tbuckley/cabot-search huggingface dataset:
Abstract 1963: BB102, a highly selective and potent reversible-covalent FGFR4 inhibitor effective in multiple xenograft tumor models
Authors: Qi Wang, Gongping Duan, Wei Hua, Xianglong Wei, Min Li, Junheng Wang, Xingmin Zhang
Journal: Cancer Research (2024)

Abstract Introduction: Fibroblast growth factor receptor 4 (FGFR4) belongs to the FGFR family which interact with fibroblast growth factors (FGFs) to regulate cell proliferation, differentiation and apoptosis. Due to unique structural domain, FGFR4 is specifically bound by FGF19 with high affinity in the presence of co-receptor β-Klotho. Hyperactivated FGF19/FGFR4 signaling, induced by FGF19/FGFR4 overexpression and FGFR4 mutation, was reported to be associated with the growth, metastasis and invasion of various cancer. Thus, FGFR4 is considered as a novel target to treat cancer with hyperactivated FGF19/FGFR4 signaling. Here we report BB102 as a highly selective and potent reversible-covalent FGFR4 inhibitor. Methods: BB102 was developed through structure-based drug design, and optimized by SAR analysis and medicinal chemistry iteration. Biochemical and cell assays were applied in evaluation of BB102 inhibitory activity. Preclinical studies including pharmacokinetic (PK) and toxicity were performed in rats and dogs. Xenograft tumor models in mice were conducted to demonstrate the in vivo efficacy of BB102. Results: As a reversible-covalent FGFR4 inhibitor, about half compound of BB102 dissociated from FGFR4 kinase within 24 h, which was conducive to overcome the fast re-synthesis rate of FGFR4 (&amp;lt; 2 h) in hepatocellular carcinoma cells. BB102 only inhibited kinase activity of FGFR4WT, FGFR4N535K and FGFR4V550L at nanomolar levels in 207 kinase panel screening. BB102 completely blocked the phosphorylation of the downstream protein ERK at 16.7 nM. BB102 exhibited strong inhibitory effects on the cell proliferation in vitro and tumor growth in mouse models inoculated with the high expression of both FGF19 and FGFR4, or FGFR4 mutated tumor cells. PK profile of BB102 showed good oral bioavailability (F&amp;gt;70%) with a nearly linear dose-dependent exposure. The compound had no effects on the respiratory and central nervous systems in rats, cardiovascular system in Beagle dogs or hERG liability in vitro. In comprehensive safety evaluation, the Severely Toxic Dose in 10% (STD10) in rats was 300 mg/kg/day and the Highest Non-Severely Toxic Dose (HNSTD) in dogs were 100 mg/kg/day. Conclusion: BB102 is a highly selective and potent reversible-covalent FGFR4 inhibitor with promising efficacy in high expression of both FGF19 and FGFR4, and/or FGFR4 mutated tumor models and good safety in preclinical studies. The phase I study of BB102 is in progress. Citation Format: Qi Wang, Gongping Duan, Wei Hua, Xianglong Wei, Min Li, Junheng Wang, Xingmin Zhang. BB102, a highly selective and potent reversible-covalent FGFR4 inhibitor effective in multiple xenograft tumor models [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 1963.
Abstract 4593: A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells
Authors: Umamaheswari Natarajan, Appu Rathinavelu
Journal: Cancer Research (2024)

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) is the most prevalent type among lung cancers, contributing to the high mortality seen with this deadly disease. Despite aggressive treatments, the 5-year survival rate for lung cancer is only 23.7% in the United States. MDM2 and AURKB are two cancer-driving genes that are highly expressed in a broad range of cancer types including lung cancers. Furthermore, MDM2 overexpression can positively impact AURKB expression and contribute to oncogenesis and cancer progression. Therefore, blocking MDM2 with specific inhibitors has become a promising strategy for the restoration of p53 function that could be used for the treatment of different types of cancers including lung cancers. In this regard, both MDM2 and AURKB inhibitors have shown promising antitumor activity against NSCLC. Therefore, the main objective of this study was to understand the molecular mechanisms linking MDM2 and ARKB using RG7388, CM272, BMS-582949 (p38 inhibitor), and Ralimetinib (p38 inhibitor) in A549 and H460 lung cancer cells. We analyzed the individual or combination treatment effects of these drugs on epigenetic modifications, cell cycle arrest, and cell death mechanisms, using the in vitro experimental model. When RG7388 was used individually, or in combination with BMS-582949 or Ralimetinib, a significant increase in the cytotoxic effect was observed in A549 and H460 cells. Induction of cell cycle arrest by RG7388 in cancer cells was evidenced by elevated p21 expression levels. In addition, RG7388 and combination treatments in NSCLC cells showed significant upregulation of p53, p27, Bax, cleaved PARP, phospho-FOXO3a and down-regulation in DNMT3a, DNMT1, FOXM1, AURKB, CDC25, and CDK4 levels. It appears that during treatments with a combination of MDM2 with DNMT or p38 inhibitor, two pathways might be blocked simultaneously, which could lead to increased cancer cell death. RG7388 appears to induce cell death in a p21-dependent manner and CM272, BMS-582949, and Ralimetinib seem to induce cell death via a p21-independent manner by inhibiting a downstream pathway. However, further studies are needed to fully understand the intracellular link between MDM2 and AURKB that is disrupted by the anti-cancer agents used in our study. (This project was supported by the PFRDG Grant of Nova Southeastern University and by the Generous support from the Royal Dames of Cancer Research Ft. Lauderdale, FL) Citation Format: Umamaheswari Natarajan, Appu Rathinavelu. A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4593.
Abstract 7012: Studying mosaic epimutations at scale
Authors: Oleksii Nikolaienko, Per E. Lønning, Stian Knappskog
Journal: Cancer Research (2024)

Abstract Mosaic epimutations (i.e., epigenetic gene inactivation) within the BRCA1 gene promoter occur in 5-8% of healthy individuals and are associated with a significantly elevated risk of breast and ovarian cancer. These epimutations arise prenatally and then serve as an underlying cause of cancer in adulthood, likely accounting for about 20% of triple-negative breast cancers. Similar mosaic epimutations have been detected in some other tumor suppressor genes as well, but the intraindividual and population frequencies of this phenomenon remain unknown. To address this gap, we have developed novel methodology for detection of mosaic epimutations. The experimental technique is a multiplexed, hybridization capture-based, targeted methylation sequencing assay covering gene regulatory areas. It allows cost-effective assessment of epimutations in established and emerging tumor suppressor genes. An accompanying tailored data analysis pipeline is designed to quantify epimutations. The pipeline is sensitive and robust to variance in methylation, sequencing errors and batch effects. We applied this method to a set of samples from healthy young males. Analysis uncovered significant interindividual epimutational heterogeneity and confirmed high sensitivity of the assay and its superiority compared to methylation profiling using microarrays. Here, we present details on the highly sensitive, scalable and robust methodology for analysis of mosaic epimutations together with the results on initial assessment of the prevalence of epimutations in healthy individuals. We anticipate that this method will become widely used for studies of epigenetic gene regulation and related cancer risk. Citation Format: Oleksii Nikolaienko, Per E. Lønning, Stian Knappskog. Studying mosaic epimutations at scale [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 7012.
Abstract 7035: Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics
Authors: Mi-So Park, Hyunbin Cho, Hyeree Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won
Journal: Cancer Research (2024)

Abstract As the fifth leading cause of cancer-related mortality, liver cancer imposes a global burden. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with a five-year overall survival rate of less than 20% for advanced-stage cases. Even the most advanced immunotherapy for HCC has disparate response rates in each patient with HCC, which has led to efforts to unravel the underlying factors in the progression of HCC using bioinformatic approaches. In recent decades, numerous studies have explored T-cell subtypes with tissue-specific residency, suggesting their early protective functions and therapeutic potential within tumor microenvironment (TME). This study aimed to understand inter-individual and intercellular TME through single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) in five recurrent/non-recurrent HCC patients. We identified tumor-associated tissue-resident memory T (TA-TRM) cells and investigated the heterogeneous characteristics of two TRM clusters (CD69+ and CD103+). Whereas CD69+ TA-TRM showed high expression of genes associated with immunological activation, CD103+ TA-TRM exhibited upregulation of genes related to proliferation capacity. To validate the unique molecular patterns, we analyzed an independent HCC dataset (GSE140228) and observed high concordance of significant core marker genes for TA-TRM clusters between the two datasets. Moreover, we assessed the association of gene expression in TA-TRM cells with overall and recurrence-free survival by conducting survival analysis in two independent large-scale cohorts. The cross-validation approach was applied to estimate risk scores for patients with primary HCC tumors in The Cancer Genome Atlas (TCGA), and the trained model was evaluated using the International Cancer Genome Consortium (ICGC) data. The result of calculating the risk scores clearly indicates that TA-TRM cells are associated with survival in HCC. Therefore, our study characterized two distinct subtypes of TA-TRM cells in HCC, delineated their unique molecular signatures, and established their relevance to survival outcomes. The findings can potentially enhance the understanding of the roles of TA-TRM cells in the context of HCC. Citation Format: Mi-So Park, Hyunbin Cho, Hyeree Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won. Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics [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 7035.
Abstract 1022: Integration of cerebrospinal fluid methylome and proteome can obviate the need for biopsy in central nervous system lymphoma
Authors: Alex P. Landry, Jeffrey A. Zuccato, Vikas Patil, Mathew Voisin, Justin Z. Wang, Yosef Ellenbogen, Chloe Gui, Andrew Ajisebutu, Farshad Nassiri, Gelareh Zadeh
Journal: Cancer Research (2024)

Abstract Background: The diagnosis of intra-axial brain tumors requires histopathological examination of tissue obtained by neurosurgery in current clinical practice, which comes with inherent risks. Some patients, particularly those with primary CNS lymphoma (PCNSL), only undergo surgery to obtain a diagnosis and do not derive any therapeutic benefit from surgical resection or debulking. Less-invasive techniques for diagnosis, such as liquid biopsy, therefore provides an opportunity to mitigate surgical risk in these patients. Methods: Patients with histopathology confirmed glioblastoma (GBM, IDH wild type), brain metastases (BM), and PCNSL with accompanying cerebrospinal fluid (CSF) samples were included in our study. Cell-free DNA methylation profiling and shotgun proteomics were obtained for all patients and used to train classifiers to distinguish each tumour entity from others. Specifically, binomial elastic net regression models were built by combining both data modalities using established early and late integration paradigms and performance was compared to classifiers built from individual data types alone. Each model was repeated 100 fold and performance assessed on an untouched testing subset. Results: Our cohort includes 20 patients with GBM, 17 with BM, and 14 with PCNSL, each with matching CSF cell-free DNA methylation and shotgun proteomic profiling. We show that these data can be integrated to fully discriminate PCNSL from its major diagnostic counterparts with a perfect median AUC of 1.00 (95% CI 1-1) and 100% specificity. Integrated "lymphoma vs other" models significantly outperform models trained on methylation or protein data alone, though the same dramatic improvement was not demonstrated in GBM or BM, suggesting synergistic biological information is specific to lymphoma. Conclusions: There is a critical need to diagnose patients with intra-axial tumours, particularly PCNSL, without relying on invasive and costly surgery. We present the most specific and accurate CNS lymphoma classifier to date by integrating the methylome and proteome of CSF. This has the potential for immediate clinical utility, eliminating the need for biopsy in an important subset of these patients. Citation Format: Alex P. Landry, Jeffrey A. Zuccato, Vikas Patil, Mathew Voisin, Justin Z. Wang, Yosef Ellenbogen, Chloe Gui, Andrew Ajisebutu, Farshad Nassiri, Gelareh Zadeh. Integration of cerebrospinal fluid methylome and proteome can obviate the need for biopsy in central nervous system lymphoma [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 1022.
Abstract 7024: Development of quality control methods for reliable NGS measurement of methylation in cfDNA
Authors: James C. Willey, Erin L. Crawford, Daniel J. Craig, Thomas M. Morrison, Hua-Jun He, James G. Herman
Journal: Cancer Research (2024)

Abstract Background and Purpose: Reliable measurement of circulating free genomic DNA (cfDNA) methylation patterns promises a means for cancer early detection as well as treatment response. Use of Next Generation Sequencing (NGS) methods to measure the cfDNA methylome across a large number of potentially methylated CpG sites may enable earlier detection by overcoming stochastic sampling associated with the small specimens obtainable by a blood draw. Wide-spread adoption of these methods for clinical diagnostic applications will be facilitated through improved quality controls that increase reliability. The goal of this study is to assess the performance of the SNAQ-SEQ™ method as a means to establish a limit of detection (LOD) for measurement of methylation at each targeted CpG site. For this purpose, we used test materials that were developed by the National Institute for Standards and Technology (NIST) to mimic methylated cfDNA. Methods: NIST test materials were formulated by physically shearing cell line gDNA then subjecting it to size separation to mimic a size distribution similar to that observed in cfDNA, then mixing sheared DNA in its “native” state of methylation with sheared DNA that was in vitro methylated. Non-sheared NIST test materials also were assessed in these studies. Synthetic spike-in internal standards (IS) were combined with NIST test materials and the combined samples were bisulfite converted, then subjected to PCR-amplicon library preparation. Libraries were sequenced on an Illumina MiSeq instrument and bioinformatic analysis was conducted using the Qiagen CLC Workbench. Results and Conclusions: In initial testing of an off-the-shelf IS for a region of the SOX2 gene, average methylation (preserved C) across 14 targeted CpG sites was 16.4% (0.5%-50%) in the “native” NIST non-sheared sample. This was consistent with the 11.6% methylation across all of SOX2 measured by the NIST. In contrast, in IS corresponding to the targeted SOX2 region the average preserved C was 0.32% (0.03%-0.5%). Use of synthetic internal standards enabled determination of LOD for each individual methylated site, controlling for all known sources of technical error, including inefficient bisulfite conversion, nucleotide substitution error, and alignment error. Studies are now underway that use the NIST test materials to measure methylation at five targets known to be altered in cfDNA from lung cancer subjects, SOX2, CDO1, TAC1, SOX17, and HOXA7. Citation Format: James C. Willey, Erin L. Crawford, Daniel J. Craig, Thomas M. Morrison, Hua-Jun He, James G. Herman. Development of quality control methods for reliable NGS measurement of methylation in cfDNA [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 7024.
Abstract 1044: Low-cost, high-sensitivity InSituPlex® mIF assays on the Parhelia Omni-Stainer™
Authors: Kevin Hwang, Lauren Duro, Alex Veith, Nelson Wedin, Nikolay Samusik, Je H. Lee
Journal: Cancer Research (2024)

Abstract Background: Multiplex immunofluorescence (mIF) is an important tool for extracting complex phenotypic information from normal or diseased tissues, and provides accurate and predictive insights on the tissue microenvironment faster. For patient samples in translational and clinical research, high sensitivity, specificity, and reproducibility are critical; however, throughput and cost considerations are also important in designing clinical studies. Enabling an easy-to-use high-performance assay such as InSituPlex® on robust and affordable auto-stainers like the Parhelia Omni-Stainer™ can allow researchers to gain a deeper understanding of the tissue micro-environment through high-quality multiplexed biomarker detection in a fraction of the time and cost. Methods: We performed Ultivue InSituPlex® assays with OmniVUE™ panels using the Parhelia Omni-Stainer™, a low-cost, high-throughput tissue auto-stainer with reduced requirements for reagents with a minimal dead volume. We compared the whole-slide staining performance across replicates using human tonsil and tumor tissue arrays across multiple independent runs over multiple days. The stained slides were scanned using the Zeiss AxioScan.Z1 high-throughput imaging system, and image batches were processed using Ultivue’s UltiStacker.AI and UltiAnalyzer.AI software. Results: Tighter temperature control of the slide in the Omni-Stainer supports optimal InSituPlex® signal amplification. Intra-run and inter-day analysis on serial sections of human tonsil and tumor tissue arrays demonstrated a high degree of consistency in InSituPlex® assay performance, specifically with marker-specific signal intensities and cell densities. The Omni-Stainer facilitates the use of low reagent volumes at each step of the assay due to its efficient reagent use, thus lowering the cost of reagents per slide. Conclusions: This study demonstrated a fast, simple and robust workflow to perform high-performance InSituPlex® mIF assays on the low-cost, high-throughput Parhelia Omni-Stainer™. Ultivue’s configurable OmniVUE™ mIF panels can be run on the Omni-Stainer with reduced associated reagent costs per slide. This workflow can support larger clinical and translational studies in a more cost-effective fashion, leading to in-depth analysis of tissue microenvironment through highly precise multiplexed biomarker detection. Citation Format: Kevin Hwang, Lauren Duro, Alex Veith, Nelson Wedin, Nikolay Samusik, Je H. Lee. Low-cost, high-sensitivity InSituPlex® mIF assays on the Parhelia Omni-Stainer™ [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 1044.
Abstract 6609: NRF2/ACSS2 axis regulates alcohol-induced metabolic reprogramming in esophageal squamous epithelial cells
Authors: Zhaohui Xiong, Boopathi Subramaniyan, Chorlada Paiboonrungruang, Yahui Li, Wentao He, Hong Yuan, Guofang Zhang, Xiaoxin Chen
Journal: Cancer Research (2024)

Abstract Esophageal diseases such as gastroesophageal reflux disease (GERD) and esophageal cancer have a strong association with alcohol drinking. However, the molecular mechanisms of alcohol-induced esophageal pathology remain unclear. In our previous study, we identified acyl-CoA synthetase short-chain family member 2 (ACSS2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) in the esophageal epithelial cells in vitro and in vivo. Ethanol exposure enhanced de novo lipogenesis in NRF2high cells and generated a more energetic and invasive phenotype. In this study, we aimed to investigate the role of the NRF2/ACSS2 axis in regulating alcohol-induced metabolic reprogramming in esophageal squamous epithelial cells. We first demonstrated that ethanol exposure activated NRF2 signaling and upregulated the expression of NRF2 and ACSS2 in human esophageal squamous epithelial cells. 13C-ethanol/13C-acetate metabolic flux assay showed a dramatic NRF2-dependent increase of labeling of the TCA cycle intermediates and de novo lipogenesis in NRF2high cells in comparison with NRF2null or NRF2low cells. Long-term ethanol exposure caused metabolic reprogramming, in particular induced de novo lipogenesis, in the mouse esophagus according to metabolomics profiling of 833 metabolites. PET/CT and autoradiography showed increased 11C-acetate uptake in the NRF2high esophagus of a conditional tissue-specific mouse (Sox2CreER;LSL-Nrf2E79Q) due to upregulation of transporters and metabolic enzymes. In summary, Our data demonstrated the functional role of the NRF2-ACSS2 axis in alcohol-induced metabolic reprogramming in esophageal squamous epithelial cells both in vitro and in vivo, suggesting NRF2/ACSS2 inhibition as a novel mechanism-based prevention for alcohol-associated esophageal pathology. Citation Format: Zhaohui Xiong, Boopathi Subramaniyan, Chorlada Paiboonrungruang, Yahui Li, Wentao He, Hong Yuan, Guofang Zhang, Xiaoxin Chen. NRF2/ACSS2 axis regulates alcohol-induced metabolic reprogramming in esophageal squamous epithelial 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 6609.