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  • American Association for Cancer Research (AACR)  (49)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5209-5209
    Abstract: Purpose: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer prognosis in various cancer types. However, ICIs may trigger accelerated tumor progression, regarded as hyperprogressive disease (HPD), in certain patients, and it is still challenging to define HPD. We aimed to investigate the landscape of HPD and the prognostic value of its different definitions in advanced solid cancer patients treated with ICIs. Methods: We conducted a multicenter, prospective cohort study for solid cancer patients receiving ICIs. Among them, only unresectable or metastatic cancer patients were included in this analysis. Tumor response was evaluated according to RECIST 1.1. In patients who showed progressive disease (PD) by RECIST 1.1 at the first tumor evaluation, HPD was defined according to the following three criteria: A) tumor growth kinetics (TGK) ratio (TGKpost-ICI/TGKpre-ICI & gt;=2, B) & gt;=10mm increase in sum of target lesion (SUMtarget)and at least one of the following two criteria - 1) & gt;=40% increase in SUMtarget or 2) & gt;=20% increase in SUMtarget and the appearance of new lesions in at least two different organs, C) TGK ratio & gt;=2 and & gt;50% increase in SUMtarget. The discriminatory ability of three definitions in terms of overall survival (OS) were evaluated by the chi-square, C-statistics, and prediction error with integrated Brier score. Results: A total of 427 patients were included; head and neck (n=22, 5.2%), lung (n=173, 40.5%), breast (n=8, 1.9%), gastrointestinal tract (n=99, 23.2%), hepatobiliary pancreas (n=57, 13.3%), genitourinary (n=56, 13.1%), melanoma (n=5, 1.2%), and others (n=7, 1.6%). Incidences of HPD were 4.9%, 14.8%, and 11.5% in definition A, B, C, respectively. The incidence of HPD was relatively low (2.7%-9.5%) in non-small cell lung cancer compared to other cancer types (10.1%-21.5% in esophagogastric cancer, 3.9%-21.6% in hepatobiliary pancreas cancer, and 5.5%-22.5% in genitourinary cancer). Median OS was the worst for patients with HPD, which ranged from 4.8 months to 4.9 months according to definition A-C. After multivariate analysis adjusting for cancer types, ICIs types, and the number of prior anti-cancer therapy, each definition remained a significant factor for OS (P & lt;0.001, respectively). Both chi-square and C-statistics of definition B were higher than those of definition A and C, although prediction error with integrated brier scores was similar between three definitions. Conclusions: Incidences of HPD appear to be various according to its definitions and cancer types. Given that the RECIST-based definition B not requiring pre-ICI imaging, showed similar discriminatory ability to predict dismal OS compared to TGK-based ones, it may be the most feasible and convenient measure to capture HPD in daily clinical practice. Citation Format: Jwa Hoon Kim, Soohyeon Lee, Min Hee Hong, Jee Hyun Kim, Eun Joo Kang, Tae-Yong Kim, Yeon Hee Park, Ji-Youn Han, Il-Hwan Kim, Sang-We Kim, Dae Ho Lee, Jae Lyun Lee, Jae Cheol Lee, Chang-Min Choi, Changhoon Yoo, Shinkyo Yoon, Jae Ho Jeong, Seyoung Seo, Sun Young Kim, Jin-Hee Ahn, Sook Ryun Park. Hyperprogression in various solid cancers treated with immune checkpoint inhibitors in the real world [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 5209.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 14 ( 2009-07-15), p. 5716-5725
    Abstract: The embryonic stem cell-like gene expression signature has been shown to be associated with poorly differentiated aggressive human tumors and has attracted great attention as a potential target for future cancer therapies. Here, we investigate the potential of the embryonic stem cell signature as molecular target for the therapy and the strategy to suppress the embryonic stem cell signature. The core stemness gene Nanog is abnormally overexpressed in human embryonic carcinoma NCCIT cells showing gene expression profiles similar to embryonic stem cells. Down-regulation of the gene by either small interfering RNAs targeting Nanog or histone deacetylase inhibitor apicidin causes reversion of expression pattern of embryonic stem cell signature including Oct4, Sox2, and their target genes, leading to cell cycle arrest, inhibition of colony formation in soft agar, and induction of differentiation into all three germ layers. These effects are antagonized by reintroduction of Nanog. Interestingly, embryonic carcinoma cells (NCCIT, NTERA2, and P19) exhibit a higher sensitivity to apicidin in down-regulation of Nanog compared with embryonic stem cells. Furthermore, the down-regulation of Nanog expression by apicidin is mediated by a coordinated change in recruitment of epigenetic modulators and transcription factors to the promoter region. These findings indicate that overexpression of stemness gene Nanog in NCCIT cells is associated with maintaining stem cell-like phenotype and suggest that targeting Nanog might be an approach for improved therapy of poorly differentiated tumors. [Cancer Res 2009;69(14):5716–25]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3886-3886
    Abstract: Background:The response of 1st-line EGFR-TKI treatment in advanced EGFR-mutated lung adenocarcinoma patients are highly effective, but its sustainability and clinical course are quite variable from patient to patient. In this study, we investigated the clinical impact of concomitant genetic mutations analyzed by targeted NGS on PFS and acquired resistance in advanced EGFR-mutated lung adenocarcinoma patients. Methods: Eighty-five advanced NSCLC patients harboring EGFR mutations were enrolled prospectively in multi-centers from 2019 to 2022 (NCT04122833). We performed the targeted next generation sequencing on 324 cancer-related genes by Foundation One CDx with pre-treated tumor samples. First- or second-generation EGFR-TKIs(gefitinib, afatinib, or erlotinib) were administered in 1st-line setting. After the progression, tissue re-biopsy or plasma liquid biopsy (FoundationOne Liquid CDx) for NGS if tissue biopsy is difficult or risk was performed. Results: Of the 85 patients (70.6% of female, 65.8% of nonsmoker, 56.4% of E19del and 38.8% of E21 L858R mutation), 50 patients experienced a disease progression in November, 2022. The median PFS was 20 months (95 %CI: 15.2-24.8). The most frequent co-mutations were TP53 (47.1%), CDKN2A/B loss (34.1%), MTAP loss (20%), NKX2-1amp(15.3%), MDM2amp (14.1%), RMB10, CCNE/CCND1 amp, NFKB1 amp (11.8%) and CDK4/6 amp (10.6%). Patients with TP53, CDK4/6 amp and MYC amp were independently associated with shorter PFS. In a multivariate analysis, tumors with copy number alterations such as CDK4/6 amp or Myc amp were also independently associated with shorter PFS. However, the CDKN2A/2B loss, MTAP loss, and MDM amp were not related with the PFS. In the number of co-mutations, patients harboring ≥5 co-mutations identified by NGS had shorter median PFS than patients with 0-1 or 2-4 co-mutations. (mPFS 0-1: 2-4: ≥5 co-mutations=35: 18: 9.3 months, p & lt;0.001). At progression, 22 patients harbored an acquired T790M mutation (25.8%). Before TKI treatment, patients with CDKN2A/B loss, MTP loss or CCND/CCNE1 amp in pretreatment tumor have more acquired T790M mutation after progression significantly (p & lt;0.05) Conclusion: We have demonstrated that concomitant mutations detected by targeted NGS analysis provide significant impact on the drug response and clinical course of advanced EGFR-mutated adenocarcinoma patients treated by 1st-line EGFR-TKIs. It is suggested that targeted NGS along with PCR-based detection will be necessary for precision medicine-based individualized practice of 1st-line EGFR-TKI-based combination treatment. Citation Format: In Ae Kim, Seung Joon Kim, Sung Yong Lee, Chang Min Choi, Jae Cheol Lee, Tae Won Jang, Seung Hun Jang, Chan Kwon Park, Wan Seop Kim, Jae Young Hur, Hee Joung Kim, Young Whan Kim, Key Young Lee. Analysis of concomitant genetic alterations in advanced EGFR-mutated lung adenocarcinoma by targeted NGS: A multicenter prospective and real world study. [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 3886.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 347-347
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 347-347
    Abstract: Dastinib (BMS-354825) is a FDA-approved small compound that was developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor of wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA; Orfiril) has been a well-known anti-epileptic drug worldwidely, and belong to the class I histone deacetylase inhibitor. The aim of this research is to determine the anti-leukemic effects of combination of dasatinib and VPA or their mechanism in acute myeloid leukemia (AML) cells. In this study, dasatinib showed potent inhibitory effects on VPA-treated AML cells that were associated with induced G1 phase cell cycle arrest and also apoptosis including the cleavage of PARP, caspase-3, -7 and -9. Moreover, inhibitors of caspase-3 and -9 (Z-DEVD-FMK and LEHD-CHO) efficiently inhibited dasatinib-induced apoptosis in VPA-treated AML cells. Therefore, dasatinib/VPA-induced cell death occurred via caspase-dependent apoptosis. Also, inhibitors of MEK/ERK (U0126 and PD98059) and p38 MAPK (SB203580) efficiently inhibited dasatinib/VPA-induced apoptosis. The combination of dasatinib and VPA differentiation capacity of AML cells is more powerful than each drug alone. So the combination is enough to push AML cells to death strongly by G1 cell cycle arrest and caspase-dependent apoptosis. In addition, MEK/ERK and p38 MAPK controls dasatinib/VPA-induced apoptosis as an upstream regulator. Finally, co-treatment of dasatinib and VPA is contributed to AML cell death by regulation of differentiation capacity. Taken together, these results indicate that dasatinib and VPA together have a potential for anti-leukemic therapy. Citation Format: Sook-Kyoung Heo, Eui-Kyu Noh, Dong-Joon Yoon, Jae-Cheol Jo, Jae-Hoo Park, Hawk Kim. Dasatinib accelerates valproic acid-induced acute myeloid leukemia cells death by regulation of differentiation capacity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 347. doi:10.1158/1538-7445.AM2014-347
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 1 ( 2014-01-01), p. 253-262
    Abstract: In non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKI) can occur through a generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets both MET and AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed. The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation led to resistance in HCC827/ER. The combination of gefitinib or erlotinib with NPS-1034 synergistically inhibited cell proliferation and induced cell death in both resistant cell lines. Accordingly, suppression of Akt was noted only in the presence of treatment with both drugs. NPS-1034 was also effective in xenograft mouse models of HCC827/GR. Although the H820 cell line was reported previously to have T790M and MET amplification, we discovered that AXL was also activated in this cell line. There were no antitumor effects of siRNA or inhibitors specific for EGFR or MET, whereas combined treatment with AXL siRNA or NPS-1034 and EGFR-TKIs controlled H820 cells, suggesting that AXL is the main signal responsible for resistance. In addition, NPS-1034 inhibited cell proliferation as well as ROS1 activity in HCC78 cells with ROS1 rearrangement. Our results establish the efficacy of NPS-1034 in NSCLC cells rendered resistant to EGFR-TKIs because of MET or AXL activation or ROS1 rearrangement. Cancer Res; 74(1); 253–62. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 6
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    Online Resource
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4870-4870
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4870-4870
    Abstract: We evaluated the novel gamma-lactam-based analogue, KBH-A145, for its anticancer activities. KBH-A145 markedly inhibited histone deacetylase (HDAC) activity in vitro and in vivo to an extent comparable to suberoylanilide hydroxamic acid (SAHA). The proliferation of various types of cancers was significantly suppressed by KBH-A145, among which MDA-MB-231 and MCF, human breast cancer cells and ACHN human renal cancer cells, were most sensitive. This was accompanied by induction of p21WAF1/Cip1 through compromised recruitment of HDAC1, which leads to hyperacetylation of its promoter region and thus arrested both cells in the G2/M phase. Interestingly, this compound induced apoptosis of MDA-MB-231 cells, but not ACHN cells, through cleavage of poly(ADP-ribose) polymerase (PARP). Taken together, these results show that this novel gamma -lactam-based HDAC inhibitor potently inhibits the growth of human breast and renal cancer cells. Thus KBH-A145 is a potential therapeutic agent for the treatment of these types of cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4870.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 7
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 11_Supplement ( 2013-11-01), p. C192-C192
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. C192-C192
    Abstract: Protein L-isoaspartyl methyltransferase (PIMT), the “protein repair enzyme,” specifically methylates the isoaspartyl residue generated by the spontaneous deamidation of asparagine, and this methylation is an essential step for converting isoaspartate to aspartate. However, the role of the PIMT in the regulation of protein functions is relatively less understood. Here, we show that PIMT negatively regulates the tumor suppressor protein p53 by reducing the p53 protein levels, thereby suppressing the p53-mediated transcription of target genes. In addition, PIMT depletion up-regulates the proapoptotic and checkpoint activation functions of p53. Moreover, PIMT destabilizes p53 by enhancing the p53-HDM2 interaction. These PIMT effects on p53 stability and activity are attributed to the PIMT-mediated methylation of p53 at isoaspartate residues 29 and 30. Our study provides a new insight into molecular mechanisms by which PIMT suppresses the p53 activity through carboxyl methylation, and suggests a novel therapeutic target for cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C192. Citation Format: Min-Gyu Lee, Jae-Cheol Lee, Ki-Hong Nam, Jihee Yoo, Jeehun Park, Jeung-Whan Han. Protein L-isoaspartyl methyltransferase negatively regulates p53 activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C192.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 8
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 11 ( 2020-11-01), p. 1393-1406
    Abstract: Regulatory T cells (Treg) are enriched in the tumor microenvironment (TME) and suppress antitumor immunity; however, the molecular mechanism underlying the accumulation of Tregs in the TME is poorly understood. In various tumor models, tumor-infiltrating Tregs were highly enriched in the TME and had significantly higher expression of immune checkpoint molecules. To characterize tumor-infiltrating Tregs, we performed bulk RNA sequencing (RNA-seq) and found that proliferation-related genes, immune suppression–related genes, and cytokine/chemokine receptor genes were upregulated in tumor-infiltrating Tregs compared with tumor-infiltrating CD4+Foxp3− conventional T cells or splenic Tregs from the same tumor-bearing mice. Single-cell RNA-seq and T-cell receptor sequencing also revealed active proliferation of tumor infiltrating Tregs by clonal expansion. One of these genes, ST2, an IL33 receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL33-directed ST2 signaling induced the preferential proliferation of tumor-infiltrating Tregs and enhanced tumor progression, whereas genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrated the IL33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of Tregs in the TME and suggests that the IL33/ST2 axis may be a potential therapeutic target for cancer immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 16 ( 2019-08-15), p. 4135-4148
    Abstract: Snail is a key regulator of epithelial–mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3β-dependent Snail phosphorylation and βTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38–Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38–Snail axis in ovarian cancer. Significance: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 24 ( 2016-12-15), p. 6228-6235
    Abstract: Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery. Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P & lt; 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort. Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03] . In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence. Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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