bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3674: The polyamine acetylation enzyme SAT1 drives mesenchymal features and therapeutic resistance in glioblastoma
Authors: Rana Ayush B. , Horton Timothy M. , Thakur Vijay S. , Welford Scott M. 
Published: April 2023

Abstract
Background:
Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in adults. Characterization of GBM heterogeneity has identified four molecular subtypes based on transcriptomic profile: classical, neural, proneural and mesenchymal. Tumors harboring the mesenchymal gene signature are considered the most aggressive, invasive, and multitherapy-resistant. We identify the polyamine acetylation enzyme, SAT1 (spermidine/spermine N1-acetyltransferase 1) as a component of the mesenchymal gene signature and mesenchymal-associated gene sets including (1) Hallmark EMT and (2) Hallmark TNFa signaling via NF-κB.
Design/Methods:
To validate the role of SAT1 in driving mesenchymal features in vivo, we utilized a genetically flexible, CRISPR-based model of GBM. Tumor bearing mice were generated through in utero electroporation, resulting in ablation of PTEN, P53 and NF1 in developing cortical cells. SAT1 knockout was achieved through cloning of additional guide RNA’s against SAT1 into the tumor initiating plasmid.
Results:
In our model, we found increased levels of both SAT1 and acetylated polyamines in tumors compared to normal brain. Ablation of SAT1 was insufficient to prolong overall survival in mice but rendered the otherwise treatment resistant tumors highly sensitive to chemoRT. Bulk RNA sequencing of murine tumors revealed that SAT1 knockout resulted in reduced expression of the mesenchymal gene signature as well as genes implicated in EMT and TNFa/NFKb signaling.
Conclusions:
Collectively, these results reveal that SAT1 not only identifies mesenchymal GBM but also drives expression of the mesenchymal gene signature and mesenchymal features including multi-therapy resistance.
Citation Format: Ayush B. Rana, Timothy M. Horton, Vijay S. Thakur, Scott M. Welford. The polyamine acetylation enzyme SAT1 drives mesenchymal features and therapeutic resistance in glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3674.
Abstract 368: Neutralizing antibody against GDF-15 restores cachexia
Authors: He Feng , Peng Hao , Li Jianhui , Ding Li , Hao Feng , Ning Jinying , Wu Guojin 
Published: April 2023

Abstract
Growth and differentiation factor 15 (GDF-15) is an attractive target for the treatment of cachexia. Ponsegnomab is such a therapeutical antibody in the clinical trial. Here, we developed a humanized GDF-15 neutralizing antibody (KA1641-ZY1) with better efficacy than ponsegnomab in the pre-clinical experiments. KA1641-ZY1 had high affinity to GDF-15 (KD=0.05nM), with cross-reacting to monkey GDF15. KA1641-ZY1 neutralized GDF-15 in the culture medium and disrupted GDF-15-induced GFRAL signaling more efficiently than Ponsegnomab in reporter cell assay (IC50=0.13nM vs. 0.21nM). In a mouse model with exogenous GDF15 protein-induced body decrease, KA1641-ZY1 restored body weight by giving as low as 5ug/kg while ponsegnomab failed. In the HT1080, Colo 205, and LS513 xenograft tumor-induced cachexia mouse models, KA1641-ZY1 restored the body weight decrease with 0.3mg/kg while ponsegnomab restored the weight with higher than 1mg/kg. In addition, KA1641-ZY1 also restored cisplatin-induced body decrease in GDF15 humanized mice. It has no detectable non-specific binding to red blood cells, neutrophils, PBMCs, and HUVEC cells, with a half-life of about nine days in the mouse. These results suggest that KA1641-ZY1 is a potential candidate drug for cachexia.
Citation Format: Feng He, Hao Peng, Jianhui Li, Li Ding, Feng Hao, Jinying Ning, Guojin Wu. Neutralizing antibody against GDF-15 restores cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 368.
Abstract 3875: Evaluation of resistance mechanisms to ARV471, an ER-targeted PROTAC
Authors: Friel Delia Margaret , Sandusky Zachary , Jiang Yijia , Qiu Xintao , Li Rong , Long Henry , Jeselsohn Rinath , Brown Myles 
Published: April 2023

Abstract
Estrogen receptor alpha (ER) is a ligand activated transcription factor and a driver of ER+ breast cancer. The discovery of activating mutations in ER (gene name ESR1), in patients with advanced endocrine-resistant ER+ breast cancer, has ignited a large pharmaceutical effort to develop next-generation ER antagonists that also target the mutant protein. Here, we profiled the potency and selectivity of many next-generation ER antagonists currently in clinical trials, including ER-targeted proteolysis-targeting chimeras (PROTACs), selective ER modulators (SERMs), and selective ER degraders (SERDs). To contextualize these antagonists, we evaluated their activity against the only FDA-approved SERD, Fulvestrant, at the level of chromatin, transcriptome, proteome, and cell viability, using cells expressing wild-type ER as well as activating mutant ER (ERY537S and ERD538G). Overall, we find that many of the novel oral SERDs are potent ER antagonists, including against mutant ER. To anticipate resistance mechanisms to these next-generation ER antagonists, we developed a strategy initially focused on ARV471 (the most clinically advanced ER PROTAC), with two approaches. First, we performed whole-genome CRISPR/Cas9-knockout screening in ER+ breast cancer cell lines treated with ARV471. Among the enriched gRNAs were PTEN, NF2, and CRBN. Loss of PTEN and NF2 results in activation of the PI3K and MAPK pathways, respectively, and CRBN is the ubiquitin E3 ligase required for ER protein degradation by ARV471. PTEN and NF2 are known mechanisms of endocrine resistance but it is not yet known if CRBN loss in response to PROTACs is a predominant clinical resistance mechanism. Therefore, in a second approach we generated ARV471 resistant breast cancer cell lines through long term exposure (LTE-ARV471). These cells developed an ER-independent resistance mechanism, with decreased ER expression and increased expression of pathways associated with Ras/MAPK and EMT. Therefore, as more potent ER degraders enter the clinic, such as PROTACs and oral SERDs, it may be important to monitor resistance mechanisms that involve loss of ER. Currently, we are following up our findings with LTE-ARV471 cells and performing CRISPR screening to identify targetable dependencies and combination therapies for endocrine resistant breast cancer.
Citation Format: Delia Margaret Friel, Zachary Sandusky, Yijia Jiang, Xintao Qiu, Rong Li, Henry Long, Rinath Jeselsohn, Myles Brown. Evaluation of resistance mechanisms to ARV471, an ER-targeted PROTAC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3875.
Abstract 5442: SlideQC: An AI-based tool for automated quality control of whole-slide digital pathology images
Authors: Rodrigues Daniela , Reinhard Stefan , Waldburger Therese , Martin Daniel , Couto Suzana , Zlobec Inti , Caie Peter , Burlingame Erik 
Published: April 2023

Abstract
Introduction: Artifacts are often introduced during tissue collection and processing, slide preparation, and/or when generating whole slide images (WSI). The presence of artifacts has a negative impact on the digital pathology workflow as artifacts may hinder diagnostic reporting and can lead to false positive and false negative results when using image analysis algorithms or computer-aided diagnosis systems. Manual quality control of WSI is a time-consuming procedure and therefore automated quality control tools, which report and exclude artifacts, are highly desirable to streamline digital pathology workflows. To automate the quality control step, we developed SlideQC, an AI-based quality control tool that automatically detects, reports, and outlines artifacts such as air bubbles, dust/debris, folds, out-of-focus,and pen marks, in both research and clinical workflows. Methods: SlideQC was trained with a DenseNet-based network using 1984 annotations for artifacts including air bubbles, dust/debris, folds, out-of-focus, and pen markers, across 254 Haematoxylin and Eosin (H&E) stained WSI from more than 9 tissue types. A set of 2048 annotations from synthetically generated out-of-focus images was added to supplement the training data. The performance of the SlideQC was evaluated on an external test cohort of 49 WSI H&E images sourced from the open-source database ‘HistoQCRepo’, across 375 annotations (tissue and artifact), and compared with the performance of HistoQC, an open-source quality control tool for digital pathology slides. Results: On the external test cohort, SlideQC showed high sensitivity, specificity, and F1-score with average values of 0.93, 0.99, and 0.93, across the five artifact types. In the same cohort, HistoQC attained an average sensitivity, specificity, and F1-score of 0.65, 0.79, and 0.54, respectively. Conclusions: SlideQC achieved high sensitivity, specificity, and F1-score on an external test cohort. SlideQC can add efficiency gains to a workflow by performing quality control on 100% of slides rather than the currently manually performed on only a subset of the slides in clinical pathology departments. SlideQC can allowthe triaging and alerting of slides containing a high level of artifact within a digital pathology workflow. The tool can also be used to exclude the artifact region from downstream analysis by subsequent image analysis algorithms.
Citation Format: Daniela Rodrigues, Stefan Reinhard, Therese Waldburger, Daniel Martin, Suzana Couto, Inti Zlobec, Peter Caie, Erik Burlingame. SlideQC: An AI-based tool for automated quality control of whole-slide digital pathology images. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5442.
Abstract 5722: The mutational signatures of 100,477 targeted sequenced tumors
Authors: Lee Donghyuk , Hua Min , Wang Difei , Song Lei , Zhang Tongwu , Yu Kai , Yang Xiaohong R. , Shi Jianxin , Chanock Stephen J. , Landi Maria Teresa , Zhu Bin 
Published: April 2023

Abstract
Mutational signatures, the footprints of somatic mutations, are associated with the causes of cancer and have been well-studied for tumors with whole exome or genome sequencing. However, due to the low number of detected mutations, mutational signatures were insufficiently explored for many tumors sequenced by targeted panels in clinics. It impedes the clinical application of mutational signatures. Here, we present a new method, SALMON (Signature Analyzer for Low Mutation cOuNts), to identify mutational signatures in targeted sequenced tumors based on tumor mutational burden. SALMON adjusts for panel size differences and uses a large number of targeted sequenced tumors rather than a large number of mutations per tumor (as with whole exome or genome sequencing) to overcome the challenges of mutational signature analysis for targeted sequencing. Extensive simulations and pseudo-targeted sequenced data show that SALMON can accurately detect spiky or common signatures. We applied SALMON to investigate the pan-cancer patterns of mutational signatures for 100,477 targeted sequenced tumors in AACR Project GENIE, including 14,428 lung and 11,389 breast tumors. We detected well-established signatures in tumor types that have not previously been associated with these signatures, such as the smoking signature in ovarian tumors. Interestingly, analysis of thousands of tumors per cancer type from diverse populations revealed gender discrepancies, self-described race differences, subtype heterogeneity, and metastatic enrichment of mutational signatures. For instance, most sex-biased signatures are more frequently present in males for non-gender-specific cancers. Thiopurine treatment-induced signature in glioma is enriched in Black patients. And endometrioid ovarian or uterine cancers have a higher prevalence of polymerase epsilon (POLE) deficiency-related signatures than non-endometrioid ovarian or uterine cancers, respectively. Our study demonstrates the feasibility and utility of mutational signature analysis for targeted sequenced tumors, enabling precision applications of mutational signatures in the clinical setting.
Citation Format: Donghyuk Lee, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Kai Yu, Xiaohong R. Yang, Jianxin Shi, Stephen J. Chanock, Maria Teresa Landi, Bin Zhu. The mutational signatures of 100,477 targeted sequenced tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5722.
Abstract 6129: The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice
Authors: Farhat Rayan , Dadon Laura , Nemati F , Rebollo A , Decaudin D , Wiels Joelle , Brenner Catherine , Germini Diego 
Published: April 2023

Abstract
In cancer cells, the proapoptotic proteins caspase-9 and PP2A interaction prevents them to play their role in apoptosis. PEP-010, a drug candidate developed by PEP-Therapy, a French Biotech company, is a proapoptotic peptide targeting and disrupting this interaction leading to restoration of the apoptotic cascade. PEP-010 is an innovative bifunctional peptide. It penetrates into cells thanks to its cell penetrating part and specifically disrupts the caspase-9/PP2A interaction thanks to its interfering part. PEP-010 is currently in Phase I a/b multicenter clinical trial for the treatment of advanced solid tumors.To the aim of screening different potential therapeutic targets, to investigate the molecular mechanism-of-action of PEP-010 and to identify potential pharmacodynamic biomarkers, we have tested PEP-010 efficacy on several cell models of different tumor origins. By the Annexin V/Propidium Iodide staining and flow cytometry analysis, we found that PEP-010 induces apoptosis in most of the tested models. One possible mechanism-of-action is an involvement of the PP2A which, once released by PEP-010, could regulate expression and/or activity of different intracellular factors leading to caspases activation and cell death.The identification of the major molecular features involved in PEP-010 mechanism-of-action, were instrumental to identify different pharmacodynamic biomarker candidates (e.g. active caspase-3). Hence, such biomarkers could be useful in clinical practice to monitor the effect of PEP-010 at molecular level. We have compared specific features related to the mechanism-of-action of PEP-010 in sensitive (MDA-MB-231, IGROV1) and not sensitive cell models of different tumor origins and in tissue sections derived from Patient-Derived Xenografts models of breast cancer treated or not with PEP-010. Widely used techniques as immunofluorescent staining and immunohistochemistry were employed, making these results easily transferable in clinical routine.Taken together, our pre-clinical data showed the potential of PEP-010 as an anti-cancer peptide on a wide variety of malignancies and enabled the identification of pharmacodynamic biomarker candidates, important to ease the clinical development.
Citation Format: Rayan Farhat, Laura Dadon, F Nemati, A Rebollo, D Decaudin, Joelle Wiels, Catherine Brenner, Diego Germini. The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6129.
Abstract 6647: Dostarlimab shows dose-dependent immune activation of the tumor microenvironment in a patient-derived NSCLC explant model similar to pembrolizumab
Authors: Perrin Jessica , Wippich Frank , Sherina Valeriia , Dvornikov Dmytro , Lupar Katharina , Melhem Murad M. , Hanafin Patrick , Waight Jeremy , Yu Jong , Yadavilli Sapna , Poeckel Daniel , Bergamini Giovanna 
Published: April 2023

Abstract
The ability to more faithfully mimic the tumor microenvironment (TME) of cancer patients offers a wide range of possibilities for non-clinical evaluation of anti-cancer therapeutics, including guidance for patient selection, dose, and combinations. We have established a patient-derived tumor explant (PDE) model to monitor immune activation within a structurally preserved TME, following ex vivo incubation with immune check point inhibitors (ICI). When testing anti-PD-1 agents, such as dostarlimab and pembrolizumab, in a cohort of NSCLC explants from stage I-III treatment-naïve patients, we observed that approximately half demonstrate release of inflammatory cytokines after two days incubation. Interestingly, responsive tumors presented with a high level of PD-L1 expression (high TPS), had elevated TMB, and were highly infiltrated by CD8+ T cells at baseline, in line with tumor baseline characteristics predictive of clinical response to anti-PD-1. When testing a dose-range of dostarlimab and pembrolizumab comparable potencies were observed when measuring cytokine release after treatment of the NSCLC explants. In conclusion, we describe here an in vitro patient-derived NSCLC model that mirrors the heterogeneity of patients’ response for anti-PD-1 agents observed in clinical settings, representing a valuable tool for comparative analysis of novel ICI assets and combinations, such as the CD226 axis members. Importantly, this system is also amenable to extensive multi-omics and genetics-based analyses, providing the opportunity to better identify predictive or pharmacodynamic characteristics within patient tumors.
Citation Format: Jessica Perrin, Frank Wippich, Valeriia Sherina, Dmytro Dvornikov, Katharina Lupar, Murad M. Melhem, Patrick Hanafin, Jeremy Waight, Jong Yu, Sapna Yadavilli, Daniel Poeckel, Giovanna Bergamini. Dostarlimab shows dose-dependent immune activation of the tumor microenvironment in a patient-derived NSCLC explant model similar to pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6647.
Supplemental File from Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p
Authors: Mody Hardik R. , Hung Sau Wai , AlSaggar Mohammad , Griffin Jazmine , Govindarajan Rajgopal 
Published: April 2023

<p>1.	Supplemental Materials and Methods & Supplemental Figures (Fig. S1-S13) 2.	Supplemental Tables (Table S1-S8)</p>
Supplementary Figure S4 from Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional <i>STK11</i> Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown
Authors: Pore Nabendu , Wu Song , Standifer Nathan , Jure-Kunkel Maria , de los Reyes Melissa , Shrestha Yashaswi , Halpin Rebecca , Rothstein Raymond , Mulgrew Kathy , Blackmore Stephen , Martin Philip , Meekin John , Griffin Matthew , Bisha Ina , Proia Theresa A. , Miragaia Ricardo J. , Herbst Ronald , Gupta Ashok , Abdullah Shaad E. , Raja Rajiv , Frigault Melanie M. , Barrett J. Carl , Dennis Phillip A. , Ascierto Maria Libera , Oberst Michael D. 
Published: April 2023

<p>Characterization of CT26 tumor cell lines with CRISPR-mediated STK11 loss. (A) Western blotting of STK11, phosphorylated AMPK (p-AMPK), total AMPK, and actin in lysates from wild-type CT26 cells (CT26 WT), STK11 CRISPR knock-out clones 26C16, 26C10 and 26C4, and clone 26C16 cells engineered to re-express STK11 (26C16 KI STK11). The ratio of phosphorylated AMPK to total AMPK (p-AMPK/total AMPK) is shown at bottom. (B) In vitro growth of cells in tissue culture. *p < 0.01 for STK11 KO clones 26C4 and 26C10 vs CT26 WT, one-way ANOVA. (C) In vivo tumor growth rates. â€ p < 0.001 for STK11 KO clones 26C4, 26C10, and 26C16 each vs CT26 WT comparing tumor volumes at days 13-15, one-way ANOVA.</p>
Data from Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma
Authors: Saini Neeraj Y. , Swoboda David M. , Greenbaum Uri , Ma Junsheng , Patel Romil D. , Devashish Kartik , Das Kaberi , Tanner Mark R. , Strati Paolo , Nair Ranjit , Fayad Luis , Ahmed Sairah , Lee Hun Ju , Iyer Swaminathan P. , Steiner Raphael , Jain Nitin , Nastoupil Loretta , Loghavi Sanam , Tang Guilin , Bassett Roland L. , Jain Preetesh , Wang Michael , Westin Jason R. , Green Michael R. , Sallman David A. , Padron Eric , Davila Marco L. , Locke Frederick L. , Champlin Richard E. , Garcia-Manero Guillermo , Shpall Elizabeth J. , Kebriaei Partow , Flowers Christopher R. , Jain Michael D. , Wang Feng , Futreal Andrew P. , Gillis Nancy , Neelapu Sattva S. , Takahashi Koichi 
Published: April 2023

<div>Abstract<p>To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in <i>PPM1D</i> (19/114) and <i>TP53</i> (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, <i>P</i> = 0.038). Higher toxicities with CH were primarily associated with <i>DNMT3A, TET2</i>, and <i>ASXL1</i> genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, <i>P</i> = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, <i>P</i> = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5–38.7) vs. 4.2% (95% CI, 0.3–18.4), <i>P</i> = 0.028].</p>Significance:<p>Our study reveals that CH mutations, especially those associated with inflammation (<i>DNMT3A, TET2</i>, and <i>ASXL1</i>), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted.</p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-22-0067" target="_blank">See related content by Uslu and June, p. 382</a>.</i></p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-3-5-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 369</a></i></p></div>