bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3980: Targeting Ewing sarcoma based on RNA expression
Authors: Smith Kaitlyn , Gandra Divya , McKinney Kimberly , Dykema Karl , Nagulapally Abhinav , Sholler Giselle S. , Oesterheld Javier , Trovillion Erin 
Published: June 2022

Abstract
Purpose: Ewing sarcoma (ES) is the second most common malignant bone sarcoma in children and young adults. Current treatment for Ewing sarcoma includes a combination of cytotoxic chemotherapeutic agents and local control with radiation and/or surgery. The survival rate of those with Ewing sarcoma has seen very little improvement over the past several decades and remains dismal for those with recurrent or metastatic disease. The purpose of this study is to identify novel agents currently available for use in Ewing sarcoma.
Methods: Novel targeted approaches for the treatment of ES were identified using RNA sequencing performed on 15 ES patient derived cell lines with bioinformatic analysis of gene expression. Targeted agents were tested on patient cell lines at escalating doses. At 48 hours cell viability was assessed with CellTiter-Glo 2.0 and analyzed with GraphPad Prism to determine the IC50. At 24- and 48-hours western blot analysis was performed to evaluate the effect on cell cycle and apoptosis. Combination studies with standard chemotherapy were performed to evaluate for synergy using SynergyFinder 2.0.
Results: RNA analysis identified HDAC2, ALK and JAK1 as a potential therapeutic targets. The pan-HDAC inhibitor, Panobinostat, was cytotoxic to all Ewing sarcoma cell lines tested with clinically relevant IC50s (≤200nM) and repressed expression of Cyclin D1 and pRB. ALK inhibition was cytotoxic at doses slightly higher than that of clinical relevance. HDAC and ALK expression levels correlated to cell sensitivity. JAK1 inhibition does not appear to have efficacy at clinically relevant dosing. Panobinostat synergizes with Doxorubicin at clinically relevant doses.
Conclusion: This work highlights that RNA expression may identify potential targets which could be effective in treating Ewing sarcoma or potentially improve the efficacy of standard of care drugs. HDAC and ALK inhibition show a decrease in cell viability in ES cell line models. Future studies of HDAC and ALK inhibitors will aim to determine efficacy in xenograft models.
Citation Format: Kaitlyn Smith, Divya Gandra, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Giselle S. Sholler, Javier Oesterheld, Erin Trovillion. Targeting Ewing sarcoma based on RNA expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3980.
Abstract 399: The glucocorticoid receptor and β-catenin interact in prostate cancer cells and their co-inhibition attenuates stemness and docetaxel resistance
Authors: Martinez Shannalee R. , Elix Catherine C. , Ochoa Pedro T. , Sanchez-Hernandez Evelyn S. , Alkashgari Hossam R. , Ortiz-Hernandez Greisha L. , Zhang Lubo , Casiano Carlos A. 
Published: June 2022

Abstract
The efficacy of anti-androgen receptor (AR) therapies and taxane-based chemotherapy for the treatment of advanced prostate cancer (PCa) is hindered by the development of therapy resistance. Our previous studies demonstrated that docetaxel (DTX)-resistant PCa cells activates a transcriptomic program associated with stemness and display cancer stem cell (CSC) properties, consistent with the notion that CSCs within prostate tumors contribute to chemoresistance. Glucocorticoid receptor (GR) signaling is a critical mediator of resistance to AR-targeted therapy, and has been recently implicated in the development of PCa cell tumorsphere formation and chemoresistance. Like GR, β-catenin is overexpressed in metastatic and therapy-resistant tumors, and is considered a key regulator of cancer stemness and androgen-targeted therapy resistance. Given the structural and functional overlap between GR and AR, a known interacting partner of β-catenin, we hypothesized that GR also interacts with β-catenin to support stemness and chemoresistance in PCa cells. We observed that treatment with the glucocorticoid dexamethasone induces enhanced nuclear accumulation of both GR and β-catenin in DTX-resistant PCa cells compared to their DTX-sensitive counterparts. Knockdown studies revealed that GR and β-catenin do no regulate each other at the protein level. However, using whole cell and nuclear co-immunoprecipitation, we demonstrated the interaction between GR and β-catenin in both DTX-resistant and DTX-sensitive PC3, DU145, and 22RV1 cells. Pharmacological inhibition and RNA interference-mediated silencing of GR with concomitant inhibition of β-catenin enhanced DTX cytotoxicity in resistant PCa cells grown in both adherent and spheroid cultures, and decreased CD44+/CD24- cell populations in tumorspheres. These results indicate that both GR and β-catenin interact and influence stemness, and may be promising therapeutic targets to overcome PCa chemoresistance.
Citation Format: Shannalee R. Martinez, Catherine C. Elix, Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Hossam R. Alkashgari, Greisha L. Ortiz-Hernandez, Lubo Zhang, Carlos A. Casiano. The glucocorticoid receptor and β-catenin interact in prostate cancer cells and their co-inhibition attenuates stemness and docetaxel resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 399.
Abstract 3990: MERTK is a potential therapeutic target in Ewing sarcoma
Authors: Smart Sherri K. , Yeung Tsz Y. , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , Graham Douglas K. , DeRyckere Deborah 
Published: June 2022

Abstract
Ewing sarcoma (EWS) is the second most common pediatric bone tumor, and outcomes remain poor in patients with advanced or relapsed disease. In addition, current treatments rely on multi-modal therapy that has significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. One potential therapeutic target is the receptor tyrosine kinase MERTK. MERTK is overexpressed in numerous cancers where it promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies. We demonstrated expression and phosphorylation of MERTK protein in 5 of 5 EWS family cell lines tested. Stimulation with the MERTK ligand GAS6 resulted in activation of downstream oncogenic signaling pathways, including JAK/STAT and MAPK/ERK. Moreover, publicly available data from CRISPR-based library screens suggest that EWS cell lines are particularly dependent on MERTK. Thus, therapeutic strategies targeting MERTK may be particularly effective for treatment of EWS. To explore the therapeutic impact of MERTK inhibition in various cancers, we developed MRX-2843, a first-in-class MERTK-selective tyrosine kinase inhibitor that is currently in clinical trials. Treatment with MRX-2843 decreased phosphorylation of MERTK in a dose dependent manner, with an IC50 of 123 nM (95% CI; 53-180 nM) in A673 cells, and reduced downstream STAT6 signaling. In addition, MRX-2843 had potent anti-tumor activity against all 5 EWS cell lines, leading to reduced expansion and decreased cell density in culture with IC50 values ranging from 178 - 297 nM. Of note, inhibition of MERTK phosphorylation correlated with anti-tumor activity in both the A673 and TC106 cell lines, implicating MERTK inhibition as a mechanism of MRX-2843 anti-tumor activity. Together these data validate MERTK as a promising therapeutic target in EWS and support development of MRX-2843 for treatment of EWS, with potential to directly inform and enable a clinical trial in pediatric patients and, ultimately, to improve both outcomes and quality of life for patients with this disease.
Citation Format: Sherri K. Smart, Tsz Y. Yeung, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Douglas K. Graham, Deborah DeRyckere. MERTK is a potential therapeutic target in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3990.
Abstract 3995: Identification of perp as a tumor promoter in pancreatic cancer via the utilization of an aged model of cancer cachexia
Authors: Dasgupta Aneesha , Arneson-Wissink Paige C. , Schmitt Rebecca E. , Cho Dong Seong , Ducharme Alexandra M. , Hogenson Tara L. , Krueger Eugene W. , Bamlet William R. , Zhang Lizhi , Razidlo Gina , Fernandez-Zapico Martin E. , Doles Jason D. 
Published: June 2022

Abstract
Cachexia is a multifactorial syndrome characterized by extensive body weight, lean muscle and fat mass loss. Cachexia worsens cancer patient prognoses and contributes to poor chemotherapy tolerance and response rates. About 80% of pancreatic cancer patients suffer from cachexia and one-third die due to cachexia-related complications such as respiratory failure and cardiac arrest. Although there has been considerable research into cachexia mechanisms and interventions, there are, to date, no FDA-approved cachexia therapies. A major contributing factor could be the failure of animal models to accurately recapitulate the human condition. In this study, we generated an aged murine model of pancreatic cancer cachexia to compare cachexia progression in young versus aged tumor-bearing mice. Comparative transcriptomic analyses of the muscles identified 3-methyladenine (3-MA), a known autophagy inhibitor, as a candidate anti-wasting compound. In vitro analyses confirmed anti-wasting effects while in vivo analysis demonstrated that 3-MA could rescue muscle wasting and suppress tumor growth. Surprisingly, transcriptome analyses of 3MA-treated tumor cells did not reveal autophagy-related signatures but instead implicated Perp as a novel 3-MA target. Probing further, we 1) observed significantly higher expression of Perp in pancreatic cancer cell lines compared to control cells, 2) noted a survival disadvantage associated with elevated PERP in the TCGA database, 3) found that PERP knockdown in cancer cells led to reduced tumor proliferation, and 4) confirmed that 3-MA-associated Perp reduction inhibited tumor growth. Moreover, we also demonstrate that survival benefits associated with 3MA is independent of tumor progression. Finally, we queried Perp expression in human tumor samples and observed increased Perp expression in adenocarcinoma regions compared to tumor adjacent tissue. Taken together, we report a novel mechanism linking 3-MA to Perp inhibition, and further implicate Perp as a novel tumor promoting factor in pancreatic cancer.
Citation Format: Aneesha Dasgupta, Paige C. Arneson-Wissink, Rebecca E. Schmitt, Dong Seong Cho, Alexandra M. Ducharme, Tara L. Hogenson, Eugene W. Krueger, William R. Bamlet, Lizhi Zhang, Gina Razidlo, Martin E. Fernandez-Zapico, Jason D. Doles. Identification of perp as a tumor promoter in pancreatic cancer via the utilization of an aged model of cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3995.
Abstract 4017: Defining cell type-specific pathways in both cancer and tumor-microenvironment cells that impact survival of clear cell renal carcinoma patients
Authors: Strunilin Ilya , Wu Yige , Liu Ruiyang , Caravan Wagma , Chen Feng , Ding Li 
Published: June 2022

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, with 5-year mortality of 25%. The molecular landscape of ccRCC has been elucidated by a number of next generation sequencing studies and complemented by recent global proteome and phosphoproteome results. However, a limitation of such studies is the mixture of signals from distinct cell populations, presenting challenges to subsequent interpretation. As a remedy, single nuclei RNA-seq (snRNA-seq) is able to dissect distinct cell populations and map their differential expression patterns. Using snRNA-seq from 30 ccRCC tumor samples, we identified distinct genetic pathways associated with survival in the TCGA patient cohort (525 patients) in multiple cell types, including immune and stromal components. Prognostic value of pathways was confirmed in an independent cohort with 130 patients. Multiple cancer cell-specific pathways were related to metabolism, suggesting that certain metabolites are less abundant in high-risk tumors. Using data from two independent large-scale metabolism ccRCC studies, we found metabolites’ levels changing in accordance with our predictions, when comparing low-risk to high-risk ccRCC tumors.
Citation Format: Ilya Strunilin, Yige Wu, Ruiyang Liu, Wagma Caravan, Feng Chen, Li Ding. Defining cell type-specific pathways in both cancer and tumor-microenvironment cells that impact survival of clear cell renal carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4017.
Abstract 4018: Long-term response to Trastuzumab in patients with advanced gastric or gastroesophageal adenocarcinoma - A retrospective study
Authors: Porth Isabel , Weidner Philip , Lorenzen Sylvie , Weichert Wilko , Götze Thorsten Oliver , Perner Sven , Luley Kim , Hirsch Daniela , Hofheinz Ralf-Dieter , Peckys Diana B. , Mostajeran Zahra , de Jonge Niels , Gaiser Timo 
Published: June 2022

Abstract
Since 2010, Trastuzumab combined with chemotherapy is the standard treatment for patients with HER2 (ERBB2) positive advanced or metastatic gastric and gastroesophageal junction cancer (GGEJ). While few patients show long-term response to the treatment, most suffer from rapid disease progression. Several studies revealed that genomic alterations, gene expression changes and altered HER2 signaling activity contribute to impaired therapy response. However, the underlying mechanism remains unclear. The aim of this research project is to analyze differences between patients with long and short progression-free survival by utilizing combined genetic, histologic, clinical and gene expression data. We collected a retrospective German patient cohort (n=20) including patients with HER2 positive advanced GGEJ who received Trastuzumab combined with chemotherapy. Using archival samples that were obtained prior to Trastuzumab treatment, we created a dataset including clinical information, histologic assessment, immunostaining, target amplicon sequencing (TAS; 409 gene panel) and human transcriptome data using the Affymetrix platform. To analyze the TAS sequencing data, we generated an automated analysis pipeline, which detects single nucleotide variants (SNV) and copy number alterations (CNA). Information about genomic alteration will be correlated with pathway and gene set enrichment analysis (GSEA) from the Affymetrix data. Furthermore, the data will be supported by investigating the functional status of HER2 in patient samples via electron microscopy. The results of this study could give insights on how genetic and transcriptomic alterations are connected to long-term Trastuzumab therapy response in HER2 positive GGEJ patients. This could potentially support therapy decision in personalized medicine.
Citation Format: Isabel Porth, Philip Weidner, Sylvie Lorenzen, Wilko Weichert, Thorsten Oliver Götze, Sven Perner, Kim Luley, Daniela Hirsch, Ralf-Dieter Hofheinz, Diana B. Peckys, Zahra Mostajeran, Niels de Jonge, Timo Gaiser. Long-term response to Trastuzumab in patients with advanced gastric or gastroesophageal adenocarcinoma - A retrospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4018.
Abstract 4039: Cadmium modulates steatosis, fibrogenesis, and oncogenic signaling in hepatocellular carcinoma cells through activation of Notch/AKT/mTOR pathways
Authors: Niture Suryakant , Gadi Sashi , Lin Minghui , Qi Qi , Moore John T. , Kumar Deepak 
Published: June 2022

Abstract
Cadmium (Cd) is an environmental pollutant that increases hepatotoxicity and the risk of liver diseases. In the current study, we investigated the effect of a physiologically relevant, low concentration of Cd on the regulation of liver cancer cell proliferation, steatosis, and fibrogenic/oncogenic signaling. Exposure of Cd (1 to 10 nM) increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in non-tumor derived HepaRG liver cells and in hepatocellular carcinoma (HCC) cell lines. Exposure of Cd increased Jagged1 expression and activated Notch signaling in HepaRG and HCC cell lines. Cd activated AKT/mTOR signaling by increasing phosphorylation of AKT-S473 and mTOR-S-4448 residues. Moreover, a low concentration of Cd also promoted cell steatosis and induced fibrogenic signaling in HCC cells. Similarly chronic exposure of HCC cells to a low concentration of Cd activated Notch and AKT/mTOR signaling. Further RNA seq data revealed that chronic Cd exposure modulate cell steatosis/fibrogenic gene expression that involved in fatty liver disease development. Cd induced the expression of pro-inflammatory cytokines TNFα and its downstream oncogenic protein Tumor Necrosis Factor-alpha (TNF-α)-Induced Protein 8 (TNFAIP8). Collectively our data suggest that a low concentration of Cd modulates cell steatosis and fibrogenic/oncogenic signaling in HCC by activation of Notch/AKT/mTOR pathways.
Citation Format: Suryakant Niture, Sashi Gadi, Minghui Lin, Qi Qi, John T. Moore, Deepak Kumar. Cadmium modulates steatosis, fibrogenesis, and oncogenic signaling in hepatocellular carcinoma cells through activation of Notch/AKT/mTOR pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4039.
Abstract 4041: Use of Receptor Occupancy Assays on cells from Peripheral Blood as a Surrogate Model of the Tumor Microenvironment
Authors: Jones Nicholas , Ngo Brian , Fancke Benjamin , Limson Jessica , Davis Floyd 
Published: June 2022

Abstract
In the development of monoclonal antibodies for the treatment of solid tumors, monitoring receptor occupancy (RO) on peripheral blood lymphocytes can help illustrate potential therapeutic activity occurring in the tumor environment as an assessment of pharmacodynamics (PD). There is increased interest in using these PD assessments on cells from the periphery to assess the effectiveness and efficacy of investigational therapies. In this area of therapeutic development, much focus has been placed on checkpoint inhibitors proteins/receptors such as PD-1, PD-L1, TIM3, CTLA-4, TIGIT, and multiple others. These immune checkpoint inhibitors are suitable targets since they can be upregulated and/or modulated on exhausted T cells in cancer patients. Assessing the expression of these markers in the tumor itself would be an invasive process and provide little information to correlate with pharmacokinetic results throughout the course of a clinical trial to determine optimal dose selection. However, assessment of the receptor expression and occupancy in combination with pharmacokinetics can lead to a better understanding of drug levels required to achieve optimal therapeutic performance. Monitoring the expression and binding of these molecules by drug can determine specific treatment based on the ability of the patient’s own immune system to act, while providing information to identify therapeutic responses against cancer. This poster will present an example of one such RO assessment in its development and implementation.
Citation Format: Nicholas Jones, Brian Ngo, Benjamin Fancke, Jessica Limson, Floyd Davis. Use of Receptor Occupancy Assays on cells from Peripheral Blood as a Surrogate Model of the Tumor Microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4041.
Abstract 4049: Preclinical pharmacology profile of GTX-0196: A novel, potent and highly selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of hematologic malignancies
Authors: Kaptein Allard , Lain Sonia , Brunen Diede , van Wezel Edward , Barf Tjeerd 
Published: June 2022

Abstract
Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis [Löffler et al., 1997]. Initial clinical studies with the DHODH inhibitor brequinar in solid tumors showed limited efficacy due to dose limiting adverse effects [Peters et al, 2018]. Recently, there is renewed interest in the use of more potent and selective DHODH inhibitors for the treatment of myeloid and lymphoid malignancies [Sykes et al, 2016].
Here we report the identification of the novel potent and highly selective DHODH inhibitor GTX-0196, with excellent physicochemical properties. GTX-0196 exhibited a biochemical IC50 of 3.7 nM in a DHODH biochemical assay and an antiproliferative IC50 of 1.1 nM in the MOLM-13 cell line, with brequinar showing IC50 values of 6.9 and 50 nM, respectively. The activity in the MOLM-13 proliferation assay was uridine-dependent, indicating absence of general toxicity of the compound and confirming DHODH-mediated efficacy.
Profiling of GTX-0196 in the BioPrint panel (Eurofins/CEREP, at 10 µM), showed &lt;50% inhibition for all 133 target proteins tested (GPCR’s, NR´s, kinases and other enzymes), illustrating the high selectivity for DHODH (&gt; 2000-fold selectivity versus other targets tested). Furthermore, no inhibition was observed in a human CYP panel (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4, at 30 µM) and in a panel of transporters (at 10 µM). High metabolic stability in human liver microsomes and hepatocytes was observed with t½ &gt; 6h and 10h, respectively.
Compared to an earlier lead compound, GTX-0196 demonstrated enhanced potency and metabolic stability (particularly in preclinical species). Potent and efficacious inhibition of proliferation through DHODH was confirmed in a large number of solid tumor and hematologic malignancy cell lines, illustrating the broad potential use of this chemical series. Furthermore, tumor growth inhibition was observed in the MOLM-13 xenograft mouse model.
Due to its favorable properties, GTX-0196 has progressed towards IND-enabling studies. In parallel, we are exploring mono and combination therapy opportunities in hematological malignancies as well as combination therapy opportunities in solid tumors to investigate the full therapeutic potential in oncology for this optimized DHODH inhibitor.
Löffler et al. Mol. Cell. Biochem. 1997Peters GJ et al, Nucleosides, Nucleotides and Nucleic Acids 2018Sykes DB et al. Cell 2016
Citation Format: Allard Kaptein, Sonia Lain, Diede Brunen, Edward van Wezel, Tjeerd Barf. Preclinical pharmacology profile of GTX-0196: A novel, potent and highly selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4049.