bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2497: Inhibitors of RNA Pol I and an aminoacyl-tRNA synthetase result in MYC and MYCN downregulation in MYC family protein-driven neuroblastoma cells
Authors: Ikegaki Naohiko , Zeki Jasmine , Chiu Bill , Shimada Hiroyuki 
Published: August 2018

Abstract
We have previously reported histologic variants among unfavorable histology neuroblastomas (NB), having large cell appearance with vesicular nuclei and or prominent nucleolar (PN) formation, indicating hyperactive rRNA synthesis and protein translation. These features appear to be associated with dismal outcome and high-level MYC family protein expression. PN formation could provide critical prognostic and risk-stratification information for NB. At the same time, this observation could open up an opportunity for innovative therapy for aggressive NB. To assess this possibility, we examined the effect of two potent and specific small-molecule inhibitors of RNA Pol I activity and an aminoacyl tRNA synthetase (CX-5461 and Halofuginone, respectively) on growth and MYC family protein expression in NB cell lines. These small-molecule inhibitors inhibited growth of NB cell lines at low to submicromolar concentrations in vitro in 48 hours. Moreover, the inhibitors destabilized MYC and MYCN proteins in NB cells. Interestingly, halofuginone showed a rapid effect on the stability of MYC family proteins at 500 nM-1 uM (&lt;3 hours). In contrast, CX-5461 at 1 uM was less effective at the 3-hour time. At the concentration of 100 nM-250 nM for halofuginone and 1 uM for CX-5461 for up to 48 hours of the drug treatments, MYC and MYCN expression were both downregulated. We further examined the preclinical efficacy of halofuginone in orthotopic Kelly human NB xenografts in mice using a silk film as the drug delivery device. Halofuginone showed a significant growth-suppressive effect on the xenografts, as indicated by the time periods to reach certain tumor sizes being significantly longer in the halofuginone-treated group than those in the control group. Moreover, histologic examination of the xenografts showed a marked suppression of MYCN protein expression in the halofuginone-treated xenograft at day 17 of the drug treatment. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and NB growth. Together, MYC-family protein overexpression and PN formation should be included in new NB risk stratification and considered for potential therapeutic targets.
Citation Format: Naohiko Ikegaki, Jasmine Zeki, Bill Chiu, Hiroyuki Shimada. Inhibitors of RNA Pol I and an aminoacyl-tRNA synthetase result in MYC and MYCN downregulation in MYC family protein-driven neuroblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2497.
Abstract 2508: Effect of ALK-inhibitors in synovial sarcoma (SS) cell line HS-SYII
Authors: Gyotoku Hiroshi 
Published: August 2018

Abstract
Synovial sarcoma (SS) accounts for approximately 8% of all soft tissue sarcomas (STS). The prognosis is poor because of a few effective chemotherapy regimens for STS such as Doxorubicin, Eribulin, and Trabectedin. Pazopanib, a multi-targeted tyrosine kinase inhibitor of PDGFR, VEGFR and c-Kit, is the first molecular targeted drug approved by FDA for STS. Recently, a preclinical efficacy of MET-inhibitor and ALK-inhibitor for a synovial sarcoma cell line was reported. We found that the response to ALK-inhibitors (Alectinib, Crizotinib and Lorlatinib) for SS cell line HS-SY-II different from Aska-SS cell line in a previous report. In addition, a combination of ALK-inhibitor and Pazopanib, previously reported that single-agent is effective in HS-SY-II, potentiates a cytotoxic effect by MTT assay than each single agent. Western blotting revealed that both of ALK-inhibitor single agent and the combination of Pazopanib and ALK-inhibitor suppress the phosphorylation of ERK and AKT, downstream of MAPK and PI3K pathway. Our data suggests that the combination therapy Pazopanib and ALK-inhibitor may be effective to SS patients clinically.
Citation Format: Hiroshi Gyotoku. Effect of ALK-inhibitors in synovial sarcoma (SS) cell line HS-SYII [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2508.
Abstract 2513: FGFRL1 deficiency reduces motility and tumor growth of cells derived from esophageal squamous cell carcinoma
Authors: Takei Yoshinori , Matsumura Takafumi , Watanabe Kazuaki , Nakamine Hirokazu , Sudo Tetsuo , Shimizu Kazuharu , Shimada Yutaka 
Published: August 2018

Abstract
Fibroblast growth factor receptor-like 1 (FGFRL1) belongs to the FGFR protein family. We previously reported that FGFRL1 is highly expressed in esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis and with the depth of ESCCs. Furthermore, transient inhibition of FGFRL1 expression induces cell cycle arrest and apoptosis of ESCC cells. However, the intracellular domain of FGFRL1 lacks the tyrosine kinase domain. Thus the mechanisms of which FGFRL1 contributes to the development of ESCC are unclear. Two cell lines (Clone 15 and 21) deficient for FGFRL1 expression were established from an ESCC cell line (KYSE520) using the CRISPR-Cas9 method. We evaluated the characteristics of these two cell lines in vitro and in vivo. In these FGFRL1-deficient KYSE520 cells, actin filaments around the nucleus were observed sparsely, whereas the filaments along the plasma membranes were observed as strong as those in the parent KYSE520 cells. Depleting FGFRL1 reduced cell motility in vitro and, decelerated tumor growth in a mouse xenograft model. Microarray analysis of mRNA expression revealed that FGFRL1-depletion resulted in reduced expression of MMP-1 and FGFBP1. In conclusions, FGFRL1-deficiency reduced both cell motility and tumor growth of KYSE520 cells. This is consistent with that high expression of FGFRL1 coincident with lymph node metastasis and poor prognosis. These results demonstrate that FGFRL1 expressed in ESCC cells has a role in aggressiveness of ESCCs.
Citation Format: Yoshinori Takei, Takafumi Matsumura, Kazuaki Watanabe, Hirokazu Nakamine, Tetsuo Sudo, Kazuharu Shimizu, Yutaka Shimada. FGFRL1 deficiency reduces motility and tumor growth of cells derived from esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2513.
Abstract 252: Prostate carcinogenesis inhibition through AKT-PKCα signaling pathway by diosmetin
Authors: Pakradooni Rebecca , Khalifa Ahmad , Isali Ilaha , Shukla Sanjeev 
Published: August 2018

Abstract
Mammalian target of rapamycin (mTOR) integrates nutrient and mitogen signals to regulate cell growth (increased cell mass and cell size) and cell division. mTOR protein kinase have two different complexes; complex-I contains major component raptor, whereas complex II (insensitive to rapamycin), has major component rictor. Rictor plays a critical role in AKT (Ser-473 phosphorylation), which facilitates phosphorylation of AKT on Thr-308 by PDK1 for full activation. When we genetically disrupted Rictor, it decreased AKT phosphorylation (Ser-473) and impaired PKCα (Ser-657) expressions. Growth factors viz., IGF-1 and IL-6 are the major player in prostate cancers, these increases Rictor expression. We need to have an agent that can modulate kinase activity of AKT and PKCα to inhibit prostate cancer cell growth. Diosmetin (5, 7-Trihydroxy-4′-methoxyflavone) could be such an agent. Diosmetin, a natural flavone present in plant legumes, has anti-mutagenic and anti-allergic properties. Diosmetin inhibited IGF-1 and IL-6 induced rictor expression in LNCaP and PC-3 prostate cancer cells. Diosmetin dose response treatment to these cells inhibited cell growth and induced apoptosis with no significant growth inhibition in normal prostate epithelial cells (RWPE1). Diosmetin treatment to prostate cancer cells modulated cell survival machinery by down regulating key molecules viz., c-Myc, Survivin and XIAP (X-Linked Inhibitor of Apoptosis). Similarly diosmetin (20 and 50μg/animal/day) feeding to nude mice models, which were orthotopically implanted with luciferase tag PC-3 cells in ventral prostate represented significant decrease in tumor volume than control mice. Diosmetin fed tumor bearing mice reduced phosphorylation of Rictor, (Thr-1135), AKT (Ser-473) and PKCα (Ser-657) expressions to inhibit tumor growth significantly. Moreover, luciferase activity of implanted tumor decreased after diosmetin dose response feeding than control mice. Additionally bone radiographic images suggested that diosmetin treatment inhibited homing of PC-3 cells in the bone. These effects were associated with decrease in cyclin D1 expression and their activating partner, cyclin-dependent kinase (cdk) 2 and 4 with concomitant upregulation of p27/KIP1. Further diosmetin treatment induced apoptosis which was evident by increased expression of cleaved caspase-3. We are documenting these evidences for the first time in animal model system that diosmetin acts against potential molecular targets to alter cellular events to elicit anticancer effects in prostate cancer.
Citation Format: Rebecca Pakradooni, Ahmad Khalifa, Ilaha Isali, Sanjeev Shukla. Prostate carcinogenesis inhibition through AKT-PKCα signaling pathway by diosmetin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 252.
Abstract 2538: The interaction of IGFBP3 with HIF2α in the invasion regulation of ovarian epithelial cell cancer
Authors: Shih Ho-Jun 
Published: August 2018

Abstract
Ovarian cancer is the most lethal gynecological cancer among women worldwide. The majority of malignant ovarian tumors are epithelial ovarian cancer and metastasis occurred in most patients at the time of diagnosis with worse outcome. New target therapy such as anti-angiogenesis therapy was proved to be effective to prolong progression free survival in epithelial ovarian cancer (EOC) patients. In our previous study, we have established an ovarian endometrioid carcinoma cell line OVTW59. By cDNA microarray analysis and further functional analysis, we have identified Insulin-like Growth Factor Binding Protein-3 (IGFBP-3), Calreticulin (CRT) and Thrombospondin-1(THBS1) correlated with tumor invasion in OVTW59. IGFBP3 and CRT was further found related with poor patient survival outcome. In this study, we focused on the mechanism of IGFBP3 in cancer invasion and metastasis. First we focused on the THBS1 related angiogenesis mechanism which was induced by hypoxia. Through this study, we identified HIF-2α, but not HIF-1α, playing as a significant role in EOC. By q-RT-PCR, Western blotting and immunohistochemical staining, HIF-2α showed opposite expression with IGFBP3, and high IGFBP3 was correlated with high THBS1 expression and low CRT expression. Using other cell lines, the IGFBP3/THBS1/HIF-2α/CRT expression patterns were similar in 293T, H1299 and A549. Furthermore, by Luciferase promoter assay, we verified that IGFBP3 could induce THBS1, inhibit HIF-2α expression, but does not regulate the expression of CRT. IGFBP3 is known as an invasion suppressor gene, THBS1 is an endogeneous inhibitor of angiogenesis, HIF-2α is a regulator of the hypoxia response and angiogenesis inducer, and CRT as a cell adhesion and invasion related protein. Overall, our study shows that IGFBP3 could induce tumor progression and metastasis through direct regulation of THBS1, and HIF-2α and indirect regulation of CRT in EOC.
Citation Format: Ho-Jun Shih. The interaction of IGFBP3 with HIF2α in the invasion regulation of ovarian epithelial cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2538.
Abstract 2554: To clone tumor-specific TCRs from a cell-based immunotherapy-benefit cervical cancer patient
Authors: Liang Xiaoling , Ou Shudan , Ma Minjun , Chen Xihe , Zhou Xiangjun , Han Yanyan 
Published: August 2018

Abstract
Adoptive transfer of tumor-specific T cell receptor (TCR)-engineered T cells, TCR-T therapy, has shown great efficacy in clinical trials against solid tumors. A cervical cancer patient with bone metastasis was treated with a cell-based immunotherapy, named Multiple-Antigens Stimulating Cellular Therapy (MASCT), which is a combination of multiple tumor antigen peptides loaded dendritic cells (DCs) and autologous T cells stimulated by these DCs. After repeated treatment, the patient showed partially response and remained stable disease for 20 months. Moreover, boosted specific immune responses were detected in patient's periphery blood by IFNγ-Elispot assay against various tumor antigens, such as CEA, RGS5 and HPV18/58. The clinical benefits of this patient indicated that tumor-specific T cells were expanded in vivo and played an important role to control tumor progression. These T cells may be the good sources to isolate tumor-specific TCRs for TCR-T therapies. Given that, patient's PBMCs were stimulated in vitro with selected tumor peptides respectively, such as CEA, RGS5 and HPV18 E7. Tumor-specific T cells were defined as IFNγ-secreting T cells upon peptide stimulation and were further enriched by using magnetic beads. Part of the enriched T cells were analyzed for TCR alpha/beta repertoire via NGS, the other part were sorted into single T cells and analyzed for TCR alpha/beta pairing. The TCR repertoire NGS data revealed that the tumor-specific T cells harbor several hundred unique TCR alpha/beta clonotypes. Some unique TCR alpha/beta clonotypes were considered as tumor-specific TCR candidates, since the copy numbersof these clonotypes were significantly and repeatedly increased after stimulation with CEA, RGS5 or HPV18 E7, and further increased after IFNγ enrichment. After TCR alpha/beta pairing confirmation by single T cell sequencing, alpha and beta chains of these TCRs were sent to synthesis for further investigation. In conclusion we have successfully identified specific TCR clonotypes targeting selected tumor antigens from a MASCT-benefited cervical cancer patient. After functional validations, including epitope specificity, HLA restriction as well as tumor recognition, these tumor-specific TCRs may be good candidates for developing safer and more effective TCR-T therapy targeting multiple tumor antigens.
Citation Format: Xiaoling Liang, Shudan Ou, Minjun Ma, Xihe Chen, Xiangjun Zhou, Yanyan Han. To clone tumor-specific TCRs from a cell-based immunotherapy-benefit cervical cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2554.
Abstract 2575: NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy
Authors: Lin Ya-Wen , Chang Sou-Yi , Kuo Chih-Chi , Hsiao Cheng-Wen , Hsu Chih-Hsiung , Chou Yu-Ching , Shih Yu-Lueng 
Published: August 2018

Abstract
Background: Colorectal cancer (CRC) is a common malignancy worldwide. CRC patients in the same stage often present with dramatically different clinical scenarios. Thus, robust prognostic biomarkers are urgently needed to guide therapies and improve treatment outcomes. The NKX6.1 gene has been identified as a hypermethylation marker in cervical cancer and functions as a metastatic suppressor by regulating epithelial-mesenchymal transition (EMT). Here, we investigated whether hypermethylation of NKX6.1 might be a prognostic biomarker for CRC.
Results: In this study, we analyzed the methylation and expression of NKX6.1 in CRC tissues and CRC cell lines. We quantitatively examined the NKX6.1 methylation levels in 151 pairs of CRC tissues by using methylation-specific polymerase chain reaction (MS-PCR) analysis and found that NKX6.1 was hypermethylated in 35 of 151 CRC tissues (23.18%). NKX6.1 gene expression was inversely correlated with the DNA methylation level in CRC cell lines in vitro. Then, we analyzed the association of NKX6.1 methylation with clinical characteristics of these CRC patients. NKX6.1 methylation was positively associated with tumor size [odds ratio (OR): 2.84; 95% confidence interval (CI): 1.24 to 6.52]. These data demonstrated that patients with NKX6.1 methylation presented poorer 5-year overall survival (p=0.0167) and disease-free survival (p=0.0083) than patients without NKX6.1 methylation after receiving adjuvant chemotherapy. Most importantly, our data revealed that stage II CRC patients with NKX6.1 methylation had poorer 5-year disease-free survival (p=0.0322) than patients without NKX6.1 methylation after adjuvant chemotherapy.
Conclusions: Our results demonstrated that methylation of NKX6.1 is a novel prognostic biomarker in CRC and may be used as a predictor of the response to chemotherapy.
Citation Format: Ya-Wen Lin, Sou-Yi Chang, Chih-Chi Kuo, Cheng-Wen Hsiao, Chih-Hsiung Hsu, Yu-Ching Chou, Yu-Lueng Shih. NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2575.
Abstract 2590: Race-specific differential expression of CCL25 and CCR9 in triple-negative breast cancer
Authors: King Jeronay , Kapur Neeraj , Mir Hina , Gales Dominique N. , Lillard James W. , Singh Shailesh 
Published: August 2018

Abstract
Breast cancer (BrCa) is the second leading cause of cancer-related deaths among women. Therapeutic intervention of the disease is impeded due to the heterogeneity contributed by inter- and intra-tumoral diversity, as well as difference among cancer-bearing individuals. Triple-negative breast cancer (TNBC) is a hormone-independent and highly aggressive subtype that disproportionally affects African-American (AA) women. However, the molecular basis of racial disparity in therapeutic response and clinical outcome in AA and Caucasian (CA) patients is still obscure. Our group was the first to show the involvement of CCR9 and its natural ligand, CCL25 in cancer progression and therapeutic response, including breast cancer. In this study, we have shown the association of CCR9 and CCL25 with TNBC. Both CCR9 and CCL25 are highly expressed in TNBC cells (MDA-MB-468 and MDA-MB-231) compared to other BrCa subtypes (MCF-7, MDA-MB-361, SKBr-3). Expression of this receptor-ligand pair was significantly elevated in TNBC cells derived from AA compared to those derived from CA patients. RNA-Seq based transcriptome data obtained from The Cancer Genome Atlas (TCGA) confirmed these results. Further, phospho-proteomic profiling of cancer signaling molecules showed race specific hyper-activation of GSK-3α, GSK-3β and NF-κB in AA derived cells. These molecules are known to provide the survival advantage to cancer cells. These findings, therefore, highlight significance of CCR9 and its association with the disparity in observed in TNBC. Hence, CCR9 targeted approach to address the disparity in the therapeutic outcome of TNBC seems to be promising.
Citation Format: Jeronay King, Neeraj Kapur, Hina Mir, Dominique N. Gales, James W. Lillard, Shailesh Singh. Race-specific differential expression of CCL25 and CCR9 in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2590.
Abstract 2609: Overexpression of YAP1 of EGFR-mutant lung adenocarcinoma before tyrosine kinase inhibitor is associated with poor survival
Authors: Hong Soon Auck , Kang Jin-Hyoung , Hong Sook Hee 
Published: August 2018

Abstract
Purpose: EGFR tyrosine kinase inhibitor (EGFR TKI) was approved as a first line treatment for EGFR mutant lung adenocarcinoma (LADC) with advanced stage. YAP1 (Yes-associated protein 1) is a main effector of hippo pathway, related with adverse prognosis and EGFR TKI modulation of non-small cell lung cancer. This study aimed to clarify a prognostic role of YAP1 in EGFR mutant LADC and efficacy for EGFR TKI through the course of EGFR TKI.
Materials and Methods: 41 patients with paired lung cancer specimen before and after EGFR TKI were enrolled in this study. The expression of YAP1 protein was evaluated by immunohistochemistry.
Results: 15 cases (36.6%) with high YAP1 expression was found in pre-EGFR TKI LADC, while high YAP1 expression in 21 cases (52.5%) was detected after EGFR-TKI. The transitional level of YAP1 between pre- and post-EGFR TKI was significantly upregulated (P=0.002). High YAP1 before EGFR TKI was related with shorter OS (P=0.023) and PFS (P=0.041). In addition, high YAP1 before EGFR TKI in T790M mutant LADC was related with poor OS (P&lt;0.001).
Conclusion: YAP1 burden before EGFR TKI was crucial role in prognosis of EGFR mutant LADC treated by EGFR TKI.
Citation Format: Soon Auck Hong, Jin-Hyoung Kang, Sook Hee Hong. Overexpression of YAP1 of EGFR-mutant lung adenocarcinoma before tyrosine kinase inhibitor is associated with poor survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2609.