bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4391: The UBE2F-CRL5Asb11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells
Authors: Sun Yi , Chang Yu , Che Qian , Li Hua , Xu Jie , Tan Mingjia , Xiong Xiufang 
Published: March 2024

Abstract
UBE2F is a neddylation E2 that couples with RBX2/SAG E3 to promote CUL-5 neddylation and Cullin-RING ligase-5 (CRL5) activation. Whether and how UBE2F regulates pancreatic tumorigenesis is previously unknown. Here we showed that UBE2F is growth essential for pancreatic cancer cells with KRAS mutant in culture. In KrasG12D mouse PDAC model, Ube2f deletion suppresses cerulein-induced pancreatitis, and progression of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Mechanistically, Ube2f deletion inactivates the Mapk-c-Myc signal pathways via blocking ubiquitylation and degradation of Diras2, which is a new substrate of Cul5Asb11 E3 ligase. Biologically, DIRAS2 suppresses growth and survival of pancreatic cancer cells with KRAS mutant, and Diras2 deletion largely rescued the phenotypes induced by Ube2f deletion, indicating its causal role. Collectively, Ube2f or Diras2 plays a tumor-promoting or tumor-suppressive role in KrasG12D PDAC model, respectively. The Ube2f-CRL5Asb11 axis could serve as a valid target for pancreatic cancer, whereas the levels of UBE2F or DIRAS2 may serve as prognostic biomarkers for PDAC patients.
Citation Format: Yi Sun, Yu Chang, Qian Che, Hua Li, Jie Xu, Mingjia Tan, Xiufang Xiong. The UBE2F-CRL5Asb11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4391.
Abstract 4430: Metabolic reprogramming by ASPSCR1::TFE3 and VCP
Authors: Patel Rahi , Pozner Amir , Dunlap Kyle , Carroll Lara , Brown Jeff , Ducker Greg , Jones Kevin 
Published: March 2024

Abstract
Alveolar soft part sarcoma (ASPS) is a lethal soft tissue malignancy typically incident among adolescents and young adults, distinguished by the t(X;17) ASPSCR1::TFE3 fusion gene (AT3). Conventional chemotherapy has shown limited efficacy against ASPS, necessitating exploration of alternative strategies. Previous investigations have shown the pivotal role of the fusion gene in sarcomagenesis in mice, particularly in lactate-rich environments. This study aims to elucidate the metabolic alterations actuated by the AT3 fusion gene, both in vitro and in vivo. To model in vitro metabolic profiles, ASPS (ASPS-1) and renal cell carcinoma (FU-UR1) cell lines, each expressing AT3, were employed. Utilizing siRNA-mediated gene silencing, AT3 and VCP, a cofactor, were targeted in vitro. Metabolomic profiling through GC-MS analyzed the impact of depletion of AT3 or its transcriptional co-factor, VCP. C13-labeled metabolites were introduced and traced in vitro and in vivo to enhance comprehension of carbon utilization in aerobic respiration. While metabolic activity and O2 consumption differed between cell lines, inhibition of AT3 and VCP led to similar metabolite alterations. Significant changes in amino acid metabolism, notably glutamate, aspartate, and alanine were observed in both cell lines. There was notable diversion of glucose carbon utilization away from typical entry into the tricarboxylic acid (TCA) cycle, with minimal carbon incorporation beyond alpha-ketoglutarate. Despite prior data indicating heightened mitophagy activity in AT3 driven cells, inhibition of lysosomal activity did not yield significant changes in cellular respiration or O2 consumption.
Citation Format: Rahi Patel, Amir Pozner, Kyle Dunlap, Lara Carroll, Jeff Brown, Greg Ducker, Kevin Jones. Metabolic reprogramming by ASPSCR1::TFE3 and VCP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4430.
Abstract 4447: ZC3H18: A novel regulator of NAD+ metabolism in high-grade serous ovarian cancer
Authors: Wilson Benjamin , Wilson Natalie , Chen Xianfeng , Zhang Shuwen , Wang Chen , Karnitz Larry M. , Kaufmann Scott H. , Kanakkanthara Arun 
Published: March 2024

Abstract
ZC3H18 is a multifunctional regulator of gene expression that is lost in a subset of high-grade serous ovarian cancers (HGSOC). Our prior studies have established that the loss of ZC3H18 diminishes BRCA1 levels, leading to the disruption of homologous recombination DNA repair (HR) and heightened sensitivity of HGSOC cells to PARP inhibitors. Here we show an additional facet to ZC3H18's impact, showing that its loss also induces a reprogramming of energy metabolism in HGSOC. Our findings demonstrate that the depletion of ZC3H18 results in reduced mRNA and protein levels of the NAD+-biosynthetic enzyme, NMNAT1, in HGSOC cells. Mechanistic studies uncovered that ZC3H18 occupies the NMNAT1 promoter, facilitating NMNAT1 transcription by recruiting CDK12 onto the promoter. Consistent with this mechanism, loss of ZC3H18 led to a reduction in CDK12 levels on the NMNAT1 promoter, diminishing NMNAT1 abundance and subsequently causing a decline in cellular NAD levels. These observations unveil a previously unknown role for ZC3H18 in HGSOC, shedding light on its involvement in the regulation of energy metabolism. Importantly, our findings provide valuable insights into potential therapeutic pathways that leverage the metabolic changes linked to ZC3H18 deficiency.
Citation Format: Benjamin Wilson, Natalie Wilson, Xianfeng Chen, Shuwen Zhang, Chen Wang, Larry M. Karnitz, Scott H. Kaufmann, Arun Kanakkanthara. ZC3H18: A novel regulator of NAD+ metabolism in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4447.
Abstract 4455: Metabolic stress induces a double positive feedback loop between AMPK and p62 conferring dual activation of AMPK and NRF2 to synergize antioxidant defense
Authors: Choi Eun-Ji , Oh Hyun-Taek , Lee Seon-Hyeong , Zhang Chen-Song , Li Mengqi , Kim Soo-Youl , Park Sunghyouk , Chang Tong-Shin , Lee Byung-Hoon , Lin Sheng-Cai , Jeon Sang-Min 
Published: March 2024

Abstract
Co-occurring mutations in KEAP1 in LKB1-mutant NSCLC activate NRF2 to compensate losing LKB1-AMPK activity during metabolic adaptation and survival. Here, we investigated the regulatory crosstalk between LKB1-AMPK and KEAP1-NRF2 pathways during metabolic stress. We found that metabolic stress activates NRF2 through the expression and phosphorylation of p62, causing the autophagic degradation of KEAP1. Intriguingly, the induction of p62 during metabolic stress is also required to activate AMPK by promoting AXIN-LKB1-AMPK complex formation and recruiting it to the lysosomal membrane. Importantly, the p62-driven dual-activation of AMPK and NRF2 was critical for tumour growth by synergizing antioxidant defences. In turn, the induction of p62 also required LKB1-AMPK activity, suggesting a double positive feedback loop between AMPK and p62. Mechanistically, the increase in lysosomal pH caused by low glucose metabolism and AMPK-dependent reduction of proton generation induced PP2A-dependent dephosphorylation of TFEB/TFE3 which increased the expression of p62. The increase of ROS caused by metabolic stress induced lysosomal MCOLN1-Ca2+ dependent activation of TAK1 which increased p62 phosphorylation. Protons provided by lactic acid abrogated all the effects caused by metabolic stress. This positive feedback loop between AMPK and p62 that activates AMPK and NRF2 can potentially explain why co-occurring mutations in LKB1 and KEAP1 occur and further provide promising therapeutic strategies for lung cancer.
Citation Format: Eun-Ji Choi, Hyun-Taek Oh, Seon-Hyeong Lee, Chen-Song Zhang, Mengqi Li, Soo-Youl Kim, Sunghyouk Park, Tong-Shin Chang, Byung-Hoon Lee, Sheng-Cai Lin, Sang-Min Jeon. Metabolic stress induces a double positive feedback loop between AMPK and p62 conferring dual activation of AMPK and NRF2 to synergize antioxidant defense [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4455.
Abstract 4457: Skeletal muscle-infiltrating CD8 T cells exacerbate muscle atrophy in a syngeneic lung cancer cachexia mouse model
Authors: Park Se-Young , Kim Bomi , Lee Myunggyo , Lee Haeseung , Song Na-Young 
Published: March 2024

Abstract
Cancer-associated cachexia (CAC) is a devastating syndrome of irreversible body weight loss and muscle wasting. CAC has been reported to often lead to poor outcomes of immune checkpoint inhibitors (ICIs), emerging as a standard treatment for various types of cancer. Previously, we have demonstrated that KRAS-mutant lung tumor tissues display an immunosuppressive microenvironment with decreased CD8 T cells and increased regulatory T cells (Tregs). In this orthotopic lung cancer mouse model, treatment with an anti-PD-L1 antibody, a representative ICI, reduced tumor burden, whereas accelerated loss of body weight and skeletal muscle mass. We thus assumed that CD8 T cells could facilitate skeletal muscle wasting in lung tumor-bearing mice, a key feature of CAC. First, we established a syngeneic CAC mouse model through orthotopic transplantation of murine lung cancer cells. At 7 weeks post-injection, these mice developed CAC, displaying over 20 % body weight loss, almost total loss of epididymal fats, and profound skeletal muscle wasting. In line with our assumption, CAC mice showed an increased number of CD8 T cells but a reduced number of Tregs in skeletal muscles, compared to tumor-free control mice. We then investigated whether skeletal muscle-infiltrating CD8 T cells directly induce muscle atrophy indeed. In CAC mice, CD8 neutralization led to restoration of muscle mass and downregulation of muscle atrophy markers, but was not able to significantly affect lung tumor burden. Moreover, direct co-culture with splenic CD8 T cells exacerbated C2C12 myotube atrophy in a conditioned medium from lung cancer cells, further supporting the involvement of CD8 T cells in CAC. To elucidate its underlying mechanism, RNA sequencing analysis was conducted in both skeletal muscles and lung tumors of CAC mice. Based on the differently expressed gene analysis, Cxcl13 was upregulated in skeletal muscles of CAC mice, while downregulated in lung tumors. It is well documented that CXCL13 can mediate recruitment of CD8 T cells. In this regard, CXCL13 might be a plausible regulator in CD8 T cell-induced skeletal muscle atrophy, which requires further investigation to fully understand the molecular mechanism.
Citation Format: Se-Young Park, Bomi Kim, Myunggyo Lee, Haeseung Lee, Na-Young Song. Skeletal muscle-infiltrating CD8 T cells exacerbate muscle atrophy in a syngeneic lung cancer cachexia mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4457.
Abstract 4461: Unveiling the links between methionine metabolism and epigenomic reprogramming in upper aerodigestive squamous cell carcinoma
Authors: Nam Chehyun 
Published: March 2024

Abstract
Upper aerodigestive squamous cell carcinoma (UASCC) presents as a prevalent and aggressive malignancy, posing challenges in terms of effective therapeutic interventions. In this study, we explored the intricacies of amino acid metabolism within UASCC, revealing an unexpected observation that distinguishes UASCC among all human cancers, having the highest methionine levels, driven by the overexpression of its transporter LAT1. Notably, LAT1 exhibits peak expression levels in UASCC, regulated at the transcriptional level by UASCC-specific promoters and enhancers, co-regulated by SCC master regulators TP63/KLF5/SREBF1.Surprisingly, our unbiased bioinformatic screen identifies EZH2 as a pivotal downstream target of the LAT1-methionine pathway, establishing a direct link between methionine metabolism and epigenomic reprogramming. This cascade emerges as crucial for the survival and proliferation of UASCC patient-derived tumor organoids. Furthermore, we find that LAT1 expression closely correlates with cellular sensitivity to inhibition of the LAT1-methionine-EZH2 axis.Significantly, the newly discovered LAT1-methionine-EZH2 cascade emerges as a promising target for intervention, with effective outcomes achievable through both pharmacological approaches and dietary interventions in vivo. In summary, this research unveils a novel mechanistic crosstalk connecting epigenomic reprogramming with methionine metabolism, revealing its biological significance in UASCC. Moreover, it identifies a unique tumor-specific vulnerability, providing avenues for exploitation through both pharmacological and dietary strategies
Citation Format: Chehyun Nam. Unveiling the links between methionine metabolism and epigenomic reprogramming in upper aerodigestive squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4461.
Abstract 4476: Novel auristatins with improved tolerability and unique bystander activity profile
Authors: Moquist Philip N. , Eng-Duncan Nicole M. , Bovee Tim , Snead Katie , Wright Jenn , Smith Kaleb , Blevins Teri , Blackburn Brittney , Ulrich Michelle , Magunda Forgivemore , Simmons Jessica , Senter Peter D. , Doronina Svetlana O. 
Published: March 2024

Abstract
Auristatins are a class of clinically validated payloads used extensively in antibody-drug conjugate (ADC) technology. There are currently 4 FDA approved ADCs utilizing the vedotin drug linker to treat an array of solid tumors and lymphomas and several more in clinical trials. Auristatin payloads have several desirable properties, including strong anticancer cytotoxicity, bystander activity, and induction of immunologic cell death. While auristatin-based ADCs have been remarkably successful, there remain opportunities to further understand and improve payload properties. Bystander activity is one such property that can greatly impact the balance between efficacy and tolerability. Herein, we present a medicinal chemistry investigation into a series of auristatins with similar tubulin binding and biochemical potency that differ in lipophilicity and ability to cross the cell membrane. This design enabled us to focus on and characterize the impact of bystander activity while maintaining all other parameters. Ultimately, this effort resulted in ADCs with similar on-target in vitro cytotoxicity but differed in the extent of off-target bystander activity. Evaluation of in vivo efficacy, in vivo bystander activity, and rodent tolerability afforded a lead drug linker that was well-tolerated as an ADC and exhibited strong antitumor growth delay.
Citation Format: Philip N. Moquist, Nicole M. Eng-Duncan, Tim Bovee, Katie Snead, Jenn Wright, Kaleb Smith, Teri Blevins, Brittney Blackburn, Michelle Ulrich, Forgivemore Magunda, Jessica Simmons, Peter D. Senter, Svetlana O. Doronina. Novel auristatins with improved tolerability and unique bystander activity profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4476.
Abstract 4509: Discovery of potent and highly efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression
Authors: Acharyya Ranjan K. , Bai Longchuan , Zhao Haibin , Wu Dimin , Hoda Metwally , Donna McEachern , Bo Wen , Sun Duxin , Wang Shaomeng 
Published: March 2024

Abstract
STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic targets for cancer and other human diseases. We have previously reported the discovery of SD-36 and SD-91 as potent, selective and highly efficacious STAT3 degraders. In the present study, we report the discovery of highly potent, selective and efficacious new STAT3 degraders. These STAT3 degraders were designed using our high-affinity STAT3 ligands and high-affinity VHL-1 ligands, with UM-STAT3-3100 being the best. In direct comparison, UM-STAT3-3100 is &gt;10-times more potent than SD-36 and SD-91 in inducing STAT3 degradation in cells and are highly selective over other STAT members in vitro and in vivo. A single intravenous administration of UM-STAT3-3100 resulted in complete and long-lasting depletion of STAT3 protein for &gt;48 hrs in tumor and native tissues. Weekly administration of UM-STAT3-3100 at 10 mg/kg achieved complete and long-lasting tumor regression in animal models of human cancer without any signs of toxicity. UM-STAT3-3100 is a promising compound for extensive evaluation for the treatment of human cancers and other human diseases in which STAT3 plays a key role.
Citation Format: Ranjan K. Acharyya, Longchuan Bai, Haibin Zhao, Dimin Wu, Metwally Hoda, McEachern Donna, Wen Bo, Duxin Sun, Shaomeng Wang. Discovery of potent and highly efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4509.
Abstract 4540: SY-7021, a novel DNA-PK inhibitor, exhibits significant anti-tumor activity in vitro and in vivo
Authors: Zhang Kai , Liu Zhihua , Gao Yuhao , Lu Chang , Cheng Shikang , Liu Xijie , Luo Hong , Sun Yinghui 
Published: March 2024

Abstract
Cancer therapies such as ionizing radiation or topoisomerase II inhibitors (for example, doxorubicin) induce DNA double-strand breaks (DSBs), which can subsequently be repaired by homologous recombination or non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine protein kinase complex, is a pivotal component of the NHEJ process that maintain genome integrity. The critical role of DNA-PK in DNA damage response (DDR) and the dysregulated DNA-PK expression in cancer make it an intriguing therapeutic target for cancer, especially when combined with DSBs agents. Here, we identified a highly potent and selective DNA-PK inhibitor, SY-7021, with an IC50 value of 0.242 nM on DNA-PK kinase and high selectivity on ATM and ATR (greater than 400-fold) in biochemical assays. In a reporter assay for NHEJ repair, SY-7021 was able to dose-dependently reduce cellular NHEJ efficiency. Functionally, SY-7021 inhibited cell proliferation in multiple cancer cell lines alone or combined with doxorubicin. Basically, combination of SY-7021 and doxorubicin induced significant G2/M phase arrest and cell apoptosis, as well as enhanced the phosphorylation on Ser139 of γH2AX, Tyrosine 68 of CHK2 and Serine15 of p53 in MDA-MB-468 cells. In a subcutaneous NCI-H1703 xenograft tumor model, SY-7021 administered orally twice daily achieved dose-dependent tumor growth inhibition in vivo, with a tumor growth inhibition (TGI) of 105.6% at 60 mg/kg and no significant weight loss was observed. In addition, SY-7021 demonstrates good PK properties and acceptable safety profiles in in vivo studies. Collectively, SY-7021, a potent and selective DNA-PK inhibitor, shows significant inhibition on tumor growth in in vitro and in vivo studies, providing a rationale treatment for multiple tumors in monotherapy or in combination with other agents.
Citation Format: Kai Zhang, Zhihua Liu, Yuhao Gao, Chang Lu, Shikang Cheng, Xijie Liu, Hong Luo, Yinghui Sun. SY-7021, a novel DNA-PK inhibitor, exhibits significant anti-tumor activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4540.
Abstract 456: A first comprehensive analysis of transcribed ultra conserved regions uncovers important regulatory functions of novel non-coding transcripts in gliomas
Authors: Gibert Myron K. , Abounader Roger 
Published: March 2024

Abstract
Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new oncogene. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein, by sponging the tumor suppressor miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.
Citation Format: Myron K. Gibert, Roger Abounader. A first comprehensive analysis of transcribed ultra conserved regions uncovers important regulatory functions of novel non-coding transcripts in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 456.