tbuckley/cabot-search huggingface dataset:
Abstract 5452: AXIN2 differentially modulates stem cell subpopulations providing a potential therapeutic opportunity for targeting colorectal cancer stem cells
Authors: Chi Zhang, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2024)

Abstract Constitutively activated WNT-signaling promotes stem cell (SC) overpopulation which drives most colorectal cancer (CRC) development. It is not known, however, how WNT-signaling activity regulates different SC sub-populations. We previously reported that SC population size decreases as AXIN2 is knocked down, and increases when AXIN2 is overexpressed. Changes in cell cycle and apoptotic rate were also observed. Here, we present our recent results on changes between different SC subpopulations (ALDH+ vs. LGR5+) that occur due to AXIN2 modulation. We hypothesize that modulation of AXIN2 promotes differential expansion between different CRC SC subpopulations (ALDH+ and LGR5+). We observed that AXIN2 not only increases LGR5+ SC population size, but also expands the ALDH+ SC population to a greater extent as shown by an increased ALDH+-to-LGR5+ SCs ratio. This indicates that AXIN2, via WNT signaling, regulates SC population size, particularly ALDH+ SCs. Since the ALDH SC marker is also a key component in the retinoic acid (RA) signaling pathway, we surmised that increased AXIN2 would not only lead to elevated ALDH levels, but also upregulate the RA-signaling pathway components in CRC cells. To this end, we conducted NanoString mRNA profiling to study the effects of AXIN2 knockdown and overexpression in HT29 and SW480 CRC cells. The results showed that increased AXIN2 significantly up-regulated several key components of the RA-signaling pathway. Taken together, our results indicate that AXIN2 drives a shift in SC subpopulation sizes favoring the ALDH+ SCs. It also promotes the RA-signaling component expression - a pathway known to regulate SC differentiation. As a potential treatment strategy for CRC, therapeutically inducing high levels of AXIN2 could shift the balance between SC populations towards ALDH+ SCs, which may provide a way to target cancer SCs with retinoids to induce their differentiation. Citation Format: Chi Zhang, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. AXIN2 differentially modulates stem cell subpopulations providing a potential therapeutic opportunity for targeting colorectal cancer stem 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 5452.
Abstract 1248: The BRD8/p53 epigenetic switch re-establishes tumor suppression in glioblastoma
Authors: Xueqin Sherine Sun, Alea A. Mills
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most common and deadly adult primary brain malignancy. Median survival is just 12-14 months, with only about 5% of GBM patients surviving 5 years after diagnosis. This picture has not substantially improved over decades and there is an urgent need to discover more specific and effective treatments for this deadly malignancy. We discovered the bromodomain-containing chromatin regulator BRD8 as essential to GBM lacking p53 mutations (TP53WT), which make up ~71% of cases (1). BRD8 maintains malignancy by crippling p53-mediated tumor suppression in a way distinct from previously described mechanisms: it reprograms the p53 network through the EP400 histone acetyltransferase complex and by bromodomain-directed occupancy of the histone variant H2AZ at p53-induced targets, enforcing a repressive chromatin state that prevents p53-mediated transactivation. Importantly, targeting BRD8 in TP53WT GBM remodels chromatin by evicting H2AZ and enhancing chromatin accessibility, enabling p53 to bind and transactivate its targets. This chromatin remodeling cascade (referred to as the “BRD8/p53 epigenetic switch”) re-establishes p53 activity in TP53WT GBM, normalizing gene expression, evoking cell cycle arrest, inhibiting gliomagenesis, and prolonging survival in xenograft models of TP53WT GBM. Our recent work: (i) reveals that BRD8 opposes p53 function in non-malignant brain cells; (ii) shows that the bromodomain of BRD8 is unique amongst the bromodomain-containing protein family, as it is the only one that selectively reprograms the p53 network; and (iii) demonstrates that targeting BRD8 works synergistically with MDM2 inhibition. Our findings present a previously unappreciated mechanism by which cancer cells side-step p53, indicate that targeting BRD8 re-establishes p53-mediated tumor suppression in TP53WT GBM, highlight unique features of the bromodomain of BRD8, and propose therapies using co-inhibition of BRD8 and MDM2 as a dual-level tactic for boosting up p53. Thus, our work sheds light on new principles of chromatin biology and offers new promise for treating patients with this devastating malignancy. (1)Sun et al., 2023 Nature 613 (7942):195-202. Citation Format: Xueqin Sherine Sun, Alea A. Mills. The BRD8/p53 epigenetic switch re-establishes tumor suppression in glioblastoma [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 1248.
Abstract 2270: UALCAN Mobile, An app for cancer gene expression data analysis
Authors: Sooryanarayana Varambally, Darshan Shimoga Chandrashekar, Gopi Chand Puli, Santhosh Kumar Karthikeyan, Upender Manne, Chad J. Creighton, Sidarth Kumar
Journal: Cancer Research (2024)

Abstract Cancer is a complex disease effecting different organs and a major cause of death and a burden on the society. Multiple molecular alteration occur during cancer initiation and disease progression and metastasis. Recent advances in technology led to generation of large amount of molecular data including transcriptome. These large datasets can be used to analyze and identify sub-class specific cancer biomarkers and targets. However, there is a need for the development user friendly tools for its analysis and dissemination of the large scale cancer molecular data. Earlier, we had developed and upgraded web based comprehensive proteogenomic platform UALCAN (ualcan.path.uab.edu), which allows users to analyze and integrate the disparate data to better understand the gene, proteins, and pathways perturbed in cancer and make discoveries. UALCAN web platform enables intuitive analysis and discovery by cancer research community. In the current study, we describe the development of UALCAN Mobile application (App) that will provide cancer transcriptomic data obtained from The Cancer Genome Atlas (TCGA) project, to evaluate protein-coding gene expression based on various stratification including stage, grade, race, gender and molecular-subtypes across over 30 types of cancers. The UALCAN Mobile app aims at providing large cancer dataset on the go. In order to find causative gene expression changes, identify biomarkers and therapeutic targets, UALCAN Mobile will assist as the data will be easily mobile and transportable with this App. Here, we describe the development of UALCAN Mobile and its utility to the cancer research community. UALCAN Mobile App can be found at both iOS/Apple and Android play store and is free to download and use. Citation Format: Sooryanarayana Varambally, Darshan Shimoga Chandrashekar, Gopi Chand Puli, Santhosh Kumar Karthikeyan, Upender Manne, Chad J. Creighton, Sidarth Kumar. UALCAN Mobile, An app for cancer gene expression data analysis [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 2270.
Abstract 1340: Modulation of the natural killer cell immune response to tumor with a synthetic tumor -immune cell agonist, NK-TICA™
Authors: Fay Dufort, Tucker Ezell, Alexandra Rezvaya, Kathleen Ho, Christopher Leitheiser, Philip Brandish, Kevin McDonnell, Nicholas Keen
Journal: Cancer Research (2024)

Abstract Natural Killer (NK) cells are highly responsive cytotoxic immune cells of the innate immune system with well characterized anti-tumor properties. Their ability to directly kill malignant cells and elicit an adaptive immune response makes them a promising candidate for a precision guided immunotherapy in oncology. Bicycle® peptides are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle® platform technology to discover and evaluate a new class of fully synthetic molecules termed NK tumor immune cell agonists (NK-TICA™). The NK-TICA™ consists of chemically coupled Bicycle® peptides that bind specifically to the key activating receptor, NKp46, and to tumor antigens, that results in highly potent, antigen-dependent receptor activation and NK cell function. We demonstrate potent, selective binding of our Bicycle® peptides to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA™ compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner. In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle® NK-TICA™ as a multifunctional immune cell engager will promote the modulation and anti-tumor activity of peripheral and intra-tumoral NK cells to solid tumors. Citation Format: Fay Dufort, Tucker Ezell, Alexandra Rezvaya, Kathleen Ho, Christopher Leitheiser, Philip Brandish, Kevin McDonnell, Nicholas Keen. Modulation of the natural killer cell immune response to tumor with a synthetic tumor -immune cell agonist, NK-TICA™ [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 1340.
Abstract 2262: Genomic profiling of leukemic cell lines, responders vs. non-responders to Narazaciclib (HX301 or ON123300), a novel kinase inhibitor with activity against CSF1R and FLT3
Authors: Jia Xue, Tao Yang, Hang Ke, Sheng Guos, Henry Qixiang Li
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) is an aggressive myeloid leukemia with global annual mortality ~150,000. While standard of care (SOC) of the 1st -line treatment being mainly induction chemotherapy, available targeted therapies cover rather limited patients carrying specific driver mutations (IDH mutations and FLT3-ITR). We previously reported a novel kinase inhibitor, Narazaciclib with strong anti-CSF1R activity (IC50 0.7nM) as well as anti-FLT3 (IC50 7nM), and also thus anti-AML activity for certain AML experimental models, as shown in vitro and in vivo (AACR Annual Meeeting, 2023). In the present study, we assessed the impact of HX301 on the in vitro proliferations of a panel of leukemic cell lines (n = 54), including a panel of AML cell lines (n = 33), that have been parallelly genomic-profiled by whole-exome sequencing and whole-transcriptome sequencing. We then set out to analyze the proliferation data and the genomic data, in attempt to elucidate genes and pathways that may be associated with the treatment responses. The biomarker analysis has been performed on gene expression, mutation and copy number variation levels, and the data been presented using common methodologies, including principal component analysis, differential expression analysis, correlation analysis, Gene Ontology enrichment analysis, gene set variation analysis, somatic gene mutation analysis, and copy number variation analysis, etc. Some of the observations have been made: 1) differential expression analysis on all leukemic cell lines shows that 254 genes have been positively associated with the responders; while expression of 191 genes are negatively correlated with AUC, i.e. positively associated with response, as revealed by Spearman correlation analysis; 2) Gene Ontology enrichment analysis revealed these response related genes are mostly involved in myeloid leukocyte activation and defense response; 3) all FLT3-ITD AML lines are responders, presumably due to the FLT3i activity of HX301; 4) CSF1R expression levels seem not correlated to drug responses; 5) pathway analysis on non FLT3-ITD AML lines reveals that STAT5 activation downstream of FLT3 signaling, IL7 pathway and NFKB pathway are significantly associated with better response. Finally, we are also attempted to use statistics learning to reveal genes, as a potential predictive biomarker, that may be correlated to drug response. Citation Format: Jia Xue, Tao Yang, Hang Ke, Sheng Guos, Henry Qixiang Li. Genomic profiling of leukemic cell lines, responders vs. non-responders to Narazaciclib (HX301 or ON123300), a novel kinase inhibitor with activity against CSF1R and FLT3 [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 2262.
Abstract 2276: Comprehensive analysis of the genomic landscape of thyroid cancer
Authors: SooHyun Im, Jong-Lyul Park, Jae-Yoon Kim, Chan-Kwon Jung, Seon-Young Kim
Journal: Cancer Research (2024)

Abstract Thyroid cancer, the most common endocrine malignancy, has a high incidence worldwide. Meanwhile, the incidence of thyroid cancer ranks first in Korea. To assess the possible influence of ethnicity on the molecular profile of thyroid cancer, we compared the genomic features of South Korean thyroid cancer with European thyroid cancer. In this study, we performed whole genome sequencing profiling (WGS) for 459 Korean thyroid cancer patients, including papillary thyroid carcinoma (PTC, n = 274), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP, n =18), follicular thyroid carcinoma (FTC, n = 16), follicular thyroid adenoma (FTA, n = 63), Hürthle cell adenoma (HCA, n = 22), and invasive encapsulated follicular variant papillary thyroid carcinoma (IEFVPTC, n = 19). We assessed the single nucleotide variant (SNV) and insertions and deletions using Mutect2, Varscan2, and Strelka2. For mutation signature and copy number alterations analysis, we used the Maftools and GISTIC2.0 packages, respectively. Our results revealed that most somatic mutations were similar between the Korean thyroid cancer dataset and the cancer genome atlas program (TCGA). However, the Korean cohort (1%) had a much lower NRAS mutation frequency than the TCGA cohort (8%). Mutation signature analysis showed that SBS6 and SBS2 were highly associated with the TCGA and Korean cohort. SBS6 is related to defective DNA mismatch repair, and SBS2 is characterized predominantly by CC &amp;gt; TT doublet base substitutions. In addition, we identified the NIFTP-specific somatic mutations such as KEAP1 and ZFP36L2. This study presents insights into the genomic landscape of Korean thyroid cancer and reveals some similarities and differences with European thyroid cancer at the molecular level. Citation Format: SooHyun Im, Jong-Lyul Park, Jae-Yoon Kim, Chan-Kwon Jung, Seon-Young Kim. Comprehensive analysis of the genomic landscape of thyroid 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 2276.
Abstract 1244: Exploiting the pathogenesis of endogenous retrovirus to tackle squamous cancers
Authors: Ying Lyu, Yejing Ge
Journal: Cancer Research (2024)

Abstract Retrotransposons are the evolution relic of ancestrally invaded retroviruses interspersed through our genome. Mostly domesticated as host regulome, retrotransposons shape lineage gene expressions or donate coding functions. A few rare evolutionarily young species remain virally active, leading to germline mutations and modulating immune functions. Aberrant retrotransposon activities have been widely observed in adult diseases, although the extent to which they ensue active viral form and function under those contexts is unclear. Their molecular trigger in adult pathophysiology is poorly defined. To address these questions, we use murine skin as our model, given its well-characterized, abundant and highly accessible adult stem cells, not only mediating postnatal remodeling and homeostatic regeneration, but also responding to stress by driving tissue repair and adaptations. By analyzing a genetic model lacking a known retrotransposon suppressor, histone methyltransferase Setdb1, which we found to be essential in the adult skin, we saw hair loss and hair follicle stem cell exhaustion phenotype, accompanied by a robust and selective surge of endogenous retroviruses (ERVs). When combined with squamous cell carcinoma drivers, Setdb1 loss significantly blocked tumor progression in vivo. Interestingly, compared to relatively mild or no induction of commonly observed evolutionarily young ERVs, the most induced species in our model is a class I ERV, murine leukemia virus (MuLV). We detected abundant retroviral peptides originated from its full-length copies through mass spectrometry and viral-like particles through transmission electron microscopy that are immunoreactive to a monoclonal MuLV env antibody. Similar viral-like particles were broadly evident across several epithelial tissues beyond skin, implicating its conserved function across squamous cancers. Epithelial originated ERVs elicit tissue wide inflammatory response, and can be ameliorated by pharmacological or genetic inhibition of retroviral activity. Physiologically, viral-coding ERVs arise as the epigenetic machinery declines in response to age-associated stress, and plummet when host safeguard prevails in UV induced skin hyperplasia. As an evolutionary conundrum, viral-coding ERVs pose a threat to host fitness and yet, they’ve resisted extinction persisting in the mammalian genome. Our findings suggest viral-coding ERVs wrestle with the host surveillance programs to regulate adult tissue physiology and pathology, thus providing a key target in eliciting innate immunity and tackling squamous cancers. Citation Format: Ying Lyu, Yejing Ge. Exploiting the pathogenesis of endogenous retrovirus to tackle squamous cancers [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 1244.
Abstract 226: Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation
Authors: Shiho Suzuki, Juntaro Matsuzaki, Toshihide Muramatsu, Yae Kanai, Yoshimasa Saito
Journal: Cancer Research (2024)

Abstract Cholangiocarcinomas are highly aggressive malignancies with a poor prognosis. The global incidence of cholangiocarcinoma patients appears to be on the rise. While surgical resection remains the curative option for cholangiocarcinoma patients, the majority of cases are diagnosed at an advanced stage, resulting in poor outcomes. Patients with inoperable cholangiocarcinomas typically undergo chemotherapy regimens, including Gemcitabine, but their efficacy is limited, leading to low 5-year survival rates. Recent advancements in organoid culture technology allow for the in vitro replication of tissue structures by culturing tissue stem cells in three dimensions, offering great promise for personalized medicine. Utilizing patient-derived organoids has proven effective in predicting the outcomes of therapeutic drugs. We have successfully established organoids using cancer tissue derived from cholangiocarcinoma patients, and stably culturing and maintaining them, promoting their application to personalized medicine (Saito Y et al. Cell Rep. 27, 1265, 2019, Saito Y et al. Cancer Cell 40, 226, 2022). IDH1 mutations have been identified in approximately 15% of intrahepatic cholangiocarcinomas and are known to convert α-ketoglutarate (α-KG) in the TCA cycle to produce 2-hydroxyglutarate (2-HG), which is observed in gliomas and acute myeloid leukemia. 2-HG acts as an antagonist to α-KG-dependent dioxygenases, promoting cancer development. This study aims to develop a novel treatment for cholangiocarcinomas with IDH1 mutations. Metabolomic analysis of patient-derived cholangiocarcinoma organoids revealed 2-HG accumulation and reduced ATP production in IDH1-mutated cholangiocarcinoma organoids compared to IDH1 wild-type cholangiocarcinoma organoids. This may suppress the protein synthesis of MCL-1 and mTOR signaling through the activation of AMPK kinase, suggesting that further inhibition of MCL-1 could be lethal in IDH1-mutated cholangiocarcinoma organoids. Indeed, exposure to S63845, an MCL-1 inhibitor, significantly inhibited cell proliferation in IDH1-mutated cholangiocarcinoma organoids, unlike in IDH1 wild-type cholangiocarcinoma organoids. Furthermore, the combination of MCL-1 inhibitor and BCL-XL inhibitor demonstrated a synergistic and potent growth inhibitory effect on cholangiocarcinoma organoids. These findings indicate that the MCL-1 inhibitor holds promise as a new therapeutic agent for cholangiocarcinoma patients with IDH1 mutations. Citation Format: Shiho Suzuki, Juntaro Matsuzaki, Toshihide Muramatsu, Yae Kanai, Yoshimasa Saito. Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation [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 226.