tbuckley/cabot-search huggingface dataset:
Abstract LB299: Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer
Authors: Austin Draycott, Matthew C. Wang, Diana Martínez Saucedo, Luisa Escobar-Hoyos, Wendy Gilbert
Journal: Cancer Research (2024)

Abstract Dihydrouridine is a universally conserved tRNA modification installed by enzymes that are important for human health. High expression of dihydrouridine synthase 2 (DUS2) predicts poor patient outcomes in lung adenocarcinoma (LUAD) for reasons that are not yet clear. Here, we show in human cells and mouse xenografts that DUS2 suppresses ferroptosis, a metal-dependent non-apoptotic form of cell death that is emerging as a therapeutic target in lung cancer. Elevated DUS2 correlates with resistance to ferroptosis inducers and loss of DUS2 causes increased sensitivity with concomitant accumulation of toxic lipid peroxides. Mechanistically, DUS2 is required to maintain tRNA CysGCA levels, supporting translation of cysteine-rich proteins including metallothioneins, key regulators of metal and redox homeostasis Notably, DUS2 KO cells cannot sustain normal levels of metallothioneins, a class of very cysteine rich proteins that serve as key regulators of both metal and redox homeostasis. Accordingly, DUS2 knockout cells are more susceptible to zinc intoxication and have lower levels of reduced glutathione, which partially explains their sensitivity to ferroptosis. Our findings demonstrate that DUS2 is required to support tRNACys levels and fend off ferroptosis in lung cancer cells. This highlights that individual tRNA substrates can play an outsized role in the biological functions of tRNA modifying enzymes, and demonstrates the therapeutic potential of targeting DUS2 in cancer. Citation Format: Austin Draycott, Matthew C. Wang, Diana Martínez Saucedo, Luisa Escobar-Hoyos, Wendy Gilbert. Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB299.
Abstract LB360: Establishment of predictive biomarkers for carcinogenesis in ulcerative colitis using RNA editing analyses
Authors: Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Kaori Nitta, Fuminori Teraishi, Yuzo Umeda, Hiroshi Tazawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2024)

Abstract Background: Ulcerative colitis (UC) is a chronic inflammatory disease continuous from the rectum. We previously reported that chronic inflammation may induce the RNA-editing enzyme ADAR1 and promote carcinogenesis (Journal of Crohn's and Colitis, 2023). However, the relationship between RNA editing and carcinogenesis in UC remains unresolved because we could not identify specific RNA editing sites. Therefore, in this study, we performed a new comprehensive RNA analysis using RNA sequencing to clarify the role of RNA editing in the carcinogenesis process in UC and to construct a prediction model of carcinogenic risk. Methods: We performed immunostaining of ADAR1, an RNA-editing enzyme, in 139 cases of ulcerative colitis. In addition, normal colorectal tissue, UC inflammatory phase, normal rectal mucosa of UC carcinoma cases, and UC carcinoma sites were submitted to RNA-Seq testing in 6 cases each (24 cases total). Bioinformatics analysis was performed to compare RNA editing sites in each group. Results: RNA-seq analysis showed a significant increase in global RNA editing sites in the inflammatory phase compared to normal colon tissue (p = 0.02). This phenomenon was due to increased ADAR1 expression associated with type 1 interferon. We hypothesized that global RNA editing was decreased in normal colonic mucosa during the remission phase but that some sites of prolonged RNA editing might promote carcinogenesis. We attempted to identify carcinogenesis-specific RNA editing sites. We identified 72 cancer-specific RNA editing sites, mainly in long noncoding RNAs such as NEAT1 and in the 3'UTR region of mRNAs such as CTSS. Assuming that the accumulation of these RNA editing leads to carcinogenesis, pathway analysis revealed that pathways promoting cancer invasion and stemness are activated. When ROC curves were generated using these editing sites as markers, the AUC was 0.935, suggesting that analysis of RNA editing in the colonic mucosa of UC patients may be able to predict the risk of carcinogenesis. Conclusions: We identified potential editing sites for carcinogenesis in UC, allowing the identification of carcinogenic mechanisms in UC and the establishment of predictive markers for carcinogenic risk. Citation Format: Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Kaori Nitta, Fuminori Teraishi, Yuzo Umeda, Hiroshi Tazawa, Toshiyoshi Fujiwara. Establishment of predictive biomarkers for carcinogenesis in ulcerative colitis using RNA editing analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB360.
Abstract LB029: Degraders of TEAD transcription factors based on interface 3 binders
Authors: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Michele Ceribelli, Craig J. Thomas, Peter Brandt
Journal: Cancer Research (2024)

Abstract TEAD transcription factors have emerged as clinically validated targets for Hippo-altered cancers, e.g. mesothelioma driven by NF2 inactivation/deficiency. We have developed a series of novel small molecule targeted protein degraders of TEAD based on pan-TEAD interface 3 ligands. In cells, the compounds induce degradation of TEAD by formation of a ternary complex with Cereblon, leading to ubiquitination of TEAD and subsequent proteasomal degradation. In a cell-based luciferase reporter assay the degraders show low nanomolar activity. The downstream effects of TEAD degradation were further investigated by qPCR and WB analyses of bona fide YAP-TEAD target genes such as CTGF, Cyr61 and AMOTL2. The effectiveness of the TEAD degraders were compared to other classes of TEAD modulators such as palmitoylation inhibitors and YAP-TEAD protein-protein inhibitors by means of cellular viability assays using various mesothelioma cell lines. Finally, we performed an unbiased, quantitative high-throughput drug combination screening by combining a TEAD degrader with a library of approximately 2,800 oncology-focused drugs. This research was supported in part by the Intramural/Extramural research program of the NCATS, NIH. Citation Format: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Michele Ceribelli, Craig J. Thomas, Peter Brandt. Degraders of TEAD transcription factors based on interface 3 binders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB029.
Abstract LB390: Enhancing prostate cancer diagnosis: A deep learning approach for DNA ploidy prediction from whole slide images
Authors: Josselyn Sofia Vergara Cobos, Francisco Carrillo-Perez, Marija Pizurica, Noemi Andor, Olivier Gevaert
Journal: Cancer Research (2024)

Abstract Prostate cancer is distinguished by unique histological alterations in glandular architecture, observable in Whole Slide Images (WSIs). The disease is further characterized by pronounced genomic instability, exemplified by biomarkers such as DNA ploidy. While the Gleason Score effectively assesses the histological changes, the manual evaluation of DNA ploidy is subjective and time-consuming. Addressing the need for an objective diagnostic tool, our study developed a deep learning model aimed at accurately predicting DNA ploidy using publicly available WSI from the Cancer Genome Atlas (TCGA). Utilizing a ResNet-18 convolutional neural network, we trained the model on WSIs from 200 TCGA patients to extract features and predict total mRNA expression. The model was further refined using data from 19 TCGA patients, focusing on ploidy number prediction. Comparative analysis against a random reference model revealed significant improvements of ploidy prediction in Mean Absolute Error (MAE) by 43.52%, Mean Absolute Percentage Error (MAPE) by 43.59%, and Mean Squared Error (MSE) by 67.86%. These enhancements were statistically validated (p-values: MAE - 7.07E-06, MAPE - 7.69E-06, MSE - 3.14E-05) and substantiated by large Cohen's d values (MAE - 2.88, MAPE - 2.86, MSE - 2.42), confirming the model's advanced predictive accuracy and practical utility. This approach, validated further on a separate TCGA hold-out test set, signifies a major leap in prostate cancer diagnostics. By integrating mRNA prediction checkpoints, our model not only refines ploidy assessment but also sets the stage for correlating these predictions with patient clinical outcomes. These developments promise to enhance existing diagnostic methods, offering a more objective and efficient tool for DNA ploidy assessment in prostate cancer prognosis and treatment planning. Citation Format: Josselyn Sofia Vergara Cobos, Francisco Carrillo-Perez, Marija Pizurica, Noemi Andor, Olivier Gevaert. Enhancing prostate cancer diagnosis: A deep learning approach for DNA ploidy prediction from whole slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB390.
Abstract LB035: Targeting cytoplasmic condensates in the stress response of cancer cells
Authors: Ku-Lung Hsu, Anthony M. Ciancone, Kyung W. Seo, Miaomiao Chen, Adam L. Borne, Adam H. Libby, Dina L. Bai, Ralph E. Kleiner
Journal: Cancer Research (2024)

Abstract RNA-binding proteins (RBPs) constitute a large and diverse class of proteins (&amp;gt;1400 human proteins) that control RNA metabolism and function. RBPs bind sequence and/or structural motifs in single- or double-stranded RNA using RNA-binding domains (RBDs) to assemble ribonucleoprotein (RNP) complexes. RNPs regulate gene expression and non-coding RNA (ncRNA) function by organizing RNA-protein networks affecting the biogenesis, transport, translation, and degradation of bound RNAs. RNPs known as processing-bodies (P-bodies) and stress granules (SGs) form cytoplasmic membraneless condensates to compartmentalize cellular processes that facilitate survival of cancer cells in the tumor microenvironment and mediate resistance to anticancer treatments. The composition and dynamic regulation of RNPs and how these molecular features of RNA granules are regulated to promote cancer cell adaptation and progression remains poorly understood. Perturbing RBPs is a viable path towards RNP pharmacology but small molecules for this ‘undruggable’ class of proteins are currently lacking. Here, we described utilization of sulfonyl-triazoles (SuTEx chemistry) for disruption of cytoplasmic condensate through covalent binding of tyrosines to enable pharmacology of RNP function in cancer cells. A chemoproteomics platform founded on SuTEx chemistry was deployed for chemical biology and therapeutic investigation of P-bodies and SGs. Key findings to be presented include: (i) establishing a SuTEx-enabled screening platform for accessing ligandable tyrosine (Y)/lysine (K) residues in stressed cancer cells, (ii) identification of a set of SuTEx ligands capable of preventing or inducing SG and P-body formation in stressed cells, (iii) Discovery of a SuTEx ligand for the hyper-reactive EDC3 Y475 site for P-body modulation and (iv) validation of G3BP1 Y40 as a ligandable site that can disrupt arsenite-induced SG formation in cells. We will also describe unpublished work on efforts to advance discovery of new condensate modulators using global proteomic methods. Collectively, we describe a tractable means to reveal and ultimately target cancer vulnerabilities by disrupting tumor-specific stress coping mechanisms found in dynamic cellular compartments for therapeutic translation. Citation Format: Ku-Lung Hsu, Anthony M. Ciancone, Kyung W. Seo, Miaomiao Chen, Adam L. Borne, Adam H. Libby, Dina L. Bai, Ralph E. Kleiner. Targeting cytoplasmic condensates in the stress response of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB035.
Abstract LB246: Deep learning framework for patient recurrence and genetic marker prediction in diffuse glioma
Authors: Ko-Hong Lin, Kai Zhang, Dung-Fang Lee, Xiaoqian Jiang
Journal: Cancer Research (2024)

Abstract Investigation of important molecular features of glioma patients may reveal driving mechanisms of patient recurrence and treatment failures in glioma. Applying various deep learning techniques enables the integration and systematic comparison of multi-omics features, allowing robust marker prediction and patient stratification. We extracted mutation and copy number variation data from the Glioma Longitudinal Analysis (GLASS) Consortium, consisting of 628 primary or recurrent samples. To achieve the patient recurrence classification task, we designed a transformer-based model that learns the genomic profiles and predicts patient recurrence status. Our model outperforms traditional machine learning models, including support vector machine (SVM), logistic regression, and decision trees, for up to 34% and 40% improvement of AUROC and AUPRC, respectively. Including mutational features alone can achieve the best prediction performance, while copy number variations are less informative in predicting patient recurrence status. Our approach is an early attempt that employs deep learning for dissecting the contribution of diverse genomic profiles on glioma recurrence and might provide insights into developing novel therapies for treating glioma. Citation Format: Ko-Hong Lin, Kai Zhang, Dung-Fang Lee, Xiaoqian Jiang. Deep learning framework for patient recurrence and genetic marker prediction in diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB246.
Abstract LB298: Simultaneous reprogramming of glioblastoma tumor cells and tumor-associated macrophages by tumor-suppressive microRNA
Authors: Grace Nguyen, MinHye Noh, Yulin Dai, Zhongming Zhao, Ji Young Yoo, Tae Jin Lee
Journal: Cancer Research (2024)

Abstract Therapeutic outcomes in glioblastoma (GBM) patients remain dismal due to its resistance to conventional therapies. Tumor-supportive tumor microenvironment (TME) that is educated by tumor cells through immune editing is not properly primed for the treatment. Targeted reprogramming of both tumor cells and tumor-associated macrophages (TAMs) is expected to prime the tumor cells and the immunosuppressive TME. Tumor suppressive microRNAs (miRNAs) have been proposed as the most suitable therapeutic target to perform the tumor reprogramming role. We recently identified miR-138 as a putative tumor suppressive miRNA that can reprogram GBM tumor. However, achieving the simultaneous targeted reprogramming of two distinct cell types is a complex challenge, demanding a selective delivery system to minimize adverse side effects. Previously, we demonstrated that extracellular vesicles (EVs) can serve as carriers for the selective delivery of small noncoding therapeutic RNAs into cancer cells through the EV surface labeling with cancer-targeting ligands. Here, we report that the trypsin digestion of EV surface can enhance their surface labeling efficiency with cancer targeting ligands, such as folate, with favorable bio-distribution and pharmacokinetic profiles in GBM mice model. The folate-labeled trypsinized EVs demonstrated a potential to selectively target folate receptor (FR) positive GBM cells and TAMs both in vitro and in vivo. The selective targeting of folate-labeled trypsinized EVs led to the targeted delivery of miR-138 into both GBM tumor cells and TAMs, achieving anti-tumor efficacy. Mechanism of action studies revealed that the ectopically delivered miR-138 inhibits its previously identified known target genes to reprogram tumor cell proliferation and macrophage polarization. To our knowledge, this is the first preclinical study attempting to simultaneously modulate tumor cells and innate immunity by delivering tumor suppressive miR-138 using the trypsinized EV-based RNA delivery system for the GBM treatment. Our study results can be rapidly translated into human clinical trials in combination with current immunotherapies. Citation Format: Grace Nguyen, MinHye Noh, Yulin Dai, Zhongming Zhao, Ji Young Yoo, Tae Jin Lee. Simultaneous reprogramming of glioblastoma tumor cells and tumor-associated macrophages by tumor-suppressive microRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB298.
Abstract LB220: Farnesyltransferase inhibitors show synergistic anticancer effects in combination with novel KRAS G12C inhibitors
Authors: Jozsef Timar, Marcell Baranyi, Eszter Molnar, Ivan Randelovic, Mihaly Cserepes, Jozsef Tovari, Balazs Hegedus
Journal: Cancer Research (2024)

Abstract Background. Farnesyltransferase inhibitors (FTI) failed as monotherapies for various cancer types until the discovery of their potency in HRAS mutant human head and neck and bladder cancers. On the other hand, RAS mutant cancers have been a great challenge for cancer research until the discoveries and approvals of several KRAS-G12C allele specific inhibitors. However, G12C inhibitors were effective mainly in lung cancer and de novo and acquired resistance prompted the development of various combinational modalities including immunotherapy as well as SOS- and SHP2-inhibitors. Based on in-silico analysis of drug sensitivities of KRAS mutant cancer cell lines treated with various drugs including FTIs, we have explored the possibility of the combination of FTIs with KRAS inhibitors.Methods. Clinically approved farnesyl-transferase inhibitors (tipifarnib and lonafarnib) were combined with, novel KRAS G12C inhibitors (sotorasib and adagrasib) using human lung-, pancreatic and colorectal- adenocarcinoma cells in vitro and in vivo. Antitumoral effects were evaluated for cell proliferation, apoptosis and migratory activity. Mechanisms of action were investigated by immunoblot analyzes of various farnesylated proteins, RAS activation and signaling, videomicroscopy and also by histopathology of xenograft tumors. Results. Synergistic anticancer effects were observed upon the combination of FTIs with G12C inhibitors in KRAS G12C mutant human cancer cell lines in vitro. We found that the combination interfered with the compensatory re-activation of HRAS, farnesylation of RHEB in the PI3K/mTOR pathway and lamin. Furthermore, we observed enhanced efficacy of sotorasib upon combination with tipifarnib in the xenograft models of lung adenocarcinoma affecting mitotic- and apoptotic rates and inducing necrosis.Discussion. Our findings suggest the potential clinical applicability of the combination of KRAS-G12C inhibitors and farnesyl-transferase inhibitors. Furthermore, our preliminary data suggest that the synergistic effect of FTIs on KRAS-G12C inhibitors can be projected to G12D inhibitors as well. Citation Format: Jozsef Timar, Marcell Baranyi, Eszter Molnar, Ivan Randelovic, Mihaly Cserepes, Jozsef Tovari, Balazs Hegedus. Farnesyltransferase inhibitors show synergistic anticancer effects in combination with novel KRAS G12C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB220.
Abstract LB143: Environmental assessment of alcohol-related policies and practices at US cancer organizations
Authors: Meghan Si, Stephanie Martch, Sanjay Shete, Ernest Hawk
Journal: Cancer Research (2024)

Abstract In 1998, the International Agency for Research on Cancer (IARC) declared that the consumption of alcoholic beverages was a class I carcinogen to humans; the designation was reaffirmed in 2007 and 2010. Despite this, approximately 4% of new cancer cases worldwide in 2020 were attributable to alcohol intake. Growing evidence indicates that alcohol use increases the risk of cancers of the upper aerodigestive tract (oral cavity, pharynx, esophagus, and larynx) and lower digestive tract (colon, rectum, and liver). Over half of the 6.3 million cases of these cancers are considered preventable, underscoring notable gaps regarding alcohol consumption and cancer prevention. Despite (1) the longstanding designation of alcohol as an established carcinogen, (2) an increasing and consistent body of data noting alcohol as a leading contributor to the global cancer burden, and (3) the publication of policy statements by authoritative sources, it is unclear whether cancer-focused institutions are aware of these facts or are acting on these data (i.e., implementing evidence-based policies and practices to limit alcohol-related cancer risks for their employees, guests, or the public). Driven by these data and shortfalls, we developed a 22-item survey to inquire about cancer organizations' interpretation of current literature, existing policies, decision-making processes, inclination to act, and perceived responsibility to lead in the realms of public education and policy implementation to mitigate alcohol-related cancer risks in the public’s interest. The survey will be sent to over 100 leading U.S. cancer organizations, including NCI-designated- and other major cancer centers, cancer-oriented professional organizations, and cancer-research organizations. It underwent rigorous testing for clarity, brevity, and expected response time, also drawing upon the expertise of five survey-science professionals. The study is under institutional review board (IRB) review, and we anticipate the survey’s distribution in the first quarter of the calendar year 2024. We expect to share the survey instrument and results during the meeting. Citation Format: Meghan Si, Stephanie Martch, Sanjay Shete, Ernest Hawk. Environmental assessment of alcohol-related policies and practices at US cancer organizations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB143.