bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4327: Development of bioluminescent biosensors to monitor the interaction betweenGSDMD and caspase-1 in living cells
Authors: Kelly Tynan 
Published: March 2024

Abstract
Gasdermin D (GSDMD) is the key executioner of pyroptosis, an inflammatory form of programmed cell death implicated in various inflammation-driven diseases, including cancer, heart failure and strokes. The interaction between GSDMD and caspase-1 (CASP1) orchestrates the critical pathway of GSDMD-mediated pyroptosis. During pyroptosis, pyroptosis stimuli activate CASP1, which subsequently binds to and cleave GSDMD between GSDMD’s N- and C-terminal domains. The free N-terminal domains oligomerize and translocate to the cell membrane, forming pores and releasing proinflammatory cytokines and causing cellular lysis. Key interaction sites have been identified for GSDMD recognition and engagement by CASP1; therefore, blocking functionally significant residues presents a new therapeutic strategy for inhibiting CASP1-induced GSDMD cleavage and pyroptosis. Currently, there is no small molecule capable of specifically disrupting the GSDMD and CASP1 interaction. In response, the ongoing pursuit of identifying potential inhibitors is a driving force for developing a biosensor capable of monitoring this interaction and their roles in downstream pyroptotic effects. In this study, we utilized the NanoLuc Binary Technology (NanoBiT) to construct several bioluminescent biosensors comprising two NanoLuc luciferase enzyme fragments (LgBiT and SmBiT) fused to GSDMD and CASP1, respectively, in various combinations. Further validation of these biosensors by luciferase assays in living cells identified a GSDMD-CASP1 biosensor with highest luciferase activity. This newly developed biosensor paves the way for high-throughput screens to identify novel small molecule inhibitors disrupting the GSDMD-CASP1 interplay. These small molecule inhibitors will effectively impede GSDMD-mediated pyroptosis, holding promise for novel therapies of various human diseases.
Citation Format: Tynan Kelly. Development of bioluminescent biosensors to monitor the interaction betweenGSDMD and caspase-1 in living 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 4327.
Abstract 4355: Characterizing HRD in ovarian cancer: Insights from copy number signatures
Authors: Hawari Aliah , Tapinos Avraam , Kramer Claire J. , Gruber Andreas J. , Houlston Richard , Brenton James , Wedge David 
Published: March 2024

Abstract
Copy number changes are defining features in ovarian cancers. Two distinct methods by Steele et al. and Drews et al., published back-to-back in 2022, detail features and categories of copy number signatures. However, these methods have not been benchmarked for ovarian cancer. Mutational signatures are pivotal in understanding cancer biology and serve as predictive and prognostic biomarkers. This study aims to examine the landscape of copy number signatures to characterize the diversity of Homologous Recombination (HR) impairment within ovarian cancer. While assessing Homologous Recombination Deficiency (HRD) is crucial for targeted treatments, current HRD tests lack clarity. Using signature extraction tools SigProfilerExtractor and CINSignature, we analyzed whole-genome sequencing data (mean depth 100x) from 416 ovarian cases from Genomics England (GeL), employing both copy number signature methods. Among the signatures extracted, HRD signature CN17 from Steele et al. methodology was identified in 37% of the samples and primarily found in the high-grade serous ovarian cancer (HGSOC) subtype (77%). Additionally, higher exposure levels (median of 0.4 in n=154 compared to median of 0.29 in n=416) of Drews et al. methodology’s most complex HRD signature, CX3, was detected in samples exhibiting CN17 activity. This ongoing exploration of the copy number signatures landscape works towards identifying the spectrum of HR impairment, aiming to benchmark these two methods for a standardized diagnostic tool. This study contributes to our understanding of the mutational landscape of ovarian cancer and its potential implications for prevention and personalized treatment strategies.
Citation Format: Aliah Hawari, Avraam Tapinos, Claire J. Kramer, Andreas J. Gruber, Richard Houlston, James Brenton, David Wedge. Characterizing HRD in ovarian cancer: Insights from copy number signatures [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 4355.
Abstract 4356: An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing
Authors: Li Zhongxiao , Zhang Bin , Chan Jia Jia , Tabatabaeian Hossein , Tong Qing Yun , Chew Xiao Hong , Fan Xiaonan , Chan Charlene , Driguez Patrick , Cheong Faith , Wang Shi , Siew Bei En , Tan Ian Jse-Wei , Lee Kai-Yin , Lieske Bettina , Cheong Wai-Kit , Kappei Dennis , Tan Ker-Kan , Gao Xin , Tay Yvonne 
Published: March 2024

Abstract
Colorectal cancer (CRC), a complex and molecularly heterogenous disease that lacks robust predictive markers and targeted therapies, is the second leading cause of cancer death worldwide. In recent years, technological advances in short-read single-cell RNA sequencing (scRNA-seq) have been instrumental in deciphering tumor cell heterogeneities. However, most studies have focused on gene-level expression quantification without considering alterations in transcript structures arising from widespread alternative end processing and/or splicing which are frequently dysregulated in cancer. Here, we combined short- and long-read scRNA-seq of CRC patient samples to build the first isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 derived from the coupling of multiple alternative splicing events. Additionally, we characterized genes and isoforms associated with different colon epithelial lineages and tumor cell subpopulations exhibiting varying levels of stemness and differentiation, as well as their distinct prognostic implications. Finally, we built an algorithm by integrating mass spectrometry data and novel peptides derived from predicted open reading frames of recurrent tumor-specific transcripts to curate a panel of recurring neoepitopes. Overall, this study unveils the transcriptomic landscape of CRC and may drive the identification of neoantigens based on full-length transcriptomic atlases to aid future development of more universal neoantigen-based cancer vaccines.
Citation Format: Zhongxiao Li, Bin Zhang, Jia Jia Chan, Hossein Tabatabaeian, Qing Yun Tong, Xiao Hong Chew, Xiaonan Fan, Charlene Chan, Patrick Driguez, Faith Cheong, Shi Wang, Bei En Siew, Ian Jse-Wei Tan, Kai-Yin Lee, Bettina Lieske, Wai-Kit Cheong, Dennis Kappei, Ker-Kan Tan, Xin Gao, Yvonne Tay. An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing [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 4356.
Abstract 4429: Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank cohort
Authors: Yuan Fangcheng , Jia Guochong , Wen Wanqing , Zheng Wei 
Published: March 2024

Abstract
Background: Dysregulation of metabolic processes contributes to colorectal cancer (CRC) etiology. We aimed to comprehensively evaluate the prospective associations between pre-diagnostic metabolic biomarkers and CRC risk in 230,420 UK Biobank participants.
Methods: A total of 249 metabolic biomarkers were measured by nuclear magnetic resonance spectroscopy from baseline plasma samples. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. Subgroup analyses were performed by sex and CRC subsites (i.e., proximal colon, distal colon, rectum). We also conducted factor analyses to identify latent factors and examined their associations with CRC risk.
Results: During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified after excluding participants diagnosed with CRC within two years after blood collection. After correcting for multiple testing, 50 metabolic biomarkers, including lipids and lipoproteins, fatty acids, ketone bodies, and inflammation, were significantly associated with incident CRC risk. No statistically significant differences were observed for the biomarker-CRC associations by sex and CRC subsite. In the sensitivity analysis, excluding cholesterol-lowering medication users did not alter the main findings. In factor analyses, we identified a significant association of CRC risk (HR = 1.08; 95% CI = 1.04-1.13; P-value = 6.89×10-5) with a metabolite pattern which was positively correlated with triglycerides and inversely correlated with relative concentrations of omega-6 fatty acids and polyunsaturated fatty acids.
Conclusion: We identified multiple metabolic biomarkers and a metabolite pattern associated with CRC risk in a large prospective cohort. These findings suggest lipid metabolism may contribute to carcinogenesis of the colorectum.
Citation Format: Fangcheng Yuan, Guochong Jia, Wanqing Wen, Wei Zheng. Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank cohort [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 4429.
Abstract 4487: Simple modifications of 3-HPT for improved in-vivo activtiy
Authors: Kern Ryan E. , Huang Susanna , Arunsi Uche , Oyelere Adegboyega 
Published: March 2024

Abstract
One of the key targets in the treatment of castration resistant prostate cancer is HDAC6. HDAC6 removes acetyl groups from Heat shock protein 90 (HSP90), which is a protein chaperone that folds the androgen receptor. By inhibiting HDAC6 it is possible to prevent the expression of mutated androgen receptors, that are no longer responsive to androgen deprivation therapy, treating castration resistant prostate cancer. The Oyelere lab has previously demonstrated that 3-Hydroxypyridin-2-thione (3-HPT) can serve as a scaffold for HDAC6 inhibitors. While the unaltered 3-HPT has been shown on its own to inhibit HDAC6 in enzyme specific assays. The unaltered 3-HPT had no effect in whole cell assays. This work investigated simple modification of the 3-HPT scaffold to improve the in-vivo activity of 3-HPT. This work is an extension of work previously done in the Oyelere lab. The aim of this work is to apply simple modifications to the 3-HPT scaffold to improve the in-vitro activity. Previously 3-HPT was shown on its own to inhibit HDAC6 with an IC50 of 681nM but have no effect on cell assays. The hypothesis was that by converting the secondary amine into a tertiary amine the pharmacokinetic-properties of 3-HPT allowing can be improved focusing on cellular entry. The specific modification was the addition of alkanes and fluorinated alkanes at the secondary amine. This addition should improve the charge of the compounds improving the invitro activity. Based on molecular docking studies using Autodock vina, the introduction of fluorines improves the binding to HDAC6 by interacting with a hydrophilic pocket near the zinc ion. The preliminary in-vivo results in LnCAP and DU145 cells demonstrate that the addition of fluorinated alkanes has substantially improved the IC50 compared to the base 3-HPT compound. The base 3-HPT compound has an IC50 of greater than 100µM while the compounds with fluorinated alkanes have IC50 values in the range of 2-15µM. this data indicates improved drug likeness.
Preliminary IC50 values of compounds in prostate cancer cell lines Compound Name LNCaPIC50 (µM) DU145IC50 (µM) Vero IC50 (µM) SH-1-78 &gt;100 &gt;100 &gt;100 SH-1-94 2.50 19.29 22.53 RK-1-187 96.95 95.45 88.57 SH-1-110 1.27 21.47 17.41 RK-2-16 2.09 62.86 18.76 RK-2-17 &gt;100 &gt;100 &gt;100 RK-2-64 78.36 &gt;100 76.45 RK-2-67 14.19 26.95 11.38
Citation Format: Ryan E. Kern, Susanna Huang, Uche Arunsi, Adegboyega Oyelere. Simple modifications of 3-HPT for improved in-vivo activtiy [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 4487.
Abstract 4506: Discovery of potent, highly selective and orally efficacious SMARCA2 degraders
Authors: Leng Lingying , Yang Lin , Tu Wenbin , Rej Rohan , Allu Srinivasa Rao , Huang Liyue , Jiang Wei , Wang Yu , Stuckey Jeanne , Sarkari Farzad R , Wang Meilin , Wang Lu , Wen Bo , Sun Duxin , Wang Shaomeng 
Published: March 2024

Abstract
In human non-small cell lung cancer, 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, orally efficacious SMARCA2 PROTAC degraders exemplified by UM-SMD-8801. UM-SMD-8801 has DC50 &lt;10 nM and Dmax &gt;90% against SMARCA2 and &gt;1,000-fold degradation selectivity over SMARCA4. Consistently, UM-SMD-8801 potently inhibits cell growth in SMARCA4 mutated cancer cell lines with low nanomolar IC50 values and shows &gt;100-fold weaker activity in SMARCA4 wild-type cancer cell lines. UM-SMD-8801 has a good overall pharmacokinetic profile and an excellent oral bioavailability in mice. Oral administration of UM-SMD-8801 is highly effective in reducing SMARCA2 protein by &gt;90% in tumor tissues in mice, while having minimal effect on SMARCA4 protein. UM-SMD-8801 represents a very promising SMARCA2 degrader for extensive evaluation as a potential new therapy for the treatment of SMARCA4-deficient human cancers.
Citation Format: Lingying Leng, Lin Yang, Wenbin Tu, Rohan Rej, Srinivasa Rao Allu, Liyue Huang, Wei Jiang, Yu Wang, Jeanne Stuckey, Farzad R Sarkari, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of potent, highly selective and orally 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 4506.
Abstract 4517: Novel chemical degraders targeting NSD2 in head and neck squamous cell carcinoma (HNSCC)
Authors: Ismail Amr , Roshchina Ekaterina , Topchu Iuliia , Schiltz Gary , Boumber Yanis 
Published: March 2024

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in treatments and significant efficacy of immunotherapy drugs in HNSCC, no effective targeted therapies have been approved in this disease yet. NSD2 is a histone lysine methyltransferase, which is overexpressed in HNSCC and is implicated in tumor growth, cell cycle regulation, epithelial-mesenchymal transition (EMT) and metastasis not only in HNSCC, but also in many other solid tumors. Development of inhibitors to the catalytic activity of NSD2 has been rather limited to date, which necessitates an alternative approach. To target NSD2, we have recently developed a series of novel proteolysis targeting chimeras (PROTACs), which chemically degrade NSD2 utilizing native cellular machinery - ubiquitin-proteasome system - with VHL as an E3 ligase. A series of &gt;40 compounds were tested in HNSCC cell lines (JHU-011 and FaDu) and NSD2-dependent multiple myeloma cell line (KMS11) for degradation activity against NSD2 protein, and H3K36me2 chromatin mark reduction, using Western blot. We also tested their anti-proliferative activity in cell viability assay (CTB) and clonogenic assay. Compounds NUCC-0227381, NUCC-0227384, NUCC-0227414 and NUCC-0227383 show promising results by reducing NSD2 and H3K36me2 levels. NUCC-0227383 compound was highly promising, as it was the most potent in reducing NSD2/K36me2 levels without affecting NSD1/NSD3 levels and had profound effects on HNSCC cell growth. Lead compound NUCC-0227383 was chosen for further testing and in preliminary testing, showed a dose-dependent, VHL-mediated, and proteasome dependent function. Proteomics analysis, testing for specificity of NUCC-0227383 against a panel of histone methyltransferases, and in vivo testing of this promising compound against HNSCC is planned.
Citation Format: Amr Ismail, Ekaterina Roshchina, Iuliia Topchu, Gary Schiltz, Yanis Boumber. Novel chemical degraders targeting NSD2 in head and neck squamous cell carcinoma (HNSCC) [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 4517.
Abstract 4550: Synergistic combinations of lurbinectedin with ONC212 in pancreatic cancer
Authors: Tummala Tej , Uruchurtu Ashley S. Sevilla , Liguori Nicholas R. , Abbas E. , Azzoli Christopher G. , El-Deiry Wafik S. 
Published: March 2024

Abstract
Pancreatic cancer is a devastating disease with a poor five-year survival rate of approximately 12%. Given the poor prognosis of the disease, there is urgent need for novel therapeutic regimens. Lurbinectedin is chemotherapeutic compound that stalls and degrades RNA Polymerase II after binding to guanine-rich sequences in the minor groove of DNA. This stalls transcription machinery and leads to single- and double- stranded breaks in DNA and subsequent apoptosis. Our group recently described lurbinectedin’s potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines. We also recently discovered a synergistic interaction between lurbinectedin and ONC201/TIC10, a novel compound that induces the TRAIL apoptotic pathway, in small cell lung cancer cell lines. Synergy was accompanied by an activation of p-Chk1 and the integrated stress response. We now demonstrate a synergistic combination of lurbinectedin and ONC212, an imipridone and chemical derivative of ONC201, results in highly efficient killing of pancreatic tumor cells at sub-nanomolar concentrations of lurbinectedin and sub-micromolar concentrations of ONC212. We hypothesize that the integrated stress response underlies lurbinectedin and ONC212 synergy. We further hypothesize a combination of lurbinectedin and ONC212 will sensitize the tumor cells to CD8+ T-cell killing, which will be examined via co-culture assays. Our results are developing insights into a novel combinatorial therapeutic regimen while investigating the molecular mechanisms underlying synergism.
Citation Format: Tej Tummala, Ashley S. Sevilla Uruchurtu, Nicholas R. Liguori, E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Synergistic combinations of lurbinectedin with ONC212 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4550.
Abstract 4559: SMAD3 mediates oxaliplatin resistance in esophageal adenocarcinoma
Authors: Ballout Farah , Lu Heng , Bhat Nadeem , Chen Lei , Peng Dunfa , Chen Zheng , Zaika Alexander , McDonald Oliver , El-Rifai Wael 
Published: March 2024

Abstract
Background: Resistance to conventional treatments is a significant barrier to esophageal adenocarcinoma (EAC) therapy. TGF-β signaling appears to be important for EAC tumorigenesis; however, its role in EAC chemoresistance remains understudied. This study investigates the role of SMAD3 in EAC resistance to the frontline chemotherapeutic drug oxaliplatin.
Methods: Publicly available datasets were analyzed to determine SMAD3 expression in EAC versus normal samples. Western blot, quantitative real-time polymerase chain reaction, immunofluorescence staining, and flow cytometric analyses were utilized to validate bioinformatic results. Human EAC cell lines (OE33 and OE19) were treated with pharmacologic inhibitors or transfected with small interfering RNA and assessed for DNA damage and apoptotic cell death. Patient-derived organoids and patient-derived xenograft models of EAC were used to confirm our findings in vivo.
Results: SMAD3 was significantly upregulated in EAC versus normal tissue samples. Total and phosphorylated SMAD3 protein levels were upregulated in EAC tissues accompanied by increased expression of several genes regulated by SMAD3. Notably, oxaliplatin-resistant EAC cells exhibited overexpression of SMAD3. Chemotherapy non-responding patients showed enrichment of SMAD3 gene expression when compared to responders in the clinical dataset GSE165252. Knockdown or inhibition of SMAD3 hindered DNA repair and sensitized EAC cells to oxaliplatin treatment in vitro and in vivo. Mechanistically, SMAD3 promoted ATM phosphorylation by interacting with protein phosphatase 2A (PP2A) and sequentially inhibiting the binding of PP2A to ATM.
Conclusion: Our results reveal a pivotal role for SMAD3 in mediating oxaliplatin resistance in EAC and thus hold a significant potential in guiding future drug development and combination strategies.
Citation Format: Farah Ballout, Heng Lu, Nadeem Bhat, Lei Chen, Dunfa Peng, Zheng Chen, Alexander Zaika, Oliver McDonald, Wael El-Rifai. SMAD3 mediates oxaliplatin resistance in esophageal adenocarcinoma [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 4559.