bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5214: Copper chelation overcomes the immunosuppressive tumor microenvironment in neuroblastoma
Authors: Rouaen Jourdin R. , Mercatelli Daniele , Saletta Federica , Poursani Ensieh M. , Murray Jayne E. , Tedla Nicodemus , Giorgi Federico M. , Vittorio Orazio 
Published: June 2022

Abstract
Immunotherapy remains a promising approach in the treatment of high-risk neuroblastoma, however efficacy is hampered by the immunosuppressive tumor microenvironment. We previously reported a link between intratumoral copper levels and Programmed Death-Ligand 1 (PD-L1) expression and therefore sought to elucidate the wider impact of copper chelation on immune evasion strategies (Voli et al 2020). Here we profile key elements of the neuroblastoma tumor microenvironment which work in concert to promote immunosuppression and tumor progression. Using the murine TH-MYCN model, animals were treated daily with the copper chelation agent tetraethylenepentamine (TEPA) for seven days before tumor resection and processing. Transcriptome analyses using single-cell RNA-sequencing revealed copper chelation positively skewed the functional status of tumor, immune and stromal compartments to enhance the anti-tumor immune response. This was supported by a tissue microarray screen using NanoString Digital Spatial Profiling which identified increased immune cell infiltration and regions of active tumor killing. High-resolution mass-spectrometry detected upregulation of major histocompatibility complex (MHC) proteins and exclusive antigenic signatures in peptide repertoires. A multiplex cytokine array indicated an improved anti-tumorigenic response underscored by T cell and Natural Killer cell activation. Importantly, combination of copper chelation and anti-GD2 antibody therapy led to tumor regression and significantly improved survival in vivo. Collectively, this study demonstrates the ability of copper chelation to successfully mitigate tumoral immune evasion strategies while providing remarkable insight into neuroblastoma biology. Findings provide crucial evidence in support of combining clinically approved copper chelators with immunotherapy to improve outcomes for neuroblastoma patients.
Citation Format: Jourdin R. Rouaen, Daniele Mercatelli, Federica Saletta, Ensieh M. Poursani, Jayne E. Murray, Nicodemus Tedla, Federico M. Giorgi, Orazio Vittorio. Copper chelation overcomes the immunosuppressive tumor microenvironment in neuroblastoma [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 5214.
Abstract 5225: The PI3K inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors
Authors: Findlay Tyler , Malebranche Kristen , Eberhart Charles , Raabe Eric , Rubens Jeffrey 
Published: June 2022

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy with a four-year event-free survival of 37%. Previously, we have identified high activation of both mTORC1 and mTORC2 through immunohistochemistry of 18 primary human AT/RT. The PI3K-Akt-mTOR signaling pathway drives tumorigenicity by promoting cancer cell growth and survival. Paxalisib is a highly brain-penetrant PI3K inhibitor acting upstream of mTORC1/2 to fully inhibit the activation of both complexes. Ongoing pediatric clinical trials have reported Paxalisib as safe and well-tolerated, with minimal dose limiting toxicities. Paxalisib treatment in mice bearing orthotopic xenografts of AT/RT slowed tumor growth and significantly extended survival from 40 to 54 days (bioluminescent imaging, log rank test p=0.0011). However, due to limited durability of single agent therapy, we conducted pilot studies to identify rational combination therapies to enhance Paxalisib survival benefits in AT/RT. RG2833 is a novel, highly brain penetrant, histone deacetylase 1/3 (HDAC1/3) inhibitor. Our preliminary data has shown that Paxalisib and RG2833 combine synergistically to decrease AT/RT cell growth (SynergyFinder ZIP score 11.1; CellTiter-Blue Cell Viability Assay, p&lt;0.0001), and increase apoptosis (Western blot cPARP, MUSE Annexin V Assay, ANOVA p&lt;0.001) compared to each agent alone and DMSO control. Additionally, our pilot combination study in orthotopic xenograft models of AT/RT demonstrated that combination therapy slows tumor growth more significantly than each agent alone and vehicle control (bioluminescent imaging). This novel combination therapy will readily translate into a new clinical trial aimed at improving survival in this deadly pediatric brain tumor.
Citation Format: Tyler Findlay, Kristen Malebranche, Charles Eberhart, Eric Raabe, Jeffrey Rubens. The PI3K inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors [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 5225.
Abstract 5235: The role of transient single MET inhibition in MET-amplified and EGFR-mutant nonsmall cell lung cancer resistant to EGFR inhibitors
Authors: Lee Youngjoo , Choi Yu-Ra , Kang Eun Hye , Kim Sunshin , Park SeogYun , Han Ji-Youn 
Published: June 2022

Abstract
Background: In recent clinical trials for EGFR-mutant lung cancer acquiring MET amplification as resistance to EGFR inhibitor, two-drug combination treatment showed promising anti-tumor activity. However, these combination treatments also resulted in increased toxicity with intolerability. Thus, this study evaluated the possible role of single MET inhibition in these distinct tumors.
Methods: Using gefitinib-resistant MET-amplified lung cancer cells (HCC827GR), we tested the sensitivity to single MET inhibitor with various conditions. Supporting preclinical data with cell lines, the matched case reports and drug-sensitivity tests using patient-derived cells were presented. Furthermore, we chronically treated HCC827GR with single MET inhibitor to establish MET inhibitor-resistant cell line (HCC827GR_PR). And then, we explored putative resistance mechanisms of the HCC827GR_PR cells.
Results: The HCC827GR cells were partially inhibited by single MET inhibitor regardless of gefitinib-free duration or drug exposure time. Three patients with stage IV MET-amplified and EGFR-mutant lung cancer resistant to EGFR inhibitor showed initially definite response to single crizotinib treatment but their disease progressed within two or three months. The copy number of MET gene in plasma circulating tumor DNA was decreased significantly during crizotinib treatment and not increased even after progression to crizotinib. In their post-crizotinib tumor, MET amplification was disappeared in fluorescence in situ hybridization test. In vitro drug test using patient-derived cells revealed the sensitivity to EGFR inhibitor was recovered after single crizotinib treatment. We established HCC827GR_PR resistant to single MET inhibitor. In the major clones of HCC827GR_PR cells, EGFR signaling pathway was reactivated and gefitinib successfully suppressed their survival. Furthermore, increased MET gene copy number or bypass activation of FGFR1 were observed as resistance mechanism in the minor clones of HCC827GR_PR cells.
Conclusions: Single MET inhibitor could be effective but its efficacy could not durable in patients with MET-amplified and EGFR-mutant lung cancer resistant to EGFR inhibitors because these resistant cells might be subclones. A novel combination strategy is needed to get both long-term efficacy and less toxicity in these lung cancer patients.
Citation Format: Youngjoo Lee, Yu-Ra Choi, Eun Hye Kang, Sunshin Kim, SeogYun Park, Ji-Youn Han. The role of transient single MET inhibition in MET-amplified and EGFR-mutant nonsmall cell lung cancer resistant to EGFR inhibitors [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 5235.
Abstract 5240: S-phase cyclinA associated protein in the ER(SCAPER)rs3812908 T&gt;C promotes the nuclear translocation of CyclinA2 and enhances DNA damage repair in radioresistance of colorectal cancer
Authors: Yu Hai-na , Jiang Ting , Liu Shuang , Yuan Yan , Xi Shao-yan , Guo Zhi-wei , Yuan Yuan-hong , Li Yan , Xiao Wei-wei 
Published: June 2022

Abstract
Radiotherapy resistance is still an obstacle of improving the survival of patients with locally advanced colorectal cancer. In this study, whole-exome sequencing and targeted sequencing were preformed on colorectal cancer tumor tissue samples which were colloected from multiple centers, and the pathologic complete response predictive model PGS-LARC(Prediction Genotype Signature for Locally Advanced Rectal Cancer) was established. A candidate SNV-SCAPER rs3812908 T&gt;C was screened using this model. To investigate the relationship between SCAPER rs3812908 T&gt;C and radiosensitivity of colorectal cancer, targeted sequencing was performed and the results revealed that proportion of CC genotype was significantly higher in resistant sequencing cohort than in sensitive ones (30% vs. 22%). And Immunohistochemistry (IHC) results revealed that SCAPER protein expressed less in CC genotype colorectal cancer tissues than in TT genotype. Here, the cell proliferation results showed that SCAPER-KD cells and SCAPER rs3812908 CC cells were more radioresistant than SCAPER-NC and TT cells. Furthermore, the immunofluorescence assay showed SCAPER rs3812908 T&gt;C promoted translocation of S phase associated protein-Cyclin A2 into nucleus and western blotting results showed that the phosphorylation of ERK and JNK(p-ERK and p-JNK) increased significantly in SCAPER CC cells, and the protein p-ATR, p-ATM, p-CDC25C and CDC25A related to homologous recombination repair were also increased in SCAPER-KD and SCAPER CC cells.Taken together, the SCAPER gene rs3812908 T&gt;C plays an important role in radioresistance of colorectal cancer. The SNV of SCAPER rs3812908 T&gt;C significantly promotes Cyclin A2 nuclear translocation, activates the MAPKs pathway, and increases homologous recombination repair, and finally leads to radioresistance.
Citation Format: Hai-na Yu, Ting Jiang, Shuang Liu, Yan Yuan, Shao-yan Xi, Zhi-wei Guo, Yuan-hong Yuan, Yan Li, Wei-wei Xiao. S-phase cyclinA associated protein in the ER(SCAPER)rs3812908 T&gt;C promotes the nuclear translocation of CyclinA2 and enhances DNA damage repair in radioresistance of colorectal 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 5240.
Abstract 5251: GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma
Authors: Ye Ling , Fan Dandan , Chen Yaoxu , Huang Mengli 
Published: June 2022

Abstract
Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including atezolizumab, pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that Tumor Mutation Burden (TMB) was significantly (p &lt; 0.001) associated with mutations in genes like GRIN2A in Non-Small Cell Lung Cancer (NSCLC), which means that the mutation of GRIN2A gene may be related to the efficacy of immunotherapy in patients with NSCLC, but the association between GRIN2A mutation and TMB or survival in melanoma is unknown.
Methods: The association between GRIN2A mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Miao2018.Pancancer.249.WES, which worked as training cohort while the validation cohort was retrieved from Melanoma.Allen2015.WES.110. Wilcoxon test was used for the comparison of TMB and Tumor Neoantigen Burden (TNB). Progress Free Survival (PFS):Overall survival (OS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p=0.05.
Results: In the training cohort, 33.8% (51/151) melanoma patients harbored GRIN2A mutation. GRIN2A mutation is associated with higher TMB (p&lt;0.001) and higher TNB (p&lt;0.001). Survival analysis demonstrated that GRIN2A mutation resulted in significantly longer PFS (5.6 vs 3.3months; HR, 0.58; p=0.027) and longer OS (22.5 vs 12.8 months; HR, 0.61; p=0.039) in melanoma patients treated with ICIs. While validation cohort1 showed that 22.7% (25/110) melanoma patients harbored GRIN2A mutation and GRIN2A mutation resulted in an increasing trend on TMB with strongly significant difference (p&lt;0.001) and significantly longer OS (22.5 vs 8.3months; HR, 0.53; p=0.025).
Conclusions: This study shows that GRIN2A mutation is correlated with higher TMB and TNB in melanoma and serve as a predictive biomarker of ICI benefit in melanoma.
Citation Format: Ling Ye, Dandan Fan, Yaoxu Chen, Mengli Huang. GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma [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 5251.
Abstract 5280: TERT promoter mutations are an independent predictor of distant metastasis in Middle Eastern papillary thyroid microcarcinoma
Authors: Ahmed Saeeda Omer , Siraj Abdul K. , Parvathareddy Sandeep K. , Iqbal Kaleem , Qadri Zeeshan , Al-Rasheed Maha , Siraj Sarah , Thangavel Saravanan , Diaz Roxanne , Benito Allianah , Victoria Ingrid F. , AlKuraya Khawla S. 
Published: June 2022

Abstract
Background: Papillary thyroid microcarcinomas (PTMCs) have been attributed to the recent increased incidence of thyroid cancer. Although indolent, a subset of PTMC could potentially develop distant metastasis (DM). This study aimed to evaluate the clinico-pathological features and molecular characteristics of PTMC and identify the risk factors for DM in PTMC patients from Middle Eastern ethnicity.
Methods: We retrospectively analyzed 210 patients with histologically confirmed PTMC. Clinico-pathological associations for DM, BRAF mutation and TERT mutation were analyzed successfully in 184 patients. Multivariate analysis was performed using Cox proportional hazards model and logistic regression analysis.
Results: Among the PTMC patients included in this cohort, DM was noted in 6.0%(11/184), whereas tumor relapse occurred in 29/184 (15.8%). Of the 11 cases with DM, lung metastasis occurred in 8 cases, bone metastasis in 2 cases and brain metastasis in 1 case. Presence of extrathyroidal extension and older age were significantly associated with DM. Molecular analysis showed BRAF V600E mutations to be the most frequent, being detected in 45.7% (84/184). TERT promoter mutations were detected in 16 (8.7%) cases and were significantly associated with DM and shorter metastasis-free survival in multivariate analysis.
Conclusions: Our study indicates a surprisingly high frequency of TERT promoter mutation in Saudi patients with PTMC. Identifying TERT promoter mutations as an independent predictor of DM in patients with microcarcinoma could explain the inherent aggressive nature of PTMC from Middle Eastern ethnicity and magnify its role in patient risk stratification, which might help in improving therapeutic strategy for these patients.
Citation Format: Saeeda Omer Ahmed, Abdul K. Siraj, Sandeep K. Parvathareddy, Kaleem Iqbal, Zeeshan Qadri, Maha Al-Rasheed, Sarah Siraj, Saravanan Thangavel, Roxanne Diaz, Allianah Benito, Ingrid F. Victoria, Khawla S. AlKuraya. TERT promoter mutations are an independent predictor of distant metastasis in Middle Eastern papillary thyroid microcarcinoma [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 5280.
Abstract 5313: A BCL-XL PROTAC degrader DT2216 synergizes with KRASG12C inhibitors for effectively treating KRASG12C-mutated cancers
Authors: Khan Sajid , Wiegand Janet , Zhang Peiyi , Hu Wanyi , Thummuri Dinesh , Budamagunta Vivekananda , Hua Nan , Jin Lingtao , Allegra Carmen J. , Kopetz Edmund S. , Zajac-Kaye Maria , Kaye Frederic J. , Zheng Guangrong , Zhou Daohong 
Published: June 2022

Abstract
Purpose: Mutations in KRAS are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor selectively targeting KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the clinical efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated solid tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy.
Experimental Design: A panel of KRASG12C-mutated cell lines from NSCLC, CRC and pancreatic cancer (PC) were treated with sotorasib alone or in combination with BCL-XL proteolysis targeting chimera (PROTAC, such as DT2216) to assess effects on cell viability, colony formation and apoptosis. To identify mechanisms underlying sotorasib+DT2216 combination responses, we analyzed KRAS downstream signaling and expression of BCL-2 family proteins, and performed co-immunoprecipitation of BCL-XL to evaluate its interaction with pro-apoptotic BH3-only proteins. Finally, therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models.
Results: We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C cell lines that partially responded to sotorasib treatment. Mechanistically, co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo.
Conclusions: Our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore its combination with a pro-apoptotic agent DT2216 shows synergistic responses and can potentially overcome resistance.
Citation Format: Sajid Khan, Janet Wiegand, Peiyi Zhang, Wanyi Hu, Dinesh Thummuri, Vivekananda Budamagunta, Nan Hua, Lingtao Jin, Carmen J. Allegra, Edmund S. Kopetz, Maria Zajac-Kaye, Frederic J. Kaye, Guangrong Zheng, Daohong Zhou. A BCL-XL PROTAC degrader DT2216 synergizes with KRASG12C inhibitors for effectively treating KRASG12C-mutated cancers [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 5313.
Abstract 5355: Mechanisms of resistance to CLN-081 (TAS6417) in non-small cell lung cancer with EGFR exon 20 insertions
Authors: Hayashida Takuma , Kagawa Yosuke , Mori Shunta , jie Liu , Kashima Yukie , Tanaka Kosuke , Udagawa Hibiki , Izumi Hiroki , Kobayashi Susumu 
Published: June 2022

Abstract
Background: EGFR exon 20 insertions are detected in approximately 10% of EGFR mutant non-small cell lung cancer (NSCLC). NSCLC with EGFR exon 20 insertions is resistance to conventional epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib. CLN-081 is a novel EGFR-TKI which shows promising anti-tumor activity for EGFR exon 20 insertions in an ongoing clinical trial. However, previous studies of other EGFR-TKIs prompted us to hypothesize that tumors would acquire resistance to CLN-081 over time. Investigation of the mechanisms of resistance to CLN-081 will provide novel therapeutic strategies for patients with CLN-081-resistant NSCLC.
Methods: We first generated Ba/F3 cells stably expressing EGFR exon 20 insertions (Ba/F3-A767_S768insSVD and Ba/F3-Y764_V765insHH) and human patient-derived cells (PDCs), BID007 and BID019 harboring A763_Y764insFQEA and N771_P772insH, respectively. These cells were treated with increasing concentrations of CLN-081 to establish resistant cells. EGFR kinase domain was sequenced for parent Ba/F3 cell and resistant Ba/F3 clones to identify acquired EGFR mutations in resistant clones. PDC cells resistant to CLN-081 were subjected to whole exome sequencing (WES) and RNA sequencing (RNA-Seq) to examine whether resistant cells harbor acquired mutations and/or show changes in gene expression.
Results: Sequencing of the EGFR kinase domain revealed the Cys797Ser (C797S) mutations in all resistant clones of Ba/F3-A767_S768insSVD and Ba/F3-Y764_V765insHH cells. WES of resistant PDC cells showed that both BID007 and BID019 cells acquired mutations in KMT2C, a gene involved in histone methylation. In addition, acquired mutations were found in several kinases such as DGKZ, PAK2, and ROCK1. RNA-Seq showed that several genes involved in inflammatory responses and antigen presentation were upregulated in PDC cells resistant to CLN-081.
Conclusion: Our preclinical study identified several mechanisms of resistance to CLN-081 including acquired mutations and inflammatory responses. These results will provide new insights into development of a novel strategy to overcome or prevent resistance to CLN-081.
Citation Format: Takuma Hayashida, Yosuke Kagawa, Shunta Mori, Liu jie, Yukie Kashima, Kosuke Tanaka, Hibiki Udagawa, Hiroki Izumi, Susumu Kobayashi. Mechanisms of resistance to CLN-081 (TAS6417) in non-small cell lung cancer with EGFR exon 20 insertions [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 5355.