bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5807: MDM2 mitochondrial translocation mediates metabolic reprogramming towards OXPHOS in TKI-resistant oncogene-addicted cancer
Authors: Eu Jie Qing , Kong Li Ren , Hirpara Jayshree , Goh Boon Cher , Wong Andrea LA , Pervaiz Shazib 
Published: June 2022

Abstract
There is mounting evidence of oxidative phosphorylation (OXPHOS) dependency in cancers resistant to tyrosine kinase inhibitors (TKI), but the cause of this metabolic switch remains elusive. Mitochondria-bound MDM2 (mtMDM2), the fraction of MDM2 oncoprotein which is actively imported into the mitochondria, has been found to dysregulate electron transport chain (ETC) complex I function and OXPHOS. AKT is known to be a regulator of MDM2 protein stability. Given that AKT phosphorylation is commonly detected in oncogene-addicted tumours, we investigated the role of mtMDM2 and AKT in promoting TKI resistance through reprogrammed cellular metabolism. EGFR+ NSCLC [HCC827 and HCC827-GR (gefitinib-resistant)] and BRAF+ melanoma [A375 and A375-VR (vemurafenib-resistant)] cells were established via repetitive pulsed strategy. Translocation of MDM2 was examined through subcellular fractionation and Western Blotting. To investigate the role of MDM2 in mediating OXPHOS, genetic knockdown of MDM2 was performed via siRNA followed by measurement of oxygen consumption rate (Seahorse Analyzer); mRNA expression of mtDNA-encoded ETC subunits by real-time PCR (qPCR). ChIP-qPCR analysis was performed to examine the binding affinity of MDM2 and TFAM (mitochondrial transcription factor A) to mitochondrial DNA (mtDNA). Mitochondrial translocation of MDM2 was predominant in TKI-sensitive cells; MDM2 silencing upregulated OXPHOS and induced mRNA expression of mtDNA-encoded ETC complex I subunits, suggesting that mtMDM2 inhibits OXPHOS. ChIP analysis revealed competitive binding of MDM2 and TFAM at the LSP region of mtDNA. Conversely, MDM2 was primarily localized the cytoplasm in TKI-resistant cells and was associated with increased OXPHOS in TKI-resistant cells. Mechanistically, both pAKT and pMDM2 (Ser166/Ser186) were higher in TKI-resistant cells. Collectively, we describe a novel observation that OXPHOS upregulation underpinning TKI resistance in cancer cells could be mediated by AKT upregulation and MDM2 localisation.
Citation Format: Jie Qing Eu, Li Ren Kong, Jayshree Hirpara, Boon Cher Goh, Andrea LA Wong, Shazib Pervaiz. MDM2 mitochondrial translocation mediates metabolic reprogramming towards OXPHOS in TKI-resistant oncogene-addicted cancer [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 5807.
Abstract 5819: Tumor nutrient conditions confer drug resistance in pancreatic cancer
Authors: Sheehan Colin , Martin James , Croley Grace , McKeever Joshua , Thomas-Toth Anika , Jonker Patrick , LaBelle James , Koh Andrew , Muir Alexander 
Published: June 2022

Abstract
Drug resistance is a major obstacle to the treatment of pancreatic ductal adenocarcinoma (PDAC). Current standard of care includes combination chemotherapies; however, the majority of patients fail to respond to these treatments. Despite significant advances in our understanding of PDAC biology, it remains unclear what biological processes drives the drug resistance observed in most PDAC cases. Contributing to our limited understanding of this problem, in vitro models of PDAC fail to recapitulate in vivo drug resistance, suggesting the tumor microenvironment is a critical regulator.A defining feature of PDAC tumors is an abnormal nutrient environment, which may carry important biological cues driving many of the undesirable cell behaviors related to disease progression. Using a novel medium formulation that mimics the nutrient conditions observed within PDAC tumors (TIFM), we find that PDAC cells cultured in TIFM become highly resistant to common chemotherapeutic agents, better recapitulating the in vivo drug resistance phenotype than standard cultures. Several of these agents engage with their intended target in TIFM cultured cells, discouraging the idea that drug resistance is primarily mediated by drug efflux. However, TIFM cultured cells display reduced apoptotic priming, enabling their survival to drug exposure. Drug resistance enabled by TIFM nutrients is not immediately reversible with standard culture and can be inherited over multiple cell generations. Consistent with this, we find that TIFM nutrient conditions results in significant alterations to the epigenetic landscape of pancreatic cancer cells, rewiring expression of genes that may function as critical regulators of cell survival in PDAC. Ultimately, the work from this project will help elucidate how poor nutrient perfusion within solid tumors regulates cell survival processes and may lead towards better treatment options for PDAC patients beyond combination chemotherapy.
Citation Format: Colin Sheehan, James Martin, Grace Croley, Joshua McKeever, Anika Thomas-Toth, Patrick Jonker, James LaBelle, Andrew Koh, Alexander Muir. Tumor nutrient conditions confer drug resistance in pancreatic cancer [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 5819.
Abstract 5832: Utilizing small noncoding RNAs as biomarkers for selinexor treatment in gastric cancer
Authors: Sexton Rachel E. , Aboukameel Amro , Li Yiwei , Khan Husain Y. , Uddin Md Hafiz , Kashyap Trishyan , Landesman Yosef , Tesfaye Anteneh , Azmi Asfar S. 
Published: June 2022

Abstract
Gastric cancer is a deadly disease with a low 5-year survival rate of 32%. This disease is characterized by high rates of chemo resistance and late initial detection. We have previously reported that inhibition of nuclear exporter protein Exportin 1 (XPO1/CRM1) with the small molecule inhibitor selinexor (KPT-330) is a viable therapeutic approach in gastric cancer. Inhibition of XPO1 blocks proliferation and suppresses tumor growth through nuclear retention of tumor suppressor proteins such as TP53. Besides nuclear retention, we also demonstrated that XPO1 inhibition leads to a perturbation of cancer specific microRNAs including microRNA-7974 downregulation (miR-7974) and microRNA-129-1-3p upregulation (miR-129-1-3p) within a small RNA sequencing study. In this study we evaluated the role of these microRNAs in gastric cancer perpetuation in respect to their naive functions in five distinct subtypes of gastric cancer. Our results show over-expression of miR-7974 and loss of miR-129-1-3p promotes gastric cancer growth and progression, based on specific subtype of disease. We have further found that the differential expression of these microRNAs leads to gastric cancer cellular changes including cell cycle alterations, upregulation of autophagy processes, chemoresistance and alterations in the cellular framework leading to more invasive phenotypes. Validation with normal gastric epithelial cells revealed these microRNAs are relevant as they are perturbed in gastric cancer as well as the proteins in which they modulate. Finally, we have validated treatment of gastric cancer cells with the XPO1 inhibitor selinexor altered the expression of miR-7974 and miR-129-1-3p differently, based on subtype, as we have previously observed in small RNA sequencing screen, leading to a reversal of the pro-cancerous phenotypes previously observed. In vivo investigation is currently ongoing to identify whether we can capture either miR-7974 or miR-129-1-3p within the serum as further evidence of microRNA perturbation as a predictive biomarker for selinexor efficacy.
Citation Format: Rachel E. Sexton, Amro Aboukameel, Yiwei Li, Husain Y. Khan, Md Hafiz Uddin, Trishyan Kashyap, Yosef Landesman, Anteneh Tesfaye, Asfar S. Azmi. Utilizing small noncoding RNAs as biomarkers for selinexor treatment in gastric cancer [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 5832.
Abstract 5834: Examining the potential oncogenic function of septins and their interaction with Chmp1A tumor suppressor in pancreatic cancer
Authors: Cai Mei , Amor Joseph , Park Maiyon 
Published: June 2022

Abstract
Introduction: Chmp1A functions as a tumor suppressor by the activation of ATM and p53 in pancreatic cancer. The nuclear localization signal (NLS) of Chmp1A is required for cell growth inhibition and activation of ATM and p53. Proteomic analysis has identified Septins (a group of GTP-binding proteins) to be associated with the NLS-deleted Chmp1A. Since NLS-deleted Chmp1A promotes cancer cell growth, we hypothesized that Septins may function as oncogenes and that Chmp1A functions as a tumor suppressor partly by inhibiting the oncogenic action of Septin proteins.
Objective: To examine whether Septin proteins exhibit oncogenic activity and to investigate whether Chmp1A inhibits the oncogenic function of Septins.
Methodology: Using normal pancreatic and cancer cells, we compared Septin transcripts using PCR assays, Septin protein expression using Western blot, and Septin cellular expression using immunocytochemistry. We performed immunohistochemical analysis to examine whether Septin expression is increased in pancreatic cancer tissues compared to corresponding normal tissues. Silencing technology was used to test whether Septin expression is regulated by Chmp1A.
Results: Our preliminary data indicates that the transcript and protein of Septins are increased in various pancreatic cancer cell lines compared to normal. Septin protein expression was increased or altered in human pancreatic ductal adenocarcinoma tissues compared to corresponding normal tissues. Additionally, our data implies that Chmp1A negatively regulates Septin expression, since Septin transcripts and proteins are increased when Chmp1A protein is silenced.
Summary and future direction: Our data suggests that Septin functions as an oncogene in pancreatic cancer cells and that Chmp1A functions as a tumor suppressor partly by inhibiting the oncogenic action of Septin proteins. For the completion of the project in the future, we plan to confirm the function of Septins by investigating the effect of Septin overexpression on pancreatic cancer cell proliferation. In addition, we will further investigate the interaction between Septins and Chmp1A by examining Septin expression and localization in pancreatic cancer cells that overexpress Chmp1A.
Citation Format: Mei Cai, Joseph Amor, Maiyon Park. Examining the potential oncogenic function of septins and their interaction with Chmp1A tumor suppressor in pancreatic cancer [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 5834.
Abstract 5838: The landscape of EGFR exon 20 insertion mutations in Chinese patients with non-small cell lung cancer
Authors: xu shun , Fu Zhichao 
Published: June 2022

Abstract
Background: The epidermal growth factor receptor (EGFR) is one of the most commonly altered genes in non-small cell lung cancer(NSCLC). Of these, insertion mutation in 20 exon (Ex20ins) of the EGFR occurs less frequently. In comparison with the common EGFR mutations (19Del/L858R), the NSCLC patients with Ex20ins have a worse prognosis. Recently, the FDA approved targeted oral therapeutic agent for NSCLC patients with EX20ins mutation, which has markedly improved their survival. Here we carry out a complete analysis of the frequency and types of EGFR 20 Exon insertion mutations in the large-scale NSCLC cohort of the Chinese population.
Methods: From January 2020 to October 2021, a total of 4,091 patients were confirmed as NSCLC were included in the study. The Next-generation sequencing was utilized for detecting genetic mutations.
Results: Among the 4,091 NSCLC patients, 2,411 (58.9%) experienced EGFR mutations. In which we identified 90 patients(2.2%) with Ex20ins. All of the Ex20ins were localized between amino acids S767-V774, and after C-helix of the EGFR kinase domain. Different from the exon 19 deletion, we found that Ex20ins exhibits various types of mutations. A total of 34 Ex20ins types were detected, with the most common A767_V769dupASV and S768_D770dupSVD mutations, accounting for 26% and 22.2% respectively. In addition, H773dupH (6.67%), H773_V774dupHV(5.56%), H773_V774insAH (2.22%), D770_N771insG (2.22%), and N771_P772insG(2.22%) were also observed in the NSCLC patients.
Conclusions: We described the landscape of EGFR Ex20ins in Chinese NSCLC patients cohort. Based on the large sample size, the frequency of the Ex20ins mutation in Chinese NSCLC patients was 2.2%, and the types of EGFR Ex20ins mutation were highly heterogeneous.
Citation Format: shun xu, Zhichao Fu. The landscape of EGFR exon 20 insertion mutations in Chinese patients with non-small cell lung cancer [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 5838.
Abstract 5841: Discovery of a novel epigenetic regulatory axis that mediates sorafenib's antineoplastic activity
Authors: Wei Tianzi , Wang Hao , Lin Risheng , Li Yueming , Lu Yi , Zhang Jian 
Published: June 2022

Abstract
As a multi-kinase inhibitor, sorafenib has been widely used to treat advanced hepatocellular carcinoma patients since 2007. Sorafenib, however, is associated with severe drug adverse effects and drug resistance. Therefore, the strategies to improve the antineoplastic effects of sorafenib are urgently needed. In this study, we observed that metallothionein-1G (MT1G), was significantly activated by sorafenib and mediated sorafenib’s antineoplastic activity both in vitro and in vivo. Our study also proved that sorafenib effectively inhibited the activity of several critical enzymes required for maintaining methylation level in hepatoma cells to activate MT1G. In addition, the ATAC-seq results demonstrated that the promotor region of MT1G become more accessible upon the treatment of sorafenib, which may make a few key transcription factors easier to bind to the promoter region of MT1G to initiate the transcription. Finally, next-generation sequencing (NGS) results showed that the expression of two tumor associated genes: KLF4 and CA9, were significantly altered by MT1G overexpression. KLF4 was required to bind to the promotor region of CA9 and then inhibit the expression of CA9, a hypoxia-induced gene involved in modulating tumor microenvironment. The decrement of CA9 expression was related to hepatoma cells suppression. Taken together, we deduce that MT1G-KLF4-CA9 axis is a potential novel pathway to suppress hepatoma cell progression regulated by sorafenib. The regulation of MT1G-KLF4-CA9 is plausible to synergize with sorafenib to improve the therapeutic effects. Supported by NSFC projects 81773146, 81972766, 81972420, 82173336; Shenzhen Science and Technology Commission Project JCYJ20180302174235893; Sanming Project of Medicine in Shenzhen SZSM202003009; Guangdong Basic and Applied Basic Research Foundation 2021A1515012161; and Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018)
Citation Format: Tianzi Wei, Hao Wang, Risheng Lin, Yueming Li, Yi Lu, Jian Zhang. Discovery of a novel epigenetic regulatory axis that mediates sorafenib's antineoplastic activity [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 5841.
Abstract 5845: The fusion gene landscape in Chinese patients with non-small cell lung cancer
Authors: lin qiuju , Fu Zhichao 
Published: June 2022

Abstract
Background: Gene fusion is one of the common types of pathogenic mutation in non-small cell lung cancer(NSCLC). Numerous fusion genes have been identified as important biomarkers and therapeutic targets in NSCLC. The identification and analysis of fusion genes will provide important insights into the mechanisms of NSCLC development and devise novel therapeutic strategies. Here, our primary objective was to describe the landscape of fusion in Chinese patients with NSCLC to explore the new treatment option in NSCLC.
Methods: A total of 1192 pathologically confirmed NSCLC samples were collected. The fusion genes were detected using next-generation sequence(NGS).
Results: A total of 168 fusion events (14.1%) were identified in 1,192 patients with NSCLC. The most common type of fusion was ALK (64.9%), RET (25%), ROS (8.93%), NTRK1 (3.57%), and FGFR3 (3.57%). In these cases, 109 patients exhibited ALK fusion, including EML4/ALK (97.2%), KIF5B/ALK (0.92%), KLC1/ALK (0.92%), and STRN/ALK (0.92%). A total of 42 patients had RET fusions, of which 83.3%, 11.9%, 2.38%, and 2.38% with KIF5B, CCDC6, GOPC, and TET1 respectively. Notably, RET gene fusions with GOPC (GOPC/RET1), TET1 (TET1/RET1) were first reported in NSCLC and the two novel fusions retained the complete kinase domain of RET. We also found three types of ROS fusions in 15 patients, CD74/ROS1(66.7%) and EZR/ROS1(20%) were the common fusions. Additionally, a new fusion LRIG3/ROS1 which retained the complete kinase domain was identified for the first time in NSCLC patients.
Conclusions: We conducted a comprehensive review of fusion genes in Chinese patients with NSCLC. With the exception of common gene fusions, we found three cases of rare fusion mutations, which help to understand the potential pathogenic mechanisms of NSCLC and translate into therapeutic applications.
Citation Format: qiuju lin, Zhichao Fu. The fusion gene landscape in Chinese patients with non-small cell lung cancer [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 5845.
Abstract 5884: Comprehensive analyzing the expression of IDO1 and TDO2 in bladder cancer
Authors: Pham Quoc Thang , Nguyen Thanh Tu , Nguyen Thao Quyen , Luu Duc Tung , Pham Thi Nhu Diem , Bui Thi Thanh Tam , Duong Thanh Tu , Phan Dang Anh Thu , Ngo Quoc Dat 
Published: June 2022

Abstract
Background: Several lines of evidence have been focused on the roles of tryptophan metabolism genes like indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) in bladder cancer progression. However, the alternative way of targeting in cancer immunotherapy has been not yet investigated in bladder cancer. Method: We explored and validated the clinicopathological significance and the correlation with immune infiltrates of IDO1 and TDO2 expression in bladder cancer using Bladder urothelial carcinoma (BLCA) and other Gene Expression Omnibus (GEO) datasets (GSE13570, GSE31684, GSE48277) downloaded from https://xenabrowser.net/ and https://www.ncbi.nlm.nih.gov/geo/. The correlation between IDO1, TDO2 expression and the immune infiltrates as well as PD-L1 gene expression in BLCA dataset was explored with TIMER2.0, http://timer.comp-genomics.org/. Immunohistochemistry was performed to validate the relationship between TDO2 and PD-L1 expression in bladder cancer. Results: We figured out the IDO1 and TDO2 expressions were significantly upregulated in basal type compared with other molecular subtypes in BLCA. P53 mutations were associated with upregulation of IDO1 and TDO2 expression (p&lt;0.01) whereas FGFR3 mutation was associated with downregulation of IDO1 and TDO2 expression (p&lt;0.001). The overexpression of IDO1, TDO2 overexpression was significantly associated with advanced disease in BC. IDO1 and TDO2 expression were significantly correlated with purity and immune cell infiltrates, including T cells CD8+, T cells CD4+, B cells, neutrophils, and macrophages as wells as myeloid dendritic cells. Interestingly, TDO2 were positively correlated with cancer-associated fibroblasts (CAFs) (rho=0.5, p=1.14e-24). PD-L1 expression was also correlated with IDO1 (rho=0.64, p=4.42e-49) and TDO2 expression (rho=0.42, p=5.01e-19). Immunohistochemistry revealed the correlation between TDO2 and PD-L1 expression (p=0.011). Conclusion: Our results pointed out that IDO1 and TDO2 could play an essential role in regulating the tumor microenvironment as well as immune tolerance in bladder cancer. Suggesting that IDO1, TDO2 might be a promising novel immunotherapy target for bladder cancer patients.
Citation Format: Quoc Thang Pham, Thanh Tu Nguyen, Thao Quyen Nguyen, Duc Tung Luu, Thi Nhu Diem Pham, Thi Thanh Tam Bui, Thanh Tu Duong, Dang Anh Thu Phan, Quoc Dat Ngo. Comprehensive analyzing the expression of IDO1 and TDO2 in bladder cancer [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 5884.
Abstract 589: Discovery of NTX-001, a potent Cbl-b inhibitor with antitumor activity in syngeneic models
Authors: Csibi-Levin Fred , Leit Silvana , Laughton David L. , Baker Tom , Jacques Suzanne L. , Browning Beth , Toms Angela V. , Garside Samantha , D'Archivio Simon , Kopycka Katarzyna , Zhu Xiaohua , Jordan Allan M. , Thomson Stuart , Loh Christine , Tummino Peter , Ciccone David N. 
Published: June 2022

Abstract
Introduction: Casitas B-lineage lymphoma b (Cbl-b), a RING finger E3 ligase and a member of a highly conserved family of Cbl proteins, catalyzes the ubiquitination of substrate proteins to regulate multiple signaling events in a variety of cell types, including immune cells. In T cells, Cbl-b negatively regulates adaptive immune system signaling by establishing the threshold for the activation of antigen receptors. Additionally, Cbl-b regulates the function of other immune cell types, including NK cells, dendritic cells (DC) and monocytes. Cbl-b deficient T cells no longer require a costimulatory signal to be fully activated. Cbl-b KO mice spontaneously reject tumors via an enhanced immune response. Taken together, these findings point to Cbl-b inhibitors as having the potential to be highly efficacious immuno-oncology agents.
Experimental Procedures: A structure-based drug design approach was used to identify potent inhibitors of Cbl-b. Biochemical and cellular binding assays, a cellular NFAT-luciferase reporter assay, as well as primary in vitro human and mouse T cell activation assays measuring IL-2 production were used to profile inhibitor compounds. In vivo activity of Cb-b inhibitors was evaluated using an anti-CD3 mouse model and a CT-26 syngeneic mouse model
Results: Cbl-b inhibitor NTX-001 potently binds to Cbl-b, preventing Cbl-b phosphorylation and binding to E2. In cells, NTX-001 treatment results in enhanced phosphorylation of ZAP-70, a protein proximal to the TCR and reported to be a direct substrate of Cbl-b. Additionally, inhibition of Cbl-b potently enhances cytokine secretion from primary human and mouse T cells. In vivo, an increase in cytokines and T cell activation markers was observed after a single dose of NTX-001. Repeated dosing of NTX-001 showed dose-dependent anti-tumor activity in the colorectal CT-26 syngeneic model.
Conclusions: NTX-001 is a potent Cbl-b inhibitor that demonstrated strong T cell activation and anti-tumor activity in a syngeneic tumor model. These data support Cbl-b inhibitors as a promising therapeutic opportunity for cancer treatment.
Citation Format: Fred Csibi-Levin, Silvana Leit, David L. Laughton, Tom Baker, Suzanne L. Jacques, Beth Browning, Angela V. Toms, Samantha Garside, Simon D'Archivio, Katarzyna Kopycka, Xiaohua Zhu, Allan M. Jordan, Stuart Thomson, Christine Loh, Peter Tummino, David N. Ciccone. Discovery of NTX-001, a potent Cbl-b inhibitor with antitumor activity in syngeneic models [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 589.