bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5280: O-GlcNAcylation of progesterone receptor promotes mammary tumorigenesis
Authors: Saunders Harmony Ivanna , Holloran Sean M. , Trinca Gloria , Slawson Chad , Hagan Christy 
Published: June 2023

Abstract
The role of hormone receptors in breast cancer has been well established as a key contributor to breast cancer tumorigenesis. Estrogen receptor and progesterone receptors are present in nearly 70% of breast cancers. The role of estrogen receptor and estrogens in breast cancer has been extensively studied and targeted effectively through endocrine therapy, however the impact of progesterone and the progesterone receptor (PR) independent of estrogen is not well understood. We have previously demonstrated that PR promotes tumor growth and drives an immune suppressive environment, therefore understanding the biology of PR in breast cancer is critical. We have also demonstrated that PR attenuates type 1 interferon signaling via inhibition of STAT1 phosphorylation and increased degradation of STAT2. Post-translational modifications such as phosphorylation and SUMOylation can influence PR target gene promoter selectivity thereby altering its function. Our recent work indicates PR is modified by O-GlcNAc, a single N-acetyl-glucosamine sugar that cycles on and off and serine or threonine amino acids in nuclear, cytoplasmic and mitochondrial proteins. Levels of total O-GlcNAc staining are higher in breast cancer tissue compared to adjacent normal tissue. Active O-GlcNAcylation, as evidenced by immunohistochemistry staining of O-GlcNAc-transferase (OGT), is elevated in patients with PR+ tumors compared to PR-. Using T47D breast cancer cells (an ER/PR-positive tumor line), mass spectrometry analysis revealed an O-GlcNAc site at S499 on PR. We then used a naturally occurring PR-negative variant of T47D cells to introduce stable expression of a mutant PR with serine to alanine substitution at the O-GlcNAc site (S499A), thereby blocking O-GlcNAc flux, in addition to wt PR as a control. RNA-Seq analysis of these cells following treatment with progesterone revealed several significant differential gene expression patterns, including rescue of PR dependent interferon signaling attenuation. T47D-mutant PR cell lines implanted into immune deficient mice had significantly decreased growth as compared to WT-PR control tumors. In syngeneic mice harboring PR-positive and PR-negative tumors, loss of O-GlcNAc flux and increased O-GlcNac levels increased tumor growth only when tumors were expressing PR, corroborating the influence of O-GlcNAc in immunodeficient mice. Together these findings indicate O-GlcNAcylation of PR is potentially a mechanism of PR driven breast cancer tumorigenesis and immune evasion.
Citation Format: Harmony Ivanna Saunders, Sean M. Holloran, Gloria Trinca, Chad Slawson, Christy Hagan. O-GlcNAcylation of progesterone receptor promotes mammary tumorigenesis. [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 5280.
Abstract 5288: Single-cell multiomics reveal divergent transcriptional and epigenetic cell states in breast cancer
Authors: Ors Aysegul , Mohammed Hisham , Doe Aaron R. , Haverlack Syber , Handu Mithila , Mulqueen Ryan 
Published: June 2023

Abstract
Over the recent years, single-cell sequencing studies have been used to better describe the highly heterogeneous nature of breast cancers on transcriptional and genetic levels. It is also known that breast cancers are highly driven by estrogen receptor alpha (ER), a transcription factor that’s important for mammary tissue homeostasis. However, little is known about how estrogen signaling heterogeneity affects cancer progression and response to anti-estrogen therapy at a single-cell level. Leveraging single-omic and multi-omic single-cell sequencing technologies, we tracked estrogen response in breast cancer cell and organoid models. We developed TITAN, a topic-modeling based analysis tool to reveal signaling gradients in single-cell RNA-seq data. With this approach we showed that distinct cells prioritize distinct gene groups in response to estrogen. We defined two of these gene networks to be driven by either ER or FOXM1. These same networks exist not only in all the models used in the study but also in breast cancer patient datasets. FOXM1 is activated in estrogen treated cells and the FOXM1 driven gene signature correlates with more aggressive types of disease. Our combined scRNA and scATAC-seq experiments also highlighted distinct chromatin accessibility states associated with either cell group. Using scNMT-seq in patient samples we were able to describe DNA methylation and chromatin accessibility influence on hormone signaling patterns at the single-cell level. Together, our results provide insights into defining transcriptional and epigenetic cell states in ER positive breast cancer.
Citation Format: Aysegul Ors, Hisham Mohammed, Aaron R. Doe, Syber Haverlack, Mithila Handu, Ryan Mulqueen. Single-cell multiomics reveal divergent transcriptional and epigenetic cell states in breast cancer. [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 5288.
Abstract 5292: Characterization of androgen receptor properties and interactome in mediating transcriptional condensates in prostate cancer
Authors: Pinette Nicholas C. , Massah Shabnam , Kochkina Sofia , Zhang Fan , Biswas Maitree , Lee Joseph , Gsponer Jörg , Lallous Nada 
Published: June 2023

Abstract
In The United States of America 1 in 8 men will develop prostate cancer (PCa) in their lifetime. The assembly of phase-separated condensates containing players of the transcriptional machinery such as transcription factors, coactivators (e.g. MED1), and RNA polymerase II enhances the transcription of key oncogenes in various cancer including PCa. Many proteins undergoing phase-separation possess intrinsically disordered regions (IDR) that mediate multivalent intra- and inter-molecular interactions, essential for condensate formation. We recently demonstrated that full-length AR, the main oncogenic driver in PCa, is more prone to form nuclear transcriptional condensates upon androgen stimulation in PCa models than in benign epithelial prostate models. In this study, we investigated the effects of mutating or truncating key residues or regions involved in AR transcriptional activity on its ability to form nuclear condensates in LNCaP cells as visualized by confocal microscopy. We also used various bioinformatics tools to predict additional AR residues and sequences with high propensity for phase-separation. We thus made various truncations and mutations and evaluated their ability to form condensates in LNCaP cells. We also tested the effect MED1 phosphorylation and treatment with various inhibitors targeting different domains of the AR on the ability of full-length protein to form droplets in vitro. We hope by better understanding what drive AR condensates formation in PCa, to elucidate this new mechanism of transcriptional regulation and to identify new therapeutic avenues for patients with advanced forms of the disease.
Citation Format: Nicholas C. Pinette, Shabnam Massah, Sofia Kochkina, Fan Zhang, Maitree Biswas, Joseph Lee, Jörg Gsponer, Nada Lallous. Characterization of androgen receptor properties and interactome in mediating transcriptional condensates in prostate cancer. [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 5292.
Abstract 539: Furin predicts prognosis and promotes PTC progression and metastasis via MEK-ERK axis
Authors: Poyil Pratheeshkumar , Siraj Abdul K. , Padmaja Divya , Parvathareddy Sandeep Kumar , Diaz Roxanne , Thangavel Saravanan , Begum Rafia , Haqawi Wael , Alobaisi Khadija , Al-Mohanna Falah Hassan , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: June 2023

Abstract
Furin belongs to the proprotein convertase family and its expression has been documented in various types of cancers, but its role in Thyroid cancer remains unclear. We investigated the expression of Furin in a large cohort of middle eastern PTC patient’s samples and explored its functional role and mechanism in PTC cell line in vitro and in vivo. Furin overexpression was observed in 44.6% of all PTC cases and it was significantly associated with aggressive clinicopathological parameters and poor outcome. We show that inactivation of Furin suppresses tumor growth, proliferation, migration, invasion, spheroid growth and progression of EMT in BRAF mutant cells, whereas its overexpression in BRAF wild-type PTC cell lines reversed the effect. Mechanistically, Furin inactivation caused MEK/ERK pathway suppression in BRAF mutant cells, while inhibition of MEK has no effect on Furin expression which suggest Furin is a functional upstream of MEK/ERK Pathway. Furthermore, study revealed the synergistic antitumor effect of Furin depletion and MEK inhibitor. These results indicate that Furin is an important prognostic marker and its inhibition can be a potential therapeutic target for aggressive PTC.
Citation Format: Pratheeshkumar Poyil, Abdul K. Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Roxanne Diaz, Saravanan Thangavel, Rafia Begum, Wael Haqawi, Khadija Alobaisi, Falah Hassan Al-Mohanna, Saif S. Al-Sobhi, Fouad Al-Dayel, Khawla S. Al-Kuraya. Furin predicts prognosis and promotes PTC progression and metastasis via MEK-ERK axis [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 539.
Abstract 5526: State-of-the-art biobanking of gastroesophageal adenocarcinoma samples: Integrating non-viable biospecimens with 3D and 2D cell models and their characterization, validation, and utilization of cell models for precision oncology
Authors: Kong Mingyang Iris , Pal Sanjima , Berube Julie , Bourdeau France , Giannias Betty , Bertos Nicholas , Sangwan Veena , Ferri Lorenzo 
Published: June 2023

Abstract
Traditionally, biobanking platforms have collected and stored non-viable biological specimens such as serum, plasma, and fresh-frozen or formalin-fixed paraffin-embedded (FFPE) tissues. These constitute key resources for clinical and contemporary genomics, transcriptomics, and proteomics studies. However, such specimens cannot be used for studies involving drug testing, high throughput target validation, and implementation for personalized medicine. Next-generation biobanking strategies rectify this issue by combining the collection of non-viable samples from patients with the propagation of viable tissue fractions as in vitro 2D and 3D cell models or in vivo xenograft models. Such cutting-edge biobanking strategies enable downstream cell-based high-throughput functional assays promoting the discovery of therapeutic targets or assessing treatment responses and resistance to treatment. Here, we provide comprehensive details of our establishment of a state-of-the-art biobanking platform for gastroesophageal adenocarcinoma (GEA) samples (n=389). Our approach opens new directions for understanding disease biology and conducting translational cancer studies. Patient-derived 2D cells (n=376), organoids (PDOs) (n=185), and xenografts (PDXs) (n= 99) included in our pipeline retain crucial features of the original human tumors, serving as valuable tools for clinical and experimental analyses in the context of precision oncology. We also discuss the entire approach of next-generation biobanking and emphasize the importance of integrating the propagation of PDOs and PDXs simultaneously. In addition, we explain each protocol optimized to propagate patient tissue-derived cell models. We validate that these models recapitulate tissue heterogeneity and are relevant preclinical models. Taken together, we described each approach used to develop one of the largest next-level biobanks for GEA.
Citation Format: Mingyang Iris Kong, Sanjima Pal, Julie Berube, France Bourdeau, Betty Giannias, Nicholas Bertos, Veena Sangwan, Lorenzo Ferri. State-of-the-art biobanking of gastroesophageal adenocarcinoma samples: Integrating non-viable biospecimens with 3D and 2D cell models and their characterization, validation, and utilization of cell models for precision oncology. [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 5526.
Abstract 5562: Prevalence and prognostic significance of malnutrition in patients with brain metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang 
Published: June 2023

Abstract
Background: Malnutrition is a severe but modifiable risk factor for cancers. However, the relationship between malnutrition and the survival of patients with brain metastases has not been fully revealed. We aimed to evaluate the prevalence of malnutrition and assess its prognostic value on patients with brain metastases.
Method: We retrospectively recruited 2633 patients with brain metastases between January 2014 and September 2020. Three malnutrition scores were used to evaluate patients' malnutrition status at their first admission, including controlling nutritional status (CONUT), the nutritional risk index (NRI), and the prognostic nutritional index (PNI). The association between malnutrition and overall survival was estimated.
Results: A total of 1984 (75.4%) of patients were assessed as any degree malnourished and 963 (36.6%) of patients were assessed as moderate to severe malnutrition by at least one malnutrition score. The three malnutrition scores were associated with each other and with BMI. Malnutrition assessed by any of the three scores was significantly associated with poor overall survival (adjust hazard ratio [HR] and 95% confidence interval [CI] for CONUT: 1.12 [1.10-1.16]; for NRI: 0.97 [0.97-0.98]; for PNI: 0.96 [0.95-0.97], all p values &lt;0.001). Furthermore, malnutrition was a better indicator than BMI, and adding malnutrition to the Graded Prognostic Assessment scoring system could significantly improve the accuracy of prognosis prediction.
Conclusion: Malnutrition was prevalent in patients with brain metastases and was significantly associated with overall survival. Malnutrition monitoring on patients' first admission could improve the survival prediction ability for brain metastasis.
Citation Format: Zheran Liu, Yu Zhang, Yiyan Pei, Yan He, Jiayi Yu, Renjie Zhang, Jingjing Wang, Weelic Chong, Yang Hai, Xingchen Peng, Fang Fang. Prevalence and prognostic significance of malnutrition in patients with brain metastasis. [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 5562.
Abstract 5564: SerpinE2: A potential biomarker for urological cancers
Authors: Kovanen Ruusu-Maaria , Koskinen Netta , Lehto Timo-Pekka , Rannikko Antti , Mirtti Tuomas , Koistinen Hannu 
Published: June 2023

Abstract
SerpinE2, also known as protease nexin-1, is an extracellular serine protease inhibitor modulating the activity of serine proteases such as thrombin, plasmin, urokinase-type plasminogen activator and trypsin. Dysregulation between extracellular serine proteases and their cognate inhibitors has been implicated in malignant progression, making serpins promising biomarkers for tumor progression and prognosis. SerpinE2 is upregulated in many cancers and promotes tumor invasion and metastasis. In this study, we analyzed serpinE2 expression by immunohistochemistry on tissue microarrays comprising of samples from prostate, bladder and kidney cancers. The studied samples were clinically hard-to-risk stratify and thus relevant for biomarker studies. We aimed to study the association of serpinE2 expression with survival and clinicopathological features in all three cancers, and evaluate its potential as an immunohistochemical biomarker. In the case of bladder cancer, association of serpinE2 expression with response to neoadjuvant chemotherapy was also assessed. We found that although the strong expression of serpinE2 was related to more aggressive prostate cancers (p = 0.017) and high grade bladder cancers (p = 0.034), it was not associated with relapse, treatment response or survival of prostate and bladder cancer patients. In renal cancer, on the contrary, serpinE2 expression was significantly lower in patients with tumor relapse (p = 0.048) and high expression predicted favorable disease-specific survival (p = 0.013). Our findings help understanding the functional role of serpinE2 in cancer progression and guide the prognostic biomarker research of serpinE2, particularly for prediction of renal cancer-specific survival.
Citation Format: Ruusu-Maaria Kovanen, Netta Koskinen, Timo-Pekka Lehto, Antti Rannikko, Tuomas Mirtti, Hannu Koistinen. SerpinE2: A potential biomarker for urological cancers. [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 5564.
Abstract 6264: NUV-868, a novel BD2-selective BET inhibitor, in combination with enzalutamide or olaparib, inhibits growth of solid tumor xenografts
Authors: Patel Hitisha , Hertzog Jennifer , Heller Laura , Vootukuri Spandana , Zhang Yan , Miller Chris , Hattersley Gary 
Published: June 2023

Abstract
The bromodomain and extraterminal domain (BET) family of proteins play a vital role in gene transcription, making it an attractive therapeutic target for cancer. BET inhibitors can also combine with many anticancer agents to enhance activity. The bromodomains of the BET protein, BD1 and BD2, have unique functions and inhibiting either domain can result in differential responses. To date, non-selective BET inhibitors have failed during early clinical development due to significant on-target toxicity and limited benefit; however, selectively targeting specific bromodomains may result in a more favorable benefit/risk profile. NUV-868 is a novel and highly selective BD2 inhibitor of the BET protein family with ~1500-fold selectivity for BRD4-BD2 relative to BRD4-BD1. Herein, we describe NUV-868 and its activity in multiple in vitro and in vivo solid tumor models. Target engagement, selectivity of bromodomain inhibition, and regulation of BET-mediated gene expression were examined. Additionally, the antitumor activity of NUV-868 in combination with enzalutamide or olaparib was studied in tumor xenograft models of prostate, breast, and pancreatic cancer. NUV-868 demonstrated high selectivity for BD2 and regulated expression of several BET target genes. NUV-868 in combination with enzalutamide inhibited growth of several prostate cancer cell line- and patient-derived xenografts. NUV-868 in combination with olaparib inhibited tumor growth in models of breast, ovarian and pancreatic cancer. Our preclinical data demonstrate that NUV-868, a BD2-selective BET inhibitor, inhibits growth of tumor xenografts in combination with enzalutamide or olaparib and provides rationale for examination of these combinations in the clinic. An ongoing, phase 1 clinical study (NCT05252390) is evaluating NUV-868 as a monotherapy and in combination with olaparib or enzalutamide in patients with advanced solid tumors.
Citation Format: Hitisha Patel, Jennifer Hertzog, Laura Heller, Spandana Vootukuri, Yan Zhang, Chris Miller, Gary Hattersley. NUV-868, a novel BD2-selective BET inhibitor, in combination with enzalutamide or olaparib, inhibits growth of solid tumor xenografts [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 6264.
Abstract 6290: Characterizing antitumor responses to EXS-74539, a novel, reversible LSD1 inhibitor with potential in small-cell lung cancer
Authors: Payne Andrew , Naik Manisha , Richards Simon , Perez Victor Sebastian , Dominguez Maria 
Published: June 2023

Abstract
Background: Lysine demethylase 1 (LSD1) is a potentially important target in oncology due to its role in demethylating histones and suppressing expression of genes required for cellular differentiation. In small-cell lung cancer (SCLC), high LSD1 expression is associated with suppressed differentiation pathways. Although selective LSD1 compounds are in clinical development, understanding of the molecular markers of tumor sensitivity to inhibition of LSD1 inhibition is incomplete. Methods: We report on the pharmacological characterization of EXS-74539, a potent, selective and reversible LSD1 inhibitor. We assessed EXS-74539 efficacy in in vitro and in vivo SCLC cell line models, encompassing the four molecular subtypes of SCLC tumor cells previously proposed (Rudin et al, 2019), based on differential expression of key transcription regulators, ASCL1, NEUROD1, POU2F3 and YAP1. Results: In vitro, EXS-74539 demonstrated similar anti-proliferative activity against both neuroendocrine (NCI-H1417 and NCI-H69, ASCL1 sub-type) and non-neuroendocrine (NCI-H526: POU2F3) SCLC cell lines, with IC50 values of 28, 12 and 11 nM, respectively. In vitro exposure of these cell lines to EXS-74539 led to concentration-dependent alterations in differentiation-associated genes. However, in vivo, significant differences in antitumor growth response upon LSD1 inhibition were observed between the cell lines; NCI-H69 tumor growth was unaffected following treatment with EXS-74539 and an irreversible LSD1 inhibitor at dose regimens which were efficacious in the NCI-H1417 and NCI-H5126 models. We describe in vitro and in vivo gene expression correlations associated with LSD1 sensitivity. Conclusions: The reversible LSD1 inhibitor, EXS-74539, is a potent inhibitor of SCLC cell line proliferation and shows in vivo efficacy. Characterizing SCLC cell line sensitivity in vitro and in vivo identified gene signatures that may have use as markers of sensitivity, which we are currently characterizing and validating in human SCLC patient samples. Rudin et al., Nat Rev Cancer, 2019
Citation Format: Andrew Payne, Manisha Naik, Simon Richards, Victor Sebastian Perez, Maria Dominguez. Characterizing antitumor responses to EXS-74539, a novel, reversible LSD1 inhibitor with potential in small-cell lung cancer [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 6290.