tbuckley/cabot-search huggingface dataset:
Abstract 3100: Interactive analysis of drug testing data for functional precision oncology with Breeze 2.0
Authors: Swapnil Potdar, Filipp Ianevski, Aleksandr Ianevski, Ziaurrehman Tanoli, Krister Wennerberg, Brinton Seashore-Ludlow, Olli Kallioniemi, Päivi Östling, Tero Aittokallio, Jani Saarela
Journal: Cancer Research (2024)

Abstract High throughput screening (HTS) is used to screen large numbers of small molecules in cell-based assays to predicting their potential therapeutic response and when applying approved drug libraries using HTS it becomes drug repurposing. The Drug Sensitivity and Resistance Testing (DSRT) platform established at FIMM has been extensively used in testing panels of approved and investigational drugs on cells, both conventional cell lines and primary cell models derived from cancer patient samples. The results help in deepen our understanding of drug efficacy in individual patients and across specific disease to guide future patient stratification. Breeze 2.0 is an open access, web-based platform for interactive analysis of drug screening data in real time. Breeze accepts raw data in a simple tabular format and generates detailed quality control metrics, plots, dose-response curve fits, drug response quantification in form of IC50/EC50/AUC and Drug Sensitivity Scores (DSS). Besides tabular results, Breeze generates interactive, informative, and intuitive visualizations, such as plate heatmaps, scatterplots, barplots, clustered heatmaps, circular plots, for further analysis. Based on manually-curated published datasets available through Breeze 2.0, users can instantly compare their drug response patterns with the existing DSRT profiles from patient samples, as well as cell lines. Importantly, Breeze 2.0 has integrated curated reference DSRT data tested on bone marrow samples from healthy control individuals, which plays a crucial role in understanding cancer-selective drug response by de-prioritizing generally toxic compounds. The end-users can select multiple healthy controls or relevant patient/cell line samples and choose the drugs of interest to visualize the overlaid dose responses, as well as response quantification metrics. Breeze 2.0 is built in R, PHP, MySQL and is freely accessible at https://breeze.fimm.fi/v2 Citation Format: Swapnil Potdar, Filipp Ianevski, Aleksandr Ianevski, Ziaurrehman Tanoli, Krister Wennerberg, Brinton Seashore-Ludlow, Olli Kallioniemi, Päivi Östling, Tero Aittokallio, Jani Saarela. Interactive analysis of drug testing data for functional precision oncology with Breeze 2.0 [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 3100.
Abstract 6250: The RNA editing landscape of lung cancer in never smokers
Authors: Jian Sang, Wei Zhao, Tongwu Zhang, Maria Teresa Landi
Journal: Cancer Research (2024)

Abstract Adenosine-to-Inosine (A-to-I) editing represents a crucial RNA modification mechanism, holding the potential to drive carcinogenesis. This sophisticated post-transcriptional process is catalyzed by a series of ADAR (adenosine deaminase acting on RNA) family members, which can profoundly reshape the cellular epitranscriptomic landscape. While previous explorations have illuminated the important role of A-to-I editing in lung cancer tumorigenesis and prognosis, most studies have focused on lung cancer from smokers. To investigate the contribution on RNA-editing in lung cancers in never smokers (LCINS) , we embarked on a rigorous dissection of A-to-I RNA editing events in 603 LCINS. Harnessing transcriptome and whole-genome sequencing technologies, we identified 15,880 A-to-I sites, of which 75% were positively linked to the enzymatic activity of ADAR1. 92.80% of detected editing sites were located at Alu repetitive regions, with the remainder in non_Alu repeat (4.1%) and non-repeat regions (3.1%). The global RNA editing levels, measured as Alu Editing Index (AEI), were found to be significantly associated with ADAR1 expression, Tumor Mutational Burden, and Neoantigens Burden. A subtle correlation between global RNA editing levels and tumor stage was also noted. Delving into cancer-associated editing events, we identified 5,539 differentially edited sites in tumors compared with normal tissues, which were located at 823 genes, including several key tumor suppressors and oncogenes, like MDM2, BRAF, TP53, BRCA2, ATM, and VHL. Subsequent pathway analysis identified TGF-beta, Notch Signaling, and DNA Damage Response as the key pathways for cancer progression. Using the characterized A-to-I editing profiles, we built a prognostic risk stratification model, with high risk scores significantly linked to poor survival outcomes, even after adjusting for other clinical factors. Our study provides a comprehensive A-to-I editing landscape of lung cancer in never smokers, highlighting the potential roles of RNA modifications in the pathogenesis of this lethal disease. Citation Format: Jian Sang, Wei Zhao, Tongwu Zhang, Maria Teresa Landi. The RNA editing landscape of lung cancer in never smokers [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 6250.
Abstract 2877: Enhancing diagnostic precision in peritoneal cancer metastasis: Photodynamic diagnosis-guided laparoscopy in a rabbit model
Authors: Hyoung-Il Kim, Adriana Rivera-Piza, Sunghwan Lee
Journal: Cancer Research (2024)

Abstract Introduction: Precise diagnostic workup is crucial for developing effective treatment strategies in cancer patients. Peritoneal carcinomatosis, often missed in preoperative CT scans and conventional laparoscopy, poses diagnostic challenges. This study aimed to assess the diagnostic accuracy of staging laparoscopy using photodynamic diagnosis (PDD) with the photosensitizer phonozen activated at 405 nm in a rabbit model of peritoneal carcinomatosis. Methods: Female New Zealand white rabbits (16-20 weeks old) were utilized to establish the model through peritoneal inoculation of VX2 sarcoma cells, resulting in distinct solid-tumor nodules for laparoscopic evaluation. A customized dual-emission laparoscope, capable of both white-light and 405 nm blue-light, was employed for PDD. To minimize blue-light background interference, a 550 nm long-pass filter was placed between the laparoscope and the video camera, optimizing the process. The PDD-enhanced diagnostic laparoscopy comprised a tripartite approach: 1) initial peritoneal cavity exploration under white-light and labeling of suspect nodules, followed by 2) utilization of blue light with the long-pass filter to identify red-light emissions from distinctly labeled tumor cells, and 3) open laparotomy served to palpate the peritoneal surface and identify additional or missed tumor nodules. Results: Analysis of data from 12 rabbits with 267 tumor nodules revealed that sensitivity and specificity of diagnostic laparoscopy for detecting tumor nodules increased from 84.9% and 18.8% with white light alone to 90.8% and 25.0% when aided by PDD, respectively. These findings underscore the substantial improvement in diagnostic accuracy achievable by combining the rabbit model of peritoneal carcinomatosis with PDD in laparoscopic procedures. Conclusion: The heightened sensitivity and specificity observed in this study hold significant promise for positively impacting clinical practice, providing a more accurate and effective approach to the diagnosis and management of peritoneal carcinomatosis. Citation Format: Hyoung-Il Kim, Adriana Rivera-Piza, Sunghwan Lee. Enhancing diagnostic precision in peritoneal cancer metastasis: Photodynamic diagnosis-guided laparoscopy in a rabbit model [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 2877.
Abstract 287: Analysis for the role of antigen-presenting cancer-associated fibroblasts in tumor microenvironment of colorectal cancer
Authors: Yasuhiro Fukui, Hiroaki Kasashima, Zizhou Wang, Ken Yonemitsu, Kishu Kitayama, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Hiroaki Tanaka, Shigeru Lee, Masakazu Yashiro, Kiyoshi Maeda
Journal: Cancer Research (2024)

Abstract A new subset of cancer associated fibroblasts (CAFs) called antigen presenting CAF (apCAF) was recently identified, and modulation of the tumor immunity might be associated with tumor progression. We examined the markers of apCAF, such as IRF5, HLA-DRA and HLA-DQA1 by bioinformatics analyses of human colorectal cancer (CRC) datasets. The expression of apCAF markers were upregulated in CAFs isolated from human CRCs and liver metastases compared with their normal counterparts. Kaplan-Meir analysis of 172 human CRC samples clarified that the patients with apCAF marker positive expression in the tumor stroma had worse prognosis than that with negative expression. In addition, the origin of apCAFs was reported to be mesothelial cells, therefore, we established cancer-associated mesothelial cells (CAmes) from ascites of human CRC patients with peritoneal dissemination. Consistently, the expression of antigen-presentation markers was highly upregulated in CAmes, however, allo-mixed lymphocyte reaction analysis demonstrated that their stimulating activity of CD4+ T lymphocytes was diminished. In an in vivo study, we applied a rectal orthotopic transplant model with mouse tumor organoid (MTO) to investigate the effect of apCAF on tumor progressions. Using fluorescence-activated cell sorting (FACS), we examined the ratios of apCAF, myCAF, and iCAF in orthotopic rectal tumors. The percentage of apCAF was highest in the 6-week-tumors and the percentage of myCAF was highest in the 9-week-tumors. Interestingly, the percentage of apCAF was higher in liver metastases than in primary tumor, consistent with bioinformatics analysis. The apCAF increased during the stage of tumor growth, and the percentage of myCAF increase in the later stage of tumor progression with fibrosis. In summary, apCAF might be associated with tumor progression in CRC. Citation Format: Yasuhiro Fukui, Hiroaki Kasashima, Zizhou Wang, Ken Yonemitsu, Kishu Kitayama, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Hiroaki Tanaka, Shigeru Lee, Masakazu Yashiro, Kiyoshi Maeda. Analysis for the role of antigen-presenting cancer-associated fibroblasts in tumor microenvironment of colorectal 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 287.
Abstract 5766: Fungal genomes in drug discovery: Application of CETSA to study the mechanism of action of brefeldin A
Authors: Tomas Friman, Benjamin M. Fontaine, Alexey Chernobrovkin, Daniel Martinez Molina, Victoria Brehmer, Stina Lundgren, Paola M. Castaldi, Gregory L. Verdine
Journal: Cancer Research (2024)

Abstract Fungal genomes encode a vast collection of chemical diversity that has evolved over millions of years to engage specific targets and modulate diverse biological processes. These Genetically Encoded small Molecules (GEMs) constitute a largely untapped source of potential therapeutics. Although fungal GEMs such as cyclosporine, lovastatin, and penicillin have revolutionized modern medicine, these GEMs were discovered serendipitously through bioactivity-guided fractionation of fungal extracts. LifeMine is redefining GEM discovery through the deployment of proprietary genomic search algorithms that enable GEM target prediction a priori. Our strategy facilitates focused search-and-retrieval campaigns to rationally discover molecules selected by Nature to modulate the desired target protein. These GEM drug leads often exhibit unique structural and mechanistic features, necessitating comprehensive deconvolution of the human target profile and mechanism of action during the development process from GEM to clinical candidate. As a proof-of-concept study, we leveraged CETSA Explore to study the biological mechanism of the fungal polyketide lactone Brefeldin A (BFA) in human THP-1 cells. This GEM, originally isolated from the filamentous fungus Penicillium brefeldianis, inhibits protein trafficking between the endoplasmic reticulum and the Golgi complex, eliciting antiviral, antifungal, and anticancer activity. Our CETSA profiling study confirmed the Golgi-associated guanine nucleotide exchange factor GBF1 as the primary target of BFA, validating the established mechanism of this GEM as an inhibitor of GBF1-mediated activation of the small GTPase ARF1. These results demonstrate the utility of integrating the LifeMine GEM discovery engine with downstream proteomic profiling technologies to facilitate the mechanistic characterization of fungal GEMs en route to novel therapeutics. Citation Format: Tomas Friman, Benjamin M. Fontaine, Alexey Chernobrovkin, Daniel Martinez Molina, Victoria Brehmer, Stina Lundgren, Paola M. Castaldi, Gregory L. Verdine. Fungal genomes in drug discovery: Application of CETSA to study the mechanism of action of brefeldin A [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 5766.
Abstract 3879: Development of potent, highly selective and efficacious SMARCA2 degraders
Authors: Lin Yang, Wenbin Tu, Liyue Huang, Lingying Leng, Wei Jiang, Meilin Wang, Bo Wen, Duxin Sun, Jeanne Stuckey, Shaomeng Wang
Journal: Cancer Research (2024)

Abstract In human lung, melanoma and other types of human cancers, the mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated, which leads to inactivation of its functions. SMARCA2, a close homologous protein of SMARCA4, is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the discovery and biological evaluation of potent, highly selective and efficacious SMARCA2 PROTAC degraders exemplified by UM-SMD-3236. UM-SMD-3236 has a DC50 value of &amp;lt;1 nM in inducing degradation of SMARCA2 in cells and demonstrates &amp;gt;400-fold selectivity over SMARCA4 protein. Of significance, while UM-SMD-3236 achieves a Dmax of &amp;gt;95% against SMARCA2, it shows a Dmax of 50% against SMARCA4 in cells. In vivo, a single intravenous dose of UM-SMD-3236 attains 85-93% of SMARCA2 depletion in tumor tissues for 7 days, while showing no reduction of the SMARCA4 protein. Weekly intravenous administration of UM-SMD-3236 is highly effective in inhibition of tumor growth in SMARCA4 deficient xenograft models of human cancer. Importantly, UM-SMD-3236 shows no signs of toxicity in mice at highly efficacious doses. UM-SMD-3236 represents a highly promising SMARCA2 degrader for extensive evaluation as a potential new therapy for the treatment of SMARCA4-deficient human cancers. References 1. Oike, T.; Ogiwara, H.; Tominaga, Y.; Ito, K.; Ando, O.; Tsuta, K.; Mizukami, T.; Shimada, Y.; Isomura, H.; Komachi, M.; Furuta, K.; Watanabe, S.-I.; Nakano, T.; Yokota, J.; Kohno, T. A Synthetic Lethality-Based Strategy to Treat Cancers Harboring a Genetic Deficiency in the Chromatin Remodeling Factor BRG1. Cancer Res. 2013, 73, 5508-5518. 2. Yang, L.; Tu, W.; Huang, L.; Miao, B.; Kaneshige, A.; Jiang, W.; Leng, L.; Wang, M.; Wen, B.; Sun, D.; Wang, S. Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity. J. Med. Chem. 2023, 66, 10761-10781. Citation Format: Lin Yang, Wenbin Tu, Liyue Huang, Lingying Leng, Wei Jiang, Meilin Wang, Bo Wen, Duxin Sun, Jeanne Stuckey, Shaomeng Wang. Development of potent, highly selective and efficacious SMARCA2 degraders [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 3879.
Abstract 5748: Inhibition of tumor growth using exosomes loaded with KRAS siRNA and surface-modified with tumor-targeted proapoptotic peptide
Authors: Li Kang, Soyeon Jeon, Sri Murugan Vadevoo, Sang-Hyun Kim, Byungheon Lee
Journal: Cancer Research (2024)

Abstract Exosomes are extracellular vesicles naturally secreted by cells and serve as carriers of RNAs and proteins for cell-to-cell communications. KRAS is frequently mutated and plays a vital role in many tumors. Receptor expressed in lymphoid tissue (RELT), also known as tumor necrosis factor receptor superfamily 19-like, is upregulated in certain tumors such as lung and pancreatic tumors and is a potential tumor target. To selectively deliver cytotoxic agents to tumor, we loaded mesenchymal stem cell (MSC)-derived exosomes with a siRNA against KRAS and surface-modified them with the RELTpep-KLA peptide comprising a RELT-binding peptide (CRQTKN, named RELTpep) and proapoptotic peptide (KLAKLAKKLAKLAK, named KLA). Exosomes were isolated from cell culture medium using ultracentrifugation and transfected with the KRAS siRNA using a lipid-based reagent and then surfaced-modified with the RELTpep-KLA using a phospholipid-based membrane anchor. Compared with control peptide-KLA, RELTpep-KLA-targeted MSC-exosomes were more efficiently internalized into A549 lung tumor and Panc-1 pancreatic tumor cells expressing RELT on their surface and exhibited cytotoxicity to these tumor cells. RELTpep-KLA-targeted and KRAS siRNA-loaded MSC-exosomes reduced the phosphorylation of Erk and exhibited an enhanced cytotoxicity in A549 and Panc-1 tumor cells. Moreover, when intravenously injected, they inhibited tumor growth in Balb/c nude mice bearing subcutaneous Panc-1 human tumor xenografts more efficiently than those loaded with control siRNA or modified with control peptide-KLA. These results demonstrate that RELTpep-KLA-targeted MSC-exosomes carrying KRAS siRNA hold a potential for exosome-based targeted therapy against cancer. Citation Format: Li Kang, Soyeon Jeon, Sri Murugan Vadevoo, Sang-Hyun Kim, Byungheon Lee. Inhibition of tumor growth using exosomes loaded with KRAS siRNA and surface-modified with tumor-targeted proapoptotic peptide [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 5748.
Abstract 2167: Microbial bile acid, 3-oxo-LCA, inhibits colorectal cancer progression
Authors: Fei Sun, Xingchen Dong, Ming Qi, Ting Fu
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) affects a significant number of individuals each year, ranking as a leading cause of cancer-related deaths in the U.S. Bile acids (BAs), natural compounds crucial for digesting dietary fats, not only influence the gut microbiota but are also involved in gut health through their interaction with the Farnesoid X Receptor (FXR). Recent findings have highlighted certain microbiota-generated BAs like 3-oxo-lithocholic acid (LCA) and IsoLCA, modulate host immunity, hinder the expansion of intestinal pathogens, and potentially anti-aging. Despite the advancements in identifying the gut microbes behind these BAs, their precise impact on intestinal cells (IECs) and their role in disease progression are largely unexplored. Our pilot investigation unveiled 3oxoLCA as an FXR agonist, restoring FXR signaling in both cancer cells and APCmin/+ mice (a classic CRC mice model). As a result, 3-oxo-LCA inhibits the growth of both human and mouse CRC cells, such as MC38, CT26 and HCT116. Additionally, 3-oxo-LCA also restrained the intestinal stem cells (ISCs)’ proliferation in organoids from both wild-type and APCmin/+ mice, and patient-derived CRC organoids (PDCOs). Remarkably, treatment with 3-oxo-LCA decreased BAs levels, improved gut barrier function, reduced tumor load, and inhibited tumor progression in APCmin/+ mice. Furthermore, 3-oxo-LCA significantly suppressed tumor growth in cancer cell-derived xenograft model mice. Crucially, the 3-oxo-LCA-FXR interaction transcriptionally regulated key apoptotic genes, encouraging cancer cell death. These discoveries highlight the therapeutic promise of incorporating 3-oxo-LCA into strategies for treating CRC. Citation Format: Fei Sun, Xingchen Dong, Ming Qi, Ting Fu. Microbial bile acid, 3-oxo-LCA, inhibits colorectal cancer progression [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 2167.
Abstract 3098: CETSA for navigating your chemistry and exploring the biology of protein degraders 
Authors: Victoria Brehmer, Stina Lundgren, Tomas Friman, Daniele Amadio, Alexey Chernobrovkin, Daniel Martinez Molina
Journal: Cancer Research (2024)

Abstract Protein degradation is a non-classical modality with the potential to tackle therapeutically interesting proteins, previously deemed undruggable. In this area, CETSA is a powerful technology for identifying new binders, assessing target engagement, and investigating the mechanism of action of the degraders in the intact cell environment - without the need to modify your compound, the proteins or the cellular environment. CETSA can provide insights into the binding of the degrader to both the E3 ligase and the protein of interest (POI), as well as follow the downstream cellular and molecular effects. Here we will exemplify how CETSA can be applied in various stages of drug discovery to provide biologically relevant data to guide the design and optimization of new degraders. For example, CETSA can provide valuable information of the cell permeability and the in-cell performance of the degrader, which is important for understanding how the degrader enters cells and reaches its target proteins. By combining data from CETSA with data from degradation readout, in our case quantitative proteomics, it is possible to correlate cellular target engagement potencies with degradation efficiency and importantly, also identify any drug:protein binding that does not result in degradation By using the proteome-wide CETSA Explore format, the selectivity of the degrader and the downstream protein consequences of the elimination of the target protein could be studied. Citation Format: Victoria Brehmer, Stina Lundgren, Tomas Friman, Daniele Amadio, Alexey Chernobrovkin, Daniel Martinez Molina. CETSA for navigating your chemistry and exploring the biology of protein degraders [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 3098.