering a new approach to find potential candidate therapeutic targets. Citation Format: Hongpan Zhang, Jingyi Wang, Zhenjia Wang, Chongzhi Zang. BARTsc: A transcription factor analysis suite for single-cell omics data [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 2342.
Abstract 3502: Multi-omics approach to cholangiocarcinoma-related biology and development of precision medicine
Authors: Woo Young Kwon, Incheon Kang, Sung Hwan Lee
Journal: Cancer Research (2024)

Abstract Introduction: Cholangiocarcinoma is a diverse tumor entity characterized by distinct tumor biology and clinical phenotypes, which are influenced by the unique tumor microenvironment (TME) and anatomical location—whether intrahepatic, peri-hilar, or distal extrahepatic. Consequently, there is a clear need for a precision strategy that relies on cancer-specific, multi-omic features, moving away from traditional molecular subtypes derived from bulk RNA sequencing. Methods: We conducted thorough multi-omic analyses utilizing data from the Cancer Dependency Map (DepMap) project. This encompassed cancer-specific molecular characterization through various omics data, genome-wide loss-of-function screening employing the CRISPR-Cas9 system, and drug sensitivity assessments via compound screening. These efforts aimed to reveal cancer-specific molecular subtypes with clinical relevance. The identified cancer-specific molecular signatures were subsequently validated in independent translational cohorts. Results: Through integrative profiling of the transcriptome in bile duct cancer cell lines (n=39) obtained from the Cancer Cell Line Encyclopedia (CCLE), we unveiled cancer-specific molecular subtypes exhibiting distinct tumor biology across all omics layers, coupled with clinical relevance and prognostic significance. The major molecular features of each subtype demonstrated reproducibility in validation cohorts. Additionally, subtype-specific molecular biomarkers, encompassing mutational signatures and metabolites, were identified. Finally, we analyzed target drugs with subtype-specific genetic dependencies to formulate a precision strategy tailored to the distinct molecular characterizations of each subtype. Conclusions: A thorough analysis utilizing a multi-omics dataset uncovered precision strategies founded on cancer-specific molecular subtypes of cholangiocarcinoma, both in terms of tumor classification and discriminative therapeutic opportunities. It is imperative to conduct prospective translational studies in conjunction with clinical trials, all centered around the cancer-specific molecular subtypes, to establish a precision strategy for effectively managing cholangiocarcinoma. Citation Format: Woo Young Kwon, Incheon Kang, Sung Hwan Lee. Multi-omics approach to cholangiocarcinoma-related biology and development of precision medicine [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 3502.
Abstract 7513: Tumor treating fields (TTFields) can induce immunogenic cell death in GBM resulting in enhanced immune modulation
Authors: Ryan T. Nitta, Si Yeon Lee, Michael Lim, Gordon Li
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most common and aggressive form of malignant primary brain tumors. Despite current standard of care, the overall survival for GBM is ~15 months. While immunotherapy using immune checkpoint inhibitors such as anti-PD-1/PD-L1 have been efficacious for solid malignancies, very little progress has been made in a clinical setting for GBM. This is mainly due to GBM being known as a “cold” and non-immunogenic tumor. It has been previously established that a tumor may become “hot” if the T cell responses can be enhanced by increasing the presentation of tumor-specific antigens to the immune system. Tumor Treating Fields (TTFields) are alternating electric fields in a specific frequency range (100-500 kHz) delivered to the human body through transducer arrays. Treatment with TTFields have been approved and have shown efficacy in GBM. TTFields have induced immunogenic cell death in GBM, which in turn can elicit anti-tumoral immunity by inducing damage-associated molecular patterns (DAMP). These patterns are important for promoting engulfment of lung cancer cells by dendritic cells and recruitment of immune cells. These findings suggest that TTFields may enhance the immune response in GBM by increasing tumor specific antigens. In this study we show in vitro that TTFields enhanced the immune response to GBM. We initially demonstrated that GBM cells (GL261 or CT2A) treated with TTFields (200 kHz) can elicit DAMP emissions as evident by the increase in secretion of ATP and HMGB1 and the enhanced translocation of calreticulin to the cell surface. Additionally, TTFields stimulated the phagocytotic activity of antigen presenting cells (Raw264.7) and increased T-cell early activation (CD69/CD4+, CD69/CD8+) and activity (IFNγ and perforin). Since our findings in vitro indicate TTFields enhanced the immune response to GBM, we studied the therapeutic potential of using TTFields together with anti- PD1 in a syngeneic mouse model. We applied TTFields to GBM cells prior to intracranial injections. While our survival studies are preliminary, our findings suggest that systemic anti-PD1 and TTFields may result in a myeloid and T-cell mediated anti-tumor response and enhanced survival. Our findings indicate that TTFields treatment may help transform GBM into a “hot” tumor thereby making it an attractive target for immunotherapy. Citation Format: Ryan T. Nitta, Si Yeon Lee, Michael Lim, Gordon Li. Tumor treating fields (TTFields) can induce immunogenic cell death in GBM resulting in enhanced immune modulation [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 7513.
Abstract 4500: A high-throughput approach to discover and characterize glueable ligase-target pairs
Authors: Arpita Sen, Phil Burke, Ruchi Bansal, Dasha Krayushkina, David Noble, Kerry McGowan, Natasha Seelam Murakowska, Paxton Reed, Juliana Barrett, Randolph Lopez
Journal: Cancer Research (2024)

Abstract Targeted protein degradation can be induced with monovalent small molecules, termed molecular glues, that modify the substrate-binding interface of E3 ligases and reroute them to novel targets. Despite there being over 600 E3 ligases encoded in the human genome, most glues have focused on only a few. Expanding to additional ligases and targets is challenging due to the low probability of successful 'glueing.' Many have suggested that a weak basal interaction between a ligase and neo-substrate is an important prerequisite for the function of a molecular glue, but such weak interactions are challenging to discover. To address this need, we have harnessed AlphaSeq, a synthetic biology platform that measures protein-protein interactions at scale and with high sensitivity, to identify and characterize novel E3-target pairs. Our approach is twofold. First, we test for novel weak interactions (~100nM to 10uM) between a panel of E3 ligases and a library of disease relevant target proteins. Second, starting from a weakly interacting protein pair, we build mutational libraries of both proteins and measure their binding strengths. Mutations that strengthen binding serve to validate the weak interaction, provide structural insights into the nature of binding, and help to inform subsequent small molecule discovery. Here, we present our approach to discover and evaluate glueable ligase-target pairs using AlphaSeq, validation through proof-of-concept experiments involving a known interaction agonized by small molecules, and examples of novel glueable ligase-target pairs that we have recently discovered. Citation Format: Arpita Sen, Phil Burke, Ruchi Bansal, Dasha Krayushkina, David Noble, Kerry McGowan, Natasha Seelam Murakowska, Paxton Reed, Juliana Barrett, Randolph Lopez. A high-throughput approach to discover and characterize glueable ligase-target pairs [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 4500.
Abstract 5905: Propentofylline enhances GBM sensitivity to temozolomide via targeting TROY signaling
Authors: Ryan Eghlimi, David Nascari, Angad Beniwal, Drake Alton, Dustin Grief, Joseph Loftus, Melanie Haluska, David Coleman, Nhan Tran
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is a high grade glioma that accounts for the majority of primary malignant brain tumors. The standard of care for GBM consists of maximal surgical resection, concurrent radiation and temozolomide (TMZ), and adjuvant TMZ. However, this has only led to a modest increase in median patient survival. TROY (TNFRSF19) is an orphan member of the TNF receptor superfamily that is differentially upregulated in GBM with low expression in normal brain tissue. Previously, we have reported that TROY is overexpressed in GBM and signals to mediate cell invasion and therapeutic resistance. Propentofylline (PPF) is a well-studied synthetic methylxanthine derivative that has strong BBB penetrance. We have shown that PPF decreases TROY expression in gliomas, inhibits invasion, and sensitizes GBM to TMZ in vitro. Here we examined the efficacy of PPF in combination with TMZ using in vivo studies of intracranial models of GBM patient-derived xenograft (PDX) models in murine. We tested 3 models of GBM PDX cells with various TROY expression levels (GBM8-high TROY; GBM43-moderate TROY; GBM22-low/no TROY). Our intracranial PDX experiments showed that PPF treatment alone did not increase survival in all PDX cells. The combination of PPF and TMZ treatment did provide a survival benefit (p &amp;lt; 0.039) relative to TMZ alone (only in GBM8-high TROY and GBM43-moderate TROY) that was partially lost when treatment was discontinued. However, continuous PPF administration following a concomitant PPF and TMZ treatment course led to extended survival (p &amp;lt; 0.0015) compared to TMZ alone resulting in increased DNA damage (γH2AX) and apoptotic markers (Cleaved Caspase-3). Immunohistochemical analyses showed that TROY expression was decreased in tumors treated with PPF. In addition, PPF-treated tumors showed a differential myeloid population with well circumscribed tumors as compared to control-treated or TMZ-treated tumors. Thus, our data demonstrates that PPF may provide a pharmacological approach to targeting TROY concomitant with standard-of-care to increase patient survival. Citation Format: Ryan Eghlimi, David Nascari, Angad Beniwal, Drake Alton, Dustin Grief, Joseph Loftus, Melanie Haluska, David Coleman, Nhan Tran. Propentofylline enhances GBM sensitivity to temozolomide via targeting TROY signaling [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 5905.
Abstract 5641: Transcriptional regulation by nuclear deformation
Authors: Andrew Cook, Rebecca Stephens, Nadezda Fursova, Carson C. Chow, Dan Larson, Yekaterina Miroshnikova
Journal: Cancer Research (2024)

Abstract Establishment and maintenance of cell identities requires transcriptional rewiring and modulation of three-dimensional genome organization. The nucleus is subject to constant mechanical forces, both intrinsic from the cytoskeleton and extrinsic, such as compression, confinement, and stretch. Recently, work from us and others implicate mechanical force, through activating biochemical signaling pathways as well as direct nuclear deformation, in remodeling nuclear architecture, chromatin state and global gene expression patterns. Thus, we hypothesize that mechanical force plays an important role in coordinating and thresholding transcriptional responses. Here, we challenge this hypothesis by quantifying the effect of nuclear deformation on transcription in real time at single cell resolution quasi genome wide. Further, recent work elucidated that the MYC oncogene exerts global effects on transcriptional output by altering the binding dynamics of transcription factors involved in the activation and productive elongation of RNA Polymerase II. This contrasts with mechanical stress which reduces global levels of RNA Polymerase II. Here we interrogate how transcriptional output is tuned for specific genetic programs/loci by mechanical force using MYC as a paradigm. Citation Format: Andrew Cook, Rebecca Stephens, Nadezda Fursova, Carson C. Chow, Dan Larson, Yekaterina Miroshnikova. Transcriptional regulation by nuclear deformation [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 5641.
Abstract 1600: Interception of pro-tumorigenic glycan signaling in pancreatic cancer
Authors: Jasper Hsu, Hyemin Song, Kristina Peck, Chelsea Bottomley, McKenna Stamp, Shira Okhovat, Dannielle D. Engle
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is a deadly malignancy. We have setup a pipeline to interrogate cancer cell intrinsic and extrinsic mechanisms contributing to treatment response. Using a combination of mouse and human organoids models together with in vivo investigation, we have systematically dissected key signaling hubs driving pro-tumorigenic cancer cell intrinsic features as well as remodeling of the tumor microenvironment (TME). We found that the glycan epitope, CA19-9, drives pancreatic inflammation, cancer, and metastasis. CA19-9 drives pro-tumorigenic intrinsic features in part through CA19-9 modification of the secreted glycoprotein Fibulin 3. We have also discovered direct and indirect mechanisms through which CA19-9 causes remodeling of the TME. Specifically, CA19-9 elevation causes expansion of all cancer associated fibroblast (CAF) subtypes, including an increase in antigen presenting CAFs and resulting increase in regulatory T cells. Further, there are dramatic increases in tumor associated macrophages (TAMs) derived from both inflammatory monocytes as well as tissue resident macrophages. To delineate the mechanisms by which these TME changes are mediated, we use novel co-culture model incorporating macrophages, organoids, and fibroblasts (MOrF). Blocking CA19-9 signaling in vitro and in vivo reverses these TME alterations. These changes to the TME are mediated through indirect effectors as well as previously unknown CA19-9 modified proteins. Overall, we elucidate previously unexplored mechanisms driving pancreatic tumorigenesis while also uncovered vulnerabilities for therapeutic exploitation. Citation Format: Jasper Hsu, Hyemin Song, Kristina Peck, Chelsea Bottomley, McKenna Stamp, Shira Okhovat, Dannielle D. Engle. Interception of pro-tumorigenic glycan signaling in pancreatic 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 1600.
Abstract 2704: cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal cancer
Authors: Bruno Beernaert, Erkin Erdal, Rose Clark, Tong Liu, Ester M. Hammond, Eileen E. Parkes
Journal: Cancer Research (2024)

Abstract Esophageal adenocarcinoma (EAC) is an aggressive disease characterized by chromosomal instability (CIN), whereby cells continuously acquire chromosomal abnormalities that promote therapeutic resistance, immune evasion and metastasis. CIN in cancers also fuels the misplacement of genomic DNA in the form of structural abnormalities of the nucleus, such as micronuclei (MN), that lead to chronic activation of the cytosolic DNA sensing cGAS-STING pathway. However, how chronic cGAS-STING pathway activation is tolerated and shapes the tumor landscape of CINhigh EAC cancers is poorly understood. Using publicly available RNA-seq and genome sequencing data of EAC tumours and esophageal cancer cell lines as well as a panel of EAC cell lines, we demonstrate that the core cGAS-STING pathway machinery is rarely inactivated in EAC despite high levels of baseline CIN and aneuploidy. Through transcriptomic profiling of an isogenic EAC precursor cell line model of variable CIN and cGASKO/WT EAC cell lines we show that both chronic and transient CIN-driven cGAS-STING activation converge on the expression of CXCR1/2 ligands and other pro-inflammatory cytokines and chemokines rather than typical anti-tumor type I interferon signalling in EAC cells. Indeed, a novel transcriptional signature of cGAS+ micronuclear burden-correlated genes correlates with orthogonal measures of CIN in EAC tumours and esophagogastric cancer cell lines and is associated with an enrichment in myeloid-derived cells as well as poor prognosis. Correspondingly, using multiplexed immunofluorescence (IF) we find that a high preponderance of cGAS+MN and STING expression in human EAC samples is associated with decreased tumor purity, increased myeloid cell and macrophage infiltration, and increased peripheral blood neutrophil counts, indicative of tumor-promoting myeloid inflammation. Ongoing multiplexed IF and single-nuclei RNAseq analysis of cGAS+MNhigh and cGAS+MNlow EAC tumors will further help characterise the components that comprise the CIN EAC tumor microenvironment (TME) and the CIN- and cGAS-STING-dependent cell-cell interactions that govern it. Taken together, our findings provide an explanation for the observed maintenance of cGAS and STING in EAC and identify disruption of cGAS-STING-dependent myeloid cell inflammation and recruitment as a potential therapeutic target for CINhigh EAC. Citation Format: Bruno Beernaert, Erkin Erdal, Rose Clark, Tong Liu, Ester M. Hammond, Eileen E. Parkes. cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal 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 2704.