bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2797: Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in older adults aged over 75 years
Authors: Nakahara Yoshiro , Watanabe Kageaki , Hosomi Yukio , Yamanaka Yuta , Kurata Takayasu , Horinouchi Hidehito , Ohe Yuichiro , Asao Tetsuhiko , Saeki Sho , Tsubata Yukari , Fujita Yu , Konishi Jun Sakakibara , Mizugaki Hidenori , Ohuchi Mayu , Yagishita Shigehiro , Hamada Akinobu 
Published: April 2023

Abstract
Background: Pembrolizumab (Pemb) is a key drug for the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, there are limited data on Pemb use in older adults aged &gt;75 years with NSCLC, especially in terms of pharmacokinetics (PK).
Methods: This open-label multicenter observational study aimed to evaluate real-world data on the safety, efficacy, and blood concentrations of Pemb (both monotherapy and combination therapies) in older adults with NSCLC. Blood samples for PK analysis were collected immediately before Pemb administration. Quantitative Pemb concentrations were measured by liquid chromatography-mass spectrometry.
Results: We enrolled 100 patients from July 2019 to September 2020; one patient was excluded due to stage migration. Patient characteristics were as follows: median age, 78 (75-87) years; male/female ratio, 70/29; performance status (PS) 0-1/2-3, 85/14; adenocarcinoma/squamous cell carcinoma/others, 62/25/12; stage I-III/IV/postoperative recurrence (TNM 7th edition), 9/60/30; PD-L1 TPS &lt;1%/1%-49%/≥50%, 12/31/48; and monotherapy/combination therapy, 65/34. The best overall efficacy was CR/PR/SD/PD (7/40/32/20), and the response rate was 47.5%. The median progression-free survival (PFS) and overall survival (OS) were 8.0 and 19.0 months, respectively. The adverse event profile was generally similar to that reported in previous studies. In total, 77 blood samples were collected immediately before the second cycle (C1 trough). Although no clear association between Pemb concentrations and patient background was found, PFS and OS were significantly shortened in the population with low C1 trough, a population characterized by lower PS, high number of metastatic organs at the beginning of treatment, and low blood albumin level.
Conclusion: In older adults aged &gt;75 years with NSCLC and low albumin levels and PS and a high number of metastatic organs, C1 trough of Pemb is reduced and not expected to prolong PFS and OS.
Citation Format: Yoshiro Nakahara, Kageaki Watanabe, Yukio Hosomi, Yuta Yamanaka, Takayasu Kurata, Hidehito Horinouchi, Yuichiro Ohe, Tetsuhiko Asao, Sho Saeki, Yukari Tsubata, Yu Fujita, Jun Sakakibara Konishi, Hidenori Mizugaki, Mayu Ohuchi, Shigehiro Yagishita, Akinobu Hamada. Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in older adults aged over 75 years [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 2797.
Abstract 280: Targeting mRNA pseudouridylation to suppress neuroblastoma metabolism
Authors: Gupta Anamika , Bansal Mohit , Ding Han-Fei 
Published: April 2023

Abstract
Pseudouridylation of mRNA is a common epigenetic modification that reduces RNA conformational flexibility and increases its structural stability and may increase its availability for translation. RNA pseudouridylation is catalyzed by the family of pseudouridine synthases, including dyskerin pseudouridine synthase 1 (DKC1). Here we report the DKC1 gene is a direct transcriptional target of MYCN, which is a major oncogene in driving the development of high-risk neuroblastoma, a childhood cancer with a poor prognosis. The transcriptional upregulation of DKC1 expression in MYCN-amplified cells is of functional significance, as DKC1 depletion by RNA interference inhibits the proliferation of neuroblastoma cell lines. Furthermore, gene expression profiling reveals that DKC1 has a key role in the regulation of amino acid biosynthesis enzymes. Genetic and pharmacological inhibition of DKC1 reduces the expression of ATF4 and its downstream target genes involved in amino acid synthesis and transport. These findings reveal a critical role of DKC1 in sustaining the proliferation of neuroblastoma cells by promoting amino acid metabolism, which could be exploited as a therapeutic strategy against high-risk neuroblastoma.
Citation Format: Anamika Gupta, Mohit Bansal, Han-Fei Ding. Targeting mRNA pseudouridylation to suppress neuroblastoma metabolism [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 280.
Abstract 2806: Patient-derived cell-based pharmacogenomic platform to uncover resistance mechanisms and novel therapeutics for advanced lung cancer
Authors: Park Charny , Yu Namhee , Hwang Mihwa , Lee Youngjoo , Song Bo Ram , Kang Eun Hye , Sim Hanna , Ahn Beung-Chul , Hwang Kum Hui , Hong Sehwa , Kim Sunshin , Han Ji-Youn 
Published: April 2023

Abstract
To uncover resistance mechanism and effective drugs for advanced lung cancer patients, we stablished a pharmacogenomic platform using patient-derived cells (PDC). Drug response screening and multi-omics datasets were obtained from lung cancer PDCs (n=102). We interrogated sensitive drugs from variant, gene expression, and clinical profiles. Machine learning approaches were applied to extract molecular target signatures and pathways associated with sensitive drugs. Next, acquired resistance pathways and drug candidates were investigated from patients to receive serial EGFR-TKI treatments. Our PDC model resembled with TCGA genomic profile. Three RNA subtypes were identified from gene expression: (1) MYC, (2) epithelial-to-mesenchymal (EMT), and (3) inflammatory activation. Drugs for mutations and subtypes were extracted. Especially, SCLC harboring both TP53 and RB1 mutations was abundant in RNA subtype 1 and showed sensitivity to cell cycle inhibitors. Among EGFR-TKI treatment groups, Osimertinib resistant group was enriched in EMT-like subtype 2 with vanishing EGFR T790M mutation and activating TGF-β pathway. The group showed sensitivity to YAP/TAZ inhibitor. Our PDC pharmacogenetic platform predict plausible drug candidates and markers for refractory lung cancer patients. We expect further studies for precision medicine by novel analysis and cohort expansion.
Citation Format: Charny Park, Namhee Yu, Mihwa Hwang, Youngjoo Lee, Bo Ram Song, Eun Hye Kang, Hanna Sim, Beung-Chul Ahn, Kum Hui Hwang, Sehwa Hong, Sunshin Kim, Ji-Youn Han. Patient-derived cell-based pharmacogenomic platform to uncover resistance mechanisms and novel therapeutics for advanced lung cancer [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 2806.
Abstract 2811: CDK4/6 inhibition plus radiotherapy enhances anti-tumor immunity in non-small cell lung cancer
Authors: Huang Zhengrong , Luo Jiang , Wang Mengqin , Xie Hongxin , Zeng Yuxin , Yuan Yu , Xiang Wan , Jiang Ziyu , Xie Conghua , Gong Yan 
Published: April 2023

Abstract
Lung cancer is the main cause of cancer-related mortality, of which non-small cell lung cancer (NSCLC) accounts for 85%. Abemaciclib, a selective CDK4/6 inhibitor, enhanced the radiosensitivity of NSCLC in vivo and in vitro and improved the prognosis of advanced NSCLC patients according to a Phase I clinical trial. This study aimed to explore the impact of CDK4/6 inhibition combined with irradiation and immunotherapy on NSCLC. The in vivo xenograft tumor mouse model was used to investigate the synergistic effects of CDK4/6 inhibitor abemaciclib and irradiation together with anti-PD-1 antibodies. The tumor infiltrating lymphocytes (TILs) in tumor microenvironment (TME) were analyzed by flow cytometry. The complete blood count and serum tests were used to determine the safety of this combination therapy. The human phospho-kinase array and dual-luciferase report assay were used to study the regulatory mechanisms of abemaciclib and irradiation combination on PD-L1 transcription in NSCLC cells in vitro. Our results indicated the significantly synergistic effects of abemaciclib, irradiation and anti-PD-1 antibodies on NSCLC growth in vivo, accompanied by increased CD8+ T cell infiltration and decreased regulatory T cells and myeloid-derived suppressor cells (MDSCs), suggesting a strong anti-tumor combination of CDK4/6 inhibition, radiotherapy and immunotherapy. This synergistic effect could be partially impaired by CD8 depletion, and alleviated the anemia and inflammation caused by tumor burden without hepatorenal toxicity. Abemaciclib induced PD-L1 transcription through JNK/c-Jun pathway in vitro, which might elevate PD-L1 expression synergistically with irradiation through TBK1/IRF3 pathway. Our studies suggested that CDK4/6 inhibition plus irradiation enhanced anti-tumor immune responses in NSCLC. Together with immunotherapy, the combination of CDK4/6 inhibitors and radiotherapy could lower the doses of individual treatment, thus alleviating the potential toxicity and side effects of CDK4/6 inhibition and irradiation on normal cells.
Citation Format: Zhengrong Huang, Jiang Luo, Mengqin Wang, Hongxin Xie, Yuxin Zeng, Yu Yuan, Wan Xiang, Ziyu Jiang, Conghua Xie, Yan Gong. CDK4/6 inhibition plus radiotherapy enhances anti-tumor immunity in non-small cell lung cancer [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 2811.
Abstract 2819: Genome-wide CRISPR screen identifies NANP as a radio-sensitizing target of GBM by regulating NF-κB pathway
Authors: Ding Yingwen , Zhang Ze-Yan , Ezhilarasan Ravesanker , Modrek Aram S. , Karp Jerome , Sulman Erik P. 
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) are the most malignant primary central nervous system tumors. The standard of care for newly diagnosed GBM patients includes surgery followed by combined radiation therapy (RT) and adjuvant temozolomide (TMZ) therapy. However, one of the therapeutic challenges is the inevitable resistance and recurrence after radiotherapy. Glioblastoma stem cells (GSC) are tumor initiating cells for GBM and plays key roles in radio resistance. Thus, we performed a genome-wide CRISPR screen using a radiation resistant GSC to identify potential RT sensitizing targets. We identified 139 potential RT sensitizing targets with a filter for only those genes associated with a greater than 2-fold reduction in representation with a p&lt;0.05. There were 22 genes with a direct function in key DNA double-strand break repair pathways including 5 genes central to non-homologous end-joining (NHEJ1, XLF, PRKDC, DCLRE1C, XRCC4, LIG4), 6 genes involved in homologous recombination (RAD51D, CYREN, ATM, TONSL, BRCA2, RFWD3), and 7 genes central to initial DNA damage sensing (RNF8, RNF168, TP53BP1, RAD17, FOXM1, RAD9A, RAD1). These results are consistent with the crucial role of DNA repair following radiation exposure and demonstrate the success of the screening. Besides that, one of the top hits is NANP (N-acylneuraminate-9-phosphatase), which is involved in sialic acid synthetic pathway. Knocking down of NANP causes more G2/M arrest followed by apoptosis after radiation. γH2A.X staining and comet assay shows more DNA damage in NANP knock down cells after radiation. Transcriptome analysis reveals NANP inhibition restrain mesenchymal status and NF-κB pathway activation. Furthermore, activation of NF-κB pathway could rescue the RT-induced G2/M arrest of NANP knock down cells. TCGA and CGGA dataset shows NANP is highly expressed in GBM patients and patients with NANP high expression have poorer survival. In conclusion, our study identified NANP as a novel radio-sensitizing target for glioblastoma by regulating NF-κB pathway and mesenchymal status of GSCs.
Citation Format: Yingwen Ding, Ze-Yan Zhang, Ravesanker Ezhilarasan, Aram S. Modrek, Jerome Karp, Erik P. Sulman. Genome-wide CRISPR screen identifies NANP as a radio-sensitizing target of GBM by regulating NF-κB pathway [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 2819.
Abstract 2830: Fluoxetine mediate radiosensitivity and inhibit metastasis of osteosarcoma cells via RANK/RANKL signaling
Authors: Tan Peggy , Tsai Jai-Jen , Hsu Fei-Ting , Liu Yu-Chiang 
Published: April 2023

Abstract
Osteosarcoma (OS) is most common primary malignant bone tumour OS was flagrantly byaffecting pediatric and young adolescents patients with its outrageous metastatic rate and poorprognosis. It was aggressive in local invasion and further metastasis, especially pulmonarymetastasis. Radiotherapy (RT) was a clinical treatment method that using high-energy ionizingradiation to control tumour growth with low risk and considerably successful rate.Contradictorily, OS was recognized as radio-resistant tumour. Meanwhile, majority of OScases were diagnosed suffering depression and influence patient’s conditions critically. Hence,aim of this prospective study was to identify that combinational therapeutic efficacy ofradiation therapy and fluoxetine (Prozac) through mediating radiosensitivity and inhibitmetastasis of OS cells via RANK/RANKL signaling. OS cell lines U2OS and MG63 were usedin this study. To investigate the cells survival fraction, clonogenic assay were performed. Next,to examine metastasis and invasions of cells wound healing assay and transwell assay werecarried out. Furthermore, TUNEL assay was used to evaluate DNA damage of OS cells.Fluoxetine effectively inhibited the metastasis and invasion ability of OS cells. Thecombinational therapy of fluoxetine and RT successfully decreased the surviving fraction ofOS cells and induced the damage of DNA. Additionally, the protein expression ofRANK/RANKL was markedly suppressed by fluoxetine as illustrated by Western blottingassay. In sum, the combination treatment of radiotherapy with the interrelation of fluoxetinewas showing its potential and consider as new treatment strategy might elevate treatmentefficacy for OS.
Keywords: Osteosarcoma (OS), Radiotherapy (RT), Fluoxetine, RANK/RANKL
Citation Format: Peggy Tan, Jai-Jen Tsai, Fei-Ting Hsu, Yu-Chiang Liu. Fluoxetine mediate radiosensitivity and inhibit metastasis of osteosarcoma cells via RANK/RANKL signaling [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 2830.
Abstract 284: Sigma1 regulates lipid droplet mediated redox homeostasis required for prostate cancer proliferation
Authors: Oyer Halley M. , Steck Alexandra R. , Longen Charles , Venkat Sanjana , Bayrak Konuralp , Munger Eleanor , Fu Dan , Sanders Christina , Myers Justin , Schiewer Matthew , Chen Nan , Mostaghel Elahe , Kim Felix J. 
Published: April 2023

Abstract
Lipid droplets (LDs) are dynamic organelles that serve as hubs of cellular metabolic processes. Emerging evidence shows that LDs also play a critical role in maintaining redox homeostasis and can mitigate lipid oxidative stress. In multiple cancers, including prostate cancer (PCa), LD accumulation is associated with cancer aggressiveness, therapy resistance, and poor clinical outcome. PCa arises as an androgen receptor (AR) driven disease. Among its myriad roles, AR mediates the biosynthesis of LDs, induces autophagy, and modulates cellular oxidative stress in a tightly regulated cycle that promotes cell proliferation. The factors regulating the interplay of these metabolic processes downstream of AR remain unclear. Here, we show that Sigma1/SIGMAR1, a unique ligand-operated scaffolding protein, regulates LD metabolism in PCa cells. Sigma1 inhibition triggers lipophagy, an LD selective form of autophagy, to prevent accumulation of LDs which normally act to sequester toxic levels of reactive oxygen species (ROS). This disrupts the interplay between LDs, autophagy, buffering of oxidative stress and redox homeostasis, and results in the suppression of cell proliferation in vitro and tumor growth in vivo. Consistent with these experimental results, SIGMAR1 transcripts are strongly associated with lipid metabolism and reactive oxygen species pathways in prostate tumors. Altogether, these data reveal a novel, pharmacologically responsive role for Sigma1 in regulating the redox homeostasis required by oncogenic metabolic programs that drive PCa proliferation.
Citation Format: Halley M. Oyer, Alexandra R. Steck, Charles Longen, Sanjana Venkat, Konuralp Bayrak, Eleanor Munger, Dan Fu, Christina Sanders, Justin Myers, Matthew Schiewer, Nan Chen, Elahe Mostaghel, Felix J. Kim. Sigma1 regulates lipid droplet mediated redox homeostasis required for prostate cancer proliferation [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 284.
Abstract 2843: RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells
Authors: Dong Xing-Duo , Lu Qisi , Li Yi-Dong , Teng Qiu-Xu , Lei Zi-Ning , Chen Zhe-Sheng 
Published: April 2023

Abstract
Overcoming ATP-binding cassette subfamily G member 2 (ABCG2)-mediated multidrug resistance (MDR) has attracted the attention of scientists because one of the critical factors leading to MDR is the overexpression of ABCG2. Identification of novel chemotherapeutic reagents as inhibitors of ABCG2 has been considered an effective strategy. RN486, a Bruton’s Tyrosine Kinase (BTK) inhibitor, was discovered to potentially reverse ABCB1-mediated MDR. In this study, we reported that RN486 effectively antagonizes ABCG2-mediated MDR in cancer cells. Non-toxic concentrations of RN486 remarkably increased the sensitivity of ABCG2-overexpressing cancer cells to conventional anticancer drugs mitoxantrone and topotecan. The reversal mechanistic studies showed that RN486 increased the accumulation and decreased the efflux of ABCG2 substrate drug in ABCG2-overexpressing cancer cells. In addition, the inhibitory effect of RN486 on ABCG2-associated ATPase activity was also verified. Docking analysis indicated a strong binding between RN486 and ABCG2 transporter. Meanwhile, the AGCG2 subcellular localization and expression level were not altered by the treatment of RN486. Taken together, our studies suggest that RN486 can antagonize ABCG2-mediated MDR in cancer cells via interacting with ABCG2 and inhibiting the transporting function. RN486 could be potentially used in combination with chemotherapy against ABCG2-mediated MDR in cancers.
Citation Format: Xing-Duo Dong, Qisi Lu, Yi-Dong Li, Qiu-Xu Teng, Zi-Ning Lei, Zhe-Sheng Chen. RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing 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 2843.
Abstract 2969: Development of a canine PD-L1 antibody and caninized PD-L1 mouse model: an essential translational research tool to raise the success rate of immunotherapy in humans
Authors: Oh Wonkyung , Kim Alyssa , Dhawan Deepika , Kirkham Perry M. , Knapp Deborah W. , Lim Seung-Oe 
Published: April 2023

Abstract
Immune checkpoint blockade therapy, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types. Despite the recent success of immune checkpoint blockade therapy, the response rates in cancer patients are limited (~20-40%). To improve immune checkpoint blockade therapy, relevant preclinical animal models are an essential component in the development and testing of multiple combination approaches and strategies. Companion dogs naturally develop several types of cancer that in many respects resemble clinical cancer in human patients. Therefore, the canine studies of immuno-oncology drugs are convertible into knowledge that informs and prioritizes new immuno-oncology therapy in humans. The challenge has been, however, that immunotherapeutic antibodies that target canine immune checkpoint molecules, such as canine PD-L1, have not been commercially available. Here, we developed a new canine PD-L1 antibody as an immuno-oncology drug and characterized its functional and biological properties by multiple assays. Furthermore, the therapeutic efficacy of cPD-L1 antibodies was evaluated in our unique caninized PD-L1 mice. Altogether, these in vitro and in vivo data including an initial safety profile in laboratory dogs, support the development of our canine PD-L1 antibody as an immune checkpoint inhibitor for studies in dogs with naturally occurring cancer for translational research. In conclusion, our new therapeutic antibody and caninized PD-L1 mouse model will be an essential translational research tool in raising the success rate of immunotherapy in both dogs and humans.
Citation Format: Wonkyung Oh, Alyssa Kim, Deepika Dhawan, Perry M. Kirkham, Deborah W. Knapp, Seung-Oe Lim. Development of a canine PD-L1 antibody and caninized PD-L1 mouse model: an essential translational research tool to raise the success rate of immunotherapy in humans [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 2969.