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  • American Association for Cancer Research (AACR)  (80)
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  • 1
    Online Resource
    Online Resource
    A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRγ), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 16 ( 2019-08-15), p. 5069-5081
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 16 ( 2019-08-15), p. 5069-5081
    Abstract: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy–refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 μmol/L), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC. Experimental Design: We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor–bearing mice were orally administered with DN200434, followed by 124I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor–bearing mice treated with DN200434 were administered 131I (beta ray–emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively. Results: DN200434–ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC. Conclusions: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-3007
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Abstract 161: Patient-derived organoids (PDOs) hub of National Cancer Center, Korea: pre-clinical model for drug screening
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 161-161
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 161-161
    Abstract: Purpose Cancer is one of the leading causes of death worldwide. Patient-derived tumor cells can serve as a powerful resource for studying pathophysiologic mechanisms and developing robust strategies for precision medicine. To address this problem, we launched the patient-derived organoids (PDOs) Hub to establish a comprehensive model of various tumor organoids from pancreatic, biliary tract, liver, colorectal, breast, gastric, ovarian, and oral cancers, with matching clinical data and molecular characteristics. Methods All specimens were collected from histologically confirmed cancer patients at the National Cancer Center. Samples obtained from surgery, biopsy, or body fluid (malignant ascites or pleural effusion) were collected for ex vivo culture of tumor cells. PDOs were managed according to our standard operating procedure (SOP), which included specimen delivery process, separation of cells from tissues, criteria for subculture, quality control (QC), production of genomic and histologic data, and the 384-well-based drug response evaluation system. Organoids were considered to be successfully cultured when they were maintained for five or more passages. Results A total of 263 PDOs were established from various cancer types, including oral cancer (N = 89), pancreatic cancer (N = 48), ovarian cancer (N = 32), breast cancer (N = 30), biliary tract cancer (N = 29), hepatocellular carcinoma (N = 17), gallbladder cancer (N = 8), gastric cancer (N = 7) and colorectal cancer (N = 3). PDOs broadly recapitulated the histologic and genetic characteristics of the patient’s tumor. These organoids available for long-term culture were cryopreserved, and a total of 2986 stocks have been accumulated. Drug screening tests were performed with 60 PDOs (pancreatic cancer, N = 36; breast cancer, N = 15; ovarian cancer, N = 6; gastric cancer, N = 3) using selected agents among the 47 drugs for each type of cancer. Profiles of cytotoxic agents were well correlated with the patient’s clinical responses to the matched drugs and tested investigational agents also showed promising antitumor activity. Conclusions We have established a model of several human cancer organoids. This will serve as the platform that can recapitulate the physiology and drug response profiles of human cancer and pave the way for screening innovative drugs, identifying novel targets, and stratifying patients for pertinent therapeutic options. (This work was supported by National Research Foundation of Korea grant, funded by the Korean government (MSIT) (No. 2020M3A9A5036362)) Citation Format: Yebeen Yu, Mi Rim Lee, Wonyoung Choi, Sumin Kang, Jeong Eun Gong, Soobeen Heo, Hye Ju Park, Sang Myung Woo, So-Youn Jung, Sung Weon Choi, Jong-Ho Lee, Myong Cheol Lim, Ji Yeon Baek, Bo Hyun Kim, Ji Hoon Kim, Yuri Cho, Sang-Jae Park, Yun-Hee Kim, Sun-Young Kong. Patient-derived organoids (PDOs) hub of National Cancer Center, Korea: pre-clinical model for drug screening [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 161.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-161
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    Arrest Defective 1 Autoacetylation Is a Critical Step in Its Ability to Stimulate Cancer Cell Proliferation
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 11 ( 2010-06-01), p. 4422-4432
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 11 ( 2010-06-01), p. 4422-4432
    Abstract: The N-acetyltransferase arrest defective 1 (ARD1) is an important regulator of cell growth and differentiation that has emerged recently as a critical molecule in cancer progression. However, the regulation of the enzymatic and biological activities of human ARD1 (hARD1) in cancer is presently poorly understood. Here, we report that hARD1 undergoes autoacetylation and that this modification is essential for its functional activation. Using liquid chromatography-tandem mass spectrometry and site-directed mutational analyses, we identified K136 residue as an autoacetylation target site. K136R mutation abolished the ability of hARD1 to promote cancer cell growth in vitro and tumor xenograft growth in vivo. Mechanistic investigations revealed that hARD1 autoacetylation stimulated cyclin D1 expression through activation of the transcription factors β-catenin and activator protein-1. Our results show that hARD1 autoacetylation is critical for its activation and its ability to stimulate cancer cell proliferation and tumorigenesis. Cancer Res; 70(11); 4422–32. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-3258
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 4
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    Abstract 6529: GI101, A novel CD80-IgG4-IL2 variant bispecific protein, inhibits tumor growth and induces anti-tumor immune response in multiple preclinical models
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 6529-6529
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 6529-6529
    Abstract: Introduction: Immune checkpoint blockades (ICBs) have revolutionized cancer treatment and broadened clinical applicability. However, the majority of patients still fail to respond to standard ICBs. To overcome such unmet needs in a clinical study, we designed GI-101, combining the extracellular domain of CD80 serve as a CTLA-4 blockade and an IL-2 variant that preferentially binds the IL-2 receptor β subunit (IL-2Rβ) together. The harmonizing mechanisms of action are projected to translate into improved clinical benefits for this first-in-class immune checkpoint inhibitor fusion protein, even in non-inflamed “cold” tumors. Methods: Binding affinity of GI101 to IL2Rs, CTLA4, and CD28 was determined by SPR. Immune cell proliferation was analyzed by CFSE assay. In vivo anti-tumor efficacy was tested by single or combination treatment on CT26, MC38 and B16F10 syngeneic tumor models. To elucidate the involvement of GI101 on tumor microenvironment (TME), immune cell population was analyzed by flow cytometry from tumor. Tumor specific T cells (surrogate marker, gp70) were measured by splenocyte proliferation assay and IFN-γ ELISPOT assay. RNA sequencing was performed to elucidate immune mechanism of GI-101. Results: GI101 highly binds to CTLA-4 (Kd, 2.9 nM) which leads to the reinforcement of endogenous CD80 and CD28 interaction resulting in the activation of T cells. Bivalent IL-2 variant of GI101 triggers both CD8+ T and NK cells proliferation in vitro and in vivo without Tregs proliferation. GI101 has no evidence for toxicity associated with IL-2 activity including vascular leakage syndrome and cytokine storm in non-GLP monkey studies whereas isolated mortality was observed in the anti-PD-1 and anti-CTLA4 combination treatment group. GI101 elicits restoration of immune functions in vitro settings using mouse splenocytes co-cultured with different PDL-1 and CTLA-4 expression level tumor cells. A dose-dependent (3 to 12 mg/kg) inhibition of tumor growth was observed in CT26 syngeneic models without toxicity. Immune profiling of tumor samples also revealed that a robust increment of M1 macrophages, CD8+ central memory T cells (Tcm) and Ki-67+ proliferating T cells but not Tregs in TME (p & lt; 0.05). Tumor specific T cells were strongly proliferated when stimulated with CT26 neoantigens (gp70, RSPWFTTLI and MGPLIVLLL) in splenocyte. IFN-γ+ cells were significantly increased in draining lymph nodes from GI101 treated mice. Furthermore, drastic tumor regression was observed in MC38 tumor-bearing mice treated with GI101 and anti-PD-1 combination. Conclusion: GI101 facilitates the dual function of checkpoint blockade and IL2 activity that enhances the proliferation and activation of T and NK cells. This novel target drug is expected to be interpreted as superior clinical efficacy and safety as indicated even in ‘cold tumor' models. GI101 is the promising immune-oncology drug to replace the first-generation ICBs by single or combining with other immunotherapies. Our findings provide a rationale for further clinical investigations. Keywords: CD80, IL-2 variant, GI101, Bispecific fusion protein, immunotherapy Citation Format: Kyoung-Ho Pyo, Young Jun Koh, Chun-Bong Synn, Jae Chan Park, Jae-Hwan Kim, Yeongseon Byeon, Sung Eun Kim, Ji Min Lee, Ha Ni Jo, Wongeun Lee, Do Hee Kim, Sungwon Park, Yoo Jeong Song, Won Jae Lee, Ji Young Kim, Hyung Nam Ji, Sang Su Park, Kyung Wha Lee, Young Gyu Cho, Young Min Oh, Bo Gie Yang, Su Youn Nam, Myoung Ho Jang, Byoung Chul Cho. GI101, A novel CD80-IgG4-IL2 variant bispecific protein, inhibits tumor growth and induces anti-tumor immune response in multiple preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6529.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-6529
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    Abstract 6219: WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6219-6219
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6219-6219
    Abstract: As the representative targeted anticancer drug for colon cancer patients, cetuximab is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild type cancers. Even some patient with KRAS wt gene did not respond cetuximab. However, there is no treatment available for cetuximab-resistant patient group, which is almost 50% of KRAS WT gene holders. Recently, our team identified cetuximab primary resistant related proteins named as mtRTK (mutant receptor tyrosine kinase) by array analysis based cetuximab responder or non-responder colon cancer patient tissues. We investigated mtRTK’s oncogenic potential as a novel anti-cancer target. A large proportion of colon cancer patients (36.2% Caucasian, 56.9% Korean) expressed the mtRTK was identified, using the sequencing analysis of patient samples. Based on these results, our efforts have led to the discovery of WM-S1, mtRTK inhibitor, which is the first mtRTK inhibitor in clinical development. The potent enzyme inhibitor showed a high anticancer activity confirmed in Patient-Derived Cells (PDC) and Patient-Derived Xenograft (PDX) animal models expressing the mutation. In preclinical studies demonstrate that WM-S1 is well tolerated in rats and dogs. Furthermore, WM-S1 has potent anticancer activities for various solid tumor (NSCLC, cholangiocarcinoma, etc.) including activated mtKRAS colon cancer expressing the mtRTK. Currently we are investigating WM-S1 in a phase 1a trial in AUS, which is the first mtRTK inhibitor in clinical development. Meanwhile, the mtRTK inhibitor WM-S1 drives antitumor immunity (with anti-PD-L1) in NSCLC. Combinational approaches with immunotherapy showed that synergistic effect of WM-S1 and anti-PD1 monoclonal antibody, suppressing tumor growth by 75% in anti-PD1 resistance NSCLC-derived humanized mouse model. A phase 1b trial is expected to develop WM-S1 through not only indication expansion but also combination therapy with immuno-checkpoint inhibitors in the USA, AUS and KOR from Q2 2022. In conclusion, mtRTK is a potential oncogenic driver mutation in various solid tumor. A first-in-class anticancer agent WM-S1 targeting mtRTK can be promising therapeutic agents for cetuximab-resistant colon cancer patients regardless of KRAS mutation status and other cancers. Citation Format: Joseph Kim, Jai-Hee Moon, Kyung-Mi Lee, Hyun Ryu, Eun Hye Park, Sang Hee Kim, Jeong Seok Kim, Young Ok Ko, Yong Seok Kim, Hyo Jin Kim, Tae Young Kim Kim, Moon Seong Yoo, Soll Jin, Seongrak Kim, Yoon Sun Park, Min Ki Lee, Mi So Lee, Ji Hyun Go, Yu Geun Ji, Jun Hyung Lee, Haneul Lee, Min Hwa Kim, Eun Hee Ko, Yeo Jin Lee, Seung-Mi Kim, Joon-yee Jeong, Yeon-seoung Choi, Seung-geon Bae, Jinwoo Lee, Won Jun Lee, Min-Kyeong Kim, Ji min Shin, Dong-in Koh, Sun-Chul Hur, Chun-Ho Park, Hyun Ho Lee, Dong-Hoon Jin. WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of 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 6219.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6219
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Gene Therapy Using TRAIL-Secreting Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells against Intracranial Glioma
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 23 ( 2008-12-01), p. 9614-9623
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 23 ( 2008-12-01), p. 9614-9623
    Abstract: Adenovirus-mediated gene therapies against brain tumors have been limited by the difficulty in tracking glioma cells infiltrating the brain parenchyma. Human umbilical cord blood–derived mesenchymal stem cells (UCB-MSC) are particularly attractive cells for clinical use in cell-based therapies. In the present study, we evaluated the tumor targeting properties and antitumor effects of UCB-MSCs as gene delivery vehicles for glioma therapy. We efficiently engineered UCB-MSCs to deliver a secretable trimeric form of tumor necrosis factor-related apoptosis-inducing ligand (stTRAIL) via adenoviral transduction mediated by cell-permeable peptides. We then confirmed the migratory capacity of engineered UCB-MSCs toward tumor cells by an in vitro migration assay and by in vivo injection of UCB-MSCs into the tumor mass or the opposite hemisphere of established human glioma in nude mice. Moreover, in vitro coculture, experiments on Transwell plates, and in vivo survival experiments showed that MSC-based stTRAIL gene delivery has more therapeutic efficacy compared with direct injection of adenovirus encoding the stTRAIL gene into a tumor mass. In vivo efficacy experiments showed that intratumoral injection of engineered UCB-MSCs (MSCs-stTRAIL) significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with controls. These results suggest that human UCB-MSCs have potential use as effective delivery vehicles for therapeutic genes in the treatment of intracranial glioma. [Cancer Res 2008;68(23):9614–23]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-0451
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 7
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    Abstract 3682: Enhanced anticancer effect of 5-fluorouracil loaded into thermoresponsive conjugated linoleic acid-incorporated poloxamer hydrogel on metastastic colon cancer models
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3682-3682
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3682-3682
    Abstract: Background: 5-Fluorouracil (5-FU) is a useful chemotherapeutic agent in the treatment of solid tumors. However, it is very short half-life in plasma circulation greatly limited the in vivo antitumor efficacy, and intravenous 5FU injection is unlikely to achieve optimal dose effectiveness within peritoneal cavity. Conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an effective drug delivery system with numerous advantages and has an anticancer activity. It was also shown that paclitaxel loaded in Plu-CLA demonstrated synergistic tumor suppression through robust cell cycle arrest and enhanced apoptosis in tumor compared to paclitaxel in poloxamer hydrogel. The aim of this work is to evaluate the therapeutic efficacy of Plu-CLA as a new intraperitoneal 5FU delivery system. Methods: Cytotoxicity was evaluated by using CT-26 murine colon carcinoma cell. We established peritoneal metastasis models and hepatic metastasis models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI). Results: MTT assay indicated that 5-FU loaded in Plu-CLA hydrogel (P-FU) could increase the cytotoxic activity of 5-FU in CT-26. P-FU significantly enhanced apoptosis compared with 5-FU control. It was found that Caspase 3 and p21 were up-regulated, whereas Bcl-2 was down-regulated. Moreover, growth of hepatic metastases in vivo was significantly reduced in mice treated with P-FU. Treatment with P-FU substantially delayed tumor growth of intraperitoneal metastasis greatly and tumor-bearing mice treated with P-FU showed a better survival tendency than the 5-FU alone. Conclusion: These results were attributed to the synergistic effect of Plu-CLA. 5-FU administered in Plu-CLA hydrogel led to significant enhancement of tumor growth suppression and cellular apoptosis. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophilic 5-FU for the effective treatment of metastatic colon cancer. . 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 3682.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3682
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 8
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    Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 5 ( 2016-03-01), p. 1256-1264
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 5 ( 2016-03-01), p. 1256-1264
    Abstract: Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2−/− and Sav1−/− mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P & lt; 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12–2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P & lt; 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256–64. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-1447
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
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    Abstract 4235: Anti-proliferative effect of (19 Z )-halichondramide from the sponge Chondrosia corticata via G2/M cell cycle arrest and suppression of mTOR signaling in human lung cancer cells
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4235-4235
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4235-4235
    Abstract: Five oxazole-containing macrolides isolated from the marine sponge Chondrosia corticata were evaluated for their anti-proliferative activity in a panel of human solid cancer cell lines. (19Z)-Halichondramide ((19Z)-HCA), a novel trisoxazole-containing macrolide, exhibited the highest potency among the macrolides, with IC50 values in the submicro-molar ranges. Prompted by the high potency of growth inhibition of cancer cells, we investigated the mechanism of action of the anti-proliferative activity of (19Z)-HCA in human A549 lung cancer cells. (19Z)-HCA induced cell cycle arrest in the G2/M phase, and this event was highly correlated with the expression of checkpoint proteins, including the up-regulation of p53 and GADD45α and the down-regulation of cyclin B1, cyclin A, CDC2, and CDC25C. In addition, the growth inhibition by (19Z)-HCA was associated with the suppression of mTOR and its downstream effector molecules 4EBP1 and p70S6K. The modulation of mTOR signaling by (19Z)-HCA was found to be mediated by the regulation of upstream proteins, including the down-regulation of Akt and p38 MAPK and the up-regulation of AMPK. These data suggest the potential of (19Z)-HCA to serve as a candidate for cancer chemotherapeutic agents derived from marine organisms by virtue of arresting the cell cycle in the G2/M phase and the modulation of mTOR/AMPK signaling pathways. [Acknowledgements: This work was supported by the MarineBio Research Program (NRF-2013045101) of the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MEST).] Citation Format: Song Yi Bae, Jayoung Song, Yoonho Shin, Won Kyung Kim, Jedo Oh, Tae Joon Choi, Eun Ju Jeong, So Hyun Park, Eun Jeong Jang, Ji In Kang, Hyen Joo Park, Ji-Young Hong, Gi Dae Kim, Ju-eun Jeon, Jongheon Shin, Sang Kook Lee. Anti-proliferative effect of (19Z)-halichondramide from the sponge Chondrosia corticata via G2/M cell cycle arrest and suppression of mTOR signaling in human lung cancer cells. [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 4235. doi:10.1158/1538-7445.AM2014-4235
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4235
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 10
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    Abstract 4237: Antitumor activity of 2-hydroxycinnamaldehyde against human colorectal cancer cells is mediated by the Wnt/β-catenin signaling pathway
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4237-4237
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4237-4237
    Abstract: The antiproliferative and antitumor activities of 2-hydroxycinnamaldehyde (1), a phenylpropanoid isolated from the bark of Cinnamomum cassia , were investigated using human colorectal cancer cells. Compound 1 exhibited antiproliferative effects in HCT116 colon cancer cells, accompanied by modulation of the Wnt/β-catenin cell signaling pathway. This substance was found also to inhibit β-catenin/T-cell factor (TCF) transcriptional activity in HEK293 cells and HCT116 colon cancer cells. Further mechanistic investigations in human colon cancer cells with aberrantly activated Wnt/β-catenin signaling showed that 1 suppressed significantly the binding of β-catenin/TCF complexes to their specific genomic targets in the nucleus and led to the down-regulation of Wnt target genes such as c-myc and cyclin D1. In an in vivo xenograft model, the intraperitoneal administration of 1 (10 or 20 mg/kg body weight, three times/week) for four weeks suppressed tumor growth in athymic nude mice implanted with HCT116 colon cancer cells significantly, without any apparent toxicity. In an ex vivo biochemical analysis of the tumors, compound 1 was also found to suppress Wnt target genes associated with tumor growth including β-catenin, c-myc, cyclin D1, and survivin. The suppression of the Wnt/β-catenin signaling pathway is a plausible mechanism of action underlying the antiproliferative and antitumor activity of 1 in human colorectal cancer cells (Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) No. 20120004939) Citation Format: Won Kyung Kim, Jedo Oh, Song Yi Bae, Jayoung Song, Yoonho Shin, Tae Joon Choi, Eun Ju Jeong, So Hyun Park, Eun Jeong Jang, Ji In Kang, Hyen Joo Park, Ji-Young Hong, Min Ai Lee, Hwa-Jin Chung, Sang Kook Lee. Antitumor activity of 2-hydroxycinnamaldehyde against human colorectal cancer cells is mediated by the Wnt/β-catenin signaling pathway. [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 4237. doi:10.1158/1538-7445.AM2014-4237
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4237
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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