bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4740: Molecular effects of histone deacetylase inhibitor Quisinostat on diffuse midline glioma of the pons
Authors: Paine Danyelle , Tang Nanyun , Hao Yue , Biery Matt , Meyers Carrie , Noll Alyssa , Vitanza Nicholas , Berens Michael 
Published: April 2023

Abstract
Diffuse Midline Glioma of the pons (DMG) is a lethal, aggressive heterogeneous brain stem tumor. Median overall survival is less than a year, with radiation as the only standard treatment. Recently, mutations in DMGs have arisen as potential therapeutic targets, specifically a mutation in one of the histone H3 genes, resulting in methionine substituted for lysine at site 27 (H3K27M). H3K27M induces a marked reduction in global acetylation of histone tails, altering chromatin structure and causing aberrant gene expression. Histone deacetylase inhibitors, HDACis, are epigenetic drugs that show anticancer activity. In our studies, Quisinostat (Quis) is used to preserve histone acetylation. Using two H3K27M-DMG treatment-naive preclinical models (PBT22 and PBT29) we detected a 100-fold differential response to the histone deacetylase inhibitor, Quisinostat. PBT-22 harbors mutations in H3F3A, TP53, and ASXL2, while PBT-29 has mutations in H3F3A, TP53, PIK3CA and FGFR1. Following Quis treatment (48 hrs) in both preclinical models, total H3K27ac protein abundance increased 3-fold, suggesting HDACi stabilizes or impedes turnover of K27 acetylated H3 histone. We are pursuing studies to test whether sensitivity to HDACi in DMGs is determined by a shift in relative or total abundance of respective H3wt- and H3K27M- histones. We posit that changes in H3K27ac manifest as shifts in nucleosome integration with genes responsible for cell survival/death. This project will profile differentially expressed genes (DEGs) from Quis-treated PBT22 and PBT29. Additionally, total and relative abundance of H3 proteins (wt and mt, me, me2, me3, and ac) from treated cells will be determined. Gene ontology analysis will focus on pathways accounting for chromatin remodeling, cell death, and growth arrest. RNA (qRT-PCR) and proteins (western blot) from analytes from a larger panel of DMG cell lines and neural stem cells treated with Quis will be used to validate the findings. Overall, the data depicts DMG preclinical models with large differential sensitivity to Quis, which may be partially due to different oncoprints between the models. The markedly different sensitivity of these models enables mechanistic study of the consequences of elevated abundance of histone 3 acetylation. The long term goal is to discover a molecular profile of DMGs indicative of the vulnerability to HDACi.
Citation Format: Danyelle Paine, Nanyun Tang, Yue Hao, Matt Biery, Carrie Meyers, Alyssa Noll, Nicholas Vitanza, Michael Berens. Molecular effects of histone deacetylase inhibitor Quisinostat on diffuse midline glioma of the pons. [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 4740.
Abstract 4754: Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis
Authors: Liu Yiman , Li Qinglan , Tang Sylvia , Gong Chujie , Wan Liling 
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is one of the most aggressive forms of hematological malignancies with a low overall 5-year survival rate (&lt; 26%). The mainstay of treatment for AML includes chemotherapy, but the response of a subset of patients to current treatment options remains poor. Thus, new therapeutic approaches are desperately needed. AML often arises from somatic mutations in chromatin regulators that result in uncontrolled proliferation and a block of differentiation in myeloid progenitor cells. As such, investigation of the role and molecular mechanism of chromatin regulator in AML is being actively pursued. Previously, we discovered the eleven-nineteen-leukemia (ENL) protein, a chromatin “reader” and transcription co-activator, as an unrecognized requirement for the survival of AML. We developed a potent and orally bioavailable small-molecule inhibitor of ENL, which displaces ENL from chromatin and blocks AML progression. Hotspot mutations have been found in ENL YEATS domains, both in Wilms tumor and in leukemia, and these mutations confer a gain of condensation property, leading to aberrant gene activation. However, the impact of ENL mutation on tumorigenesis is largely unknown. The over-arching goal of this project is to explore the impact of the hyper-activated ENL pathway (ENL mutation) in AML. Results from this project will elucidate how newly discovered chromatin reader mutations drive tumorigenesis and offer new biology insights that will facilitate both basic mechanistic studies and clinical studies.
Citation Format: Yiman Liu, Qinglan Li, Sylvia Tang, Chujie Gong, Liling Wan. Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis. [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 4754.
Abstract 4764: The therapeutic potential of lnc-HLX-2-7 in group 3 medulloblastomas in children
Authors: Katsushima Keisuke , Lee Bongyong , Yuan Menglang , Stapleton Stacie , Jallo George , Seal Sudipta , Eberhart Charles G. , Perera Ranjan J. 
Published: April 2023

Abstract
Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the non-coding RNA genome, in particular long non-coding RNAs (lncRNAs), contributes to MB formation and tumor progression. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 MBs. In this study, we report that lnc-HLX-2-7 RNA specifically accumulates in the HLX (host gene of lnc-HLX-2-7) promoter region and activates HLX expression by recruiting multiple factors including enhancer elements. RNA sequencing and chromatin immunoprecipitation revealed that HLX directly binds to the promoters of several tumor-promoting genes, including MYC, and activates their expression. Furthermore, intravenous treatment with antisense oligonucleotides targeting lnc-HLX-2-7 coated with cerium-oxide nanoparticle (CNP-lnc-HLX-2-7) reduced tumor growth (40-50%) in intracranial MB xenograft mouse model (n=10, p&lt;0.01, t-test). We found that the combinatorial therapy of CNP-lnc-HLX-2-7 and cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared to CNP-lnc-HLX-2-7 monotherapy (n=10, p&lt;0.01, t-test) only. We report here the importance of the lnc-HLX-2-7-HLX-MYC axis in regulating group 3 MB progression and provide a strong rationale for using lnc-HLX-2-7 as a specific and potent therapeutic target for the group 3 MBs in children.
Citation Format: Keisuke Katsushima, Bongyong Lee, Menglang Yuan, Stacie Stapleton, George Jallo, Sudipta Seal, Charles G. Eberhart, Ranjan J. Perera. The therapeutic potential of lnc-HLX-2-7 in group 3 medulloblastomas in children. [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 4764.
Abstract 4771: Prevention of doxorubicin-induced cardiotoxicity by benfotiamine
Authors: Taylor Justin R. , Harames Kyra 
Published: April 2023

Abstract
Anthracyclines such as daunorubicin and doxorubicin (DOX) are currently used as chemotherapeutic agents in the prevention of various cancers including breast cancer, lung cancer, leukemia, and lymphoma. Although, anthracyclines are successful in controlling various cancers growth, the major drawback is the unwanted cardiotoxicity. Specifically, high doses of DOX used for the therapy of advanced cancers could cause life threating conditions. Therefore, specific interventions are required to decrease the cardiac toxicity associated with the DOX. Benfotiamine, a lipid soluble vitamin B1 derivative has shown be a potent anti-oxidant and anti-inflammatory agent. However, the efficacy of benfotiamine in the prevention of cardiotoxicity associated with the anthracyclines is not known. In this study, we examined the effect of benfotiamine in the prevention of DOX-induced cytotoxicity in the human umbilical vascular endothelial cells (HUVECs). Treatment of HUVECs with DOX caused significant endothelial cells death and benfotiamine in a concentration-dependent manner prevented the dox-induced endothelial cell death. Further, benfotiamine prevents the DOX-induced apoptosis in endothelial cells by preventing the activation of caspase-3. Benfotiamine also prevents DOX-induced reactive oxygen species generation. Our results also indicate that benfotiamine regulates DOX-induced expression of pro-apoptotic mediators such as BAD, phosphor-P53, and pro-caspase-3, and anti-apoptotic mediators such as BCL-2, BCL-x, IAPs, and HSP and others such as FADD, DR5, and SMAC/diablo. We plan to further explore how benfotiamine prevents DOX-induced cardiotoxicity using human cardiac myocytes and mouse models. Thus, based on our cell culture studies, benfotiamine through its potent anti-oxidative property could prevent endothelial cytotoxicity and suggests that it could be further developed as adjuvant therapy in controlling cardiotoxicity associated with the anthracycline chemotherapy.
Citation Format: Justin R. Taylor, Kyra Harames. Prevention of doxorubicin-induced cardiotoxicity by benfotiamine. [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 4771.
Abstract 4775: Knockout of Sod2 accelerates KrasG12D-driven formation of pancreatic cancerous lesions
Authors: Fleming Martinez Alicia K. , Edenfield Brandy H. , Esposito Irene , Storz Peter 
Published: April 2023

Abstract
Recent studies demonstrate that mitochondrially-generated reactive oxygen species (ROS) downstream of oncogenic KRAS drive acinar-to-ductal metaplasia (ADM), a key first step in the pancreatic ductal adenocarcinoma (PDA) progression model. MnSOD/SOD2 is a mitochondrial enzyme that converts superoxide into hydrogen peroxide. Previous studies have shown that SOD2 is biologically relevant to the study of pancreatic cancer. Some patients with a SOD2 polymorphism resulting in less active MnSOD at the mitochondrial matrix are at increased risk of developing pancreatic cancer. Additionally, MnSOD is lost in high-grade human PanIN, further suggesting a role in tumor development. To elucidate the role of MnSOD in pancreatic cancer initiation and progression, we crossed Sod2lox/lox mice into the p48Cre;LSL-KrasG12D (KC) mouse model. We found increased ROS, abundantly more abnormal tissue development and presence of flat lesions indicating accelerated early progression. However, Kaplan Meyer survival analysis of KC and KC;Sod2−/− mice did not indicate faster progression to cancer, suggesting that for later steps additional signaling is needed. In summary, we identify MnSOD as a key antioxidant molecule preventing initiation of PDA.
Citation Format: Alicia K. Fleming Martinez, Brandy H. Edenfield, Irene Esposito, Peter Storz. Knockout of Sod2 accelerates KrasG12D-driven formation of pancreatic cancerous lesions. [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 4775.
Abstract 4778: Novel bioluminescence approaches for measuring fatty acid β-oxidation and production of reactive oxygen and nitrogen species
Authors: Haupt Kim , Larsen Matt , Wang Hui , Karassina Natasha , Valley Mike , Zhou Wenhui , Vidugiriene Jolanta 
Published: April 2023

Abstract
Energy uptake and utilization in eukaryotic cells is a dynamic process regulated by a series of interacting metabolic networks. Interrogation of this complex network relies on rapid, sensitive approaches that do not require extensive sample handling and are easily adaptable to 96- and 384-well plates. Previously, using the Ultra-Glo luciferase reaction we developed a panel of bioluminescent assays that can be used to monitor numerous aspects of cellular metabolism and mitochondrial function including ATP production, glucose and amino acid metabolism, and the TCA cycle. Here, we extend the use of the luciferase reaction and report on the development of novel bioluminescence probes for studying two important metabolic cellular responses: fatty acid β-oxidation (FAO) and production of reactive oxygen and nitrogen species. For studying FAO, we developed a cell permeable probe with caged-luciferin attached to a fatty acid chain. The probe enters the cells and following FAO cycling, free luciferin is released and detected using Luciferin Detection Reagent. We validated the approach using known FAO activators and inhibitors and used it to monitor the changes in FAO during T-cell activation. For measuring reactive oxygen and nitrogen species, highly selective bioluminescence probes were developed. Upon reaction of the probes with their corresponding ROS target, they form the stable D-luciferin reporter molecule, causing luciferin to accumulate. Upon treatment with luciferase in the detection step, the generated light allows for quantification of the superoxide or nitric oxide formed. Both probes are suitable for in vitro and cell-based detection of ROS in an “add and read” format, providing for a simple workflow amenable to high throughput experimentation.
Citation Format: Kim Haupt, Matt Larsen, Hui Wang, Natasha Karassina, Mike Valley, Wenhui Zhou, Jolanta Vidugiriene. Novel bioluminescence approaches for measuring fatty acid β-oxidation and production of reactive oxygen and nitrogen species. [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 4778.
Abstract 4782: A biflavonoid TY1 induced mitochondrial oxidative stress in 5-fluorouracil-resistant colorectal cancer cells to suppress tumor progression
Authors: Jian Ting-Yan , Sung Shian-Ying , Lin Yu-Ling 
Published: April 2023

Abstract
The high metastasis and drug resistance of colorectal cancer (CRC) cause high mortality and rank third among the top ten cancer deaths. TY1 is a biflavonoid isolated from Taxus x media cv. Hicksii. We have previously reported that TY1 inhibits metastatic behavior by inhibiting F-actin polymerization. However, the biological activities of TY1 to overcome drug resistance remain unclear. In this study, we investigated the pharmacological mechanism of TY1 for inhibiting 5-fluorouracil (5-FU)-resistant CRC cells and its therapeutic effect. The 5-FU sensitive (COLO205) and 5-FU resistant (HT-29) CRC cells were used to determine the antitumor activity of TY1. Bioinformatic analysis was conducted to explore the antitumor effects of TY1 in 5-FU resistant HT-29 cells. The effects of TY1 on 5-FU-resistant CRC cells were determined by cell-based analyses, including MTT assay, cellular and mitochondrial ROS-superoxide detection, and confocal images. Finally, the therapeutic effects of TY1 were evaluated in HT-29 xenograft CRC mice. We found TY1 inhibited cell proliferation but did not affect the cell cycle. TEM images showed that TY1 induced vacuole production. Transcriptome data indicated that interferon-related genes specifically mitochondrial interferon alpha-inducible protein (IFIP) were significantly decreased after TY1 treatment. TY1 increased oxidative stress generated by reactive oxygen species (ROS) and superoxide. When IFIP was overexpressed, TY1-induced oxidative stress was reduced. In xenograft CRC mouse, TY1 effectively inhibited tumor growth. The anticancer activity of TY1 is attributed to TY1-induced ROS and superoxide by downregulating mitochondrial IFIP expression. Therefore, these data suggest that TY1 may be a promising new compound in the treatment of 5-FU-resistant CRC.
Citation Format: Ting-Yan Jian, Shian-Ying Sung, Yu-Ling Lin. A biflavonoid TY1 induced mitochondrial oxidative stress in 5-fluorouracil-resistant colorectal cancer cells to suppress tumor progression. [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 4782.
Abstract 479: Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells
Authors: Jiang Chunxue , Zheng Tian , Cha HwaYoung , Kim Hyung Sik 
Published: April 2023

Abstract
Pyruvate kinase M2 (PKM2) is a key enzyme involved in the regulation of glycolysis. Although PKM2 is overexpressed in various tumor tissues, its functional role in cancer chemotherapy remains unclear. In this study, we investigated the anticancer activity of novel PKM2 inhibitors in the regulation of cell metabolism and its associated pathways in prostate cancer cells. To evaluate the molecular basis of specific PKM2 inhibitors, the interactions of compounds 3h and 3K with the PKM2 protein were assessed via molecular docking. We found that, compared to compound 3K, compound 3h exhibited a higher binding affinity for PKM2. Moreover, compound 3h significantly inhibited the pyruvate kinase activity and PKM2 expression. Cytotoxicity and colony formation assays revealed the potent anticancer activity of compound 3h against LNCaP cells. Compound 3h significantly increased the apoptotic and autophagic cell death in LNCaP cells. In addition, compound 3h induced AMPK activation along with the inhibition of mTOR/p70S6K pathway. Furthermore, compound 3h significantly inhibited glycolysis and mitochondrial respiration, as determined by analyzing extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) production. Our results revealed that compound 3h caused apoptotic and autophagic cell death by inhibiting cancer cell metabolism in LNCaP cells. Therefore, blocking glycolytic pathways using specific PKM2 inhibitors can be used to target cancer cell metabolism in PKM2-overexpressed prostate cancer cells.
Citation Format: Chunxue Jiang, Tian Zheng, HwaYoung Cha, Hyung Sik Kim. Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells [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 479.
Abstract 4804: p38 MAPK-dependent regulation of HIF-1 and expression of the hypoxia-inducible gene IGFBP-3 in leiomyosarcoma cells
Authors: Haque Nuha , Shelden Eric 
Published: April 2023

Abstract
Hypoxia is a common feature of tumor microenvironments and stimulates a variety of responses in a cell. Tumor hypoxia is also associated with poor prognosis in soft tissue sarcomas (STS), including leiomyosarcomas. Genes upregulated under hypoxia contribute to the adaptation of tumor cells and promote tumor progression. Using transcriptome-wide gene expression analysis, we identified IGFBP-3 as one of the most highly upregulated genes in SK-LMS-1 leiomyosarcoma cells in hypoxic conditions. IGFBP-3 has been studied in several tumor types, including STS, and is associated with their altered pathogenesis. Mechanisms responsible for the hypoxia-induced expression of IGFBP-3 in STS have not been previously well defined. Hypoxia results in the stabilization of the hypoxia-inducible transcription factor, HIF-1, and production of reactive oxygen species (ROS) in other cell types. Here, we examined HIF-1 and ROS-dependent mechanisms to determine their roles in the hypoxia-induced expression of IGFBP-3 and other genes in SK-LMS-1 cells. Our data indicate that both ROS production and HIF-1 activation are required for the enhanced IGFBP-3 mRNA expression in hypoxic SK-LMS-1 cells. We also tested the roles of the stress activated protein kinase p38 and the tumor suppressor p53 for their potential to contribute to the regulation of IGFBP-3 expression in these cells. Inhibition of p53 tumor suppressor activity only partially reduced IGFBP-3 expression. We also determined that neither hypoxia nor inhibition of p53 affected the expression of the p53 target gene, CDKN1A (p21), in these cells. In contrast, inhibition of p38 MAPK completely prevented the hypoxia-induced increase in IGFBP-3 expression. Additionally, we found that p38 MAPK inhibition reduced HIF-1 protein accumulation and activity but had no effect on its mRNA expression under hypoxic conditions. Together these results suggest that ROS-dependent activation of p38 MAPK stabilizes HIF-1 and promotes the downstream expression of IGFBP-3. In contrast, p53 appears to have a limited effect on the expression of IGFBP-3 in SK-LMS-1 cells. Our results clarify the signaling pathway involved in the response of soft tissue sarcoma cells to hypoxia and may provide new avenues for intervention in cancer progression.
Citation Format: Nuha Haque, Eric Shelden. p38 MAPK-dependent regulation of HIF-1 and expression of the hypoxia-inducible gene IGFBP-3 in leiomyosarcoma cells. [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 4804.