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  • American Association for Cancer Research (AACR)  (36)
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  • 1
    Online Resource
    Online Resource
    Tumor Suppressive Effects of Bromodomain-Containing Protein 7 (BRD7) in Epithelial Ovarian Carcinoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 3 ( 2014-02-01), p. 565-575
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 3 ( 2014-02-01), p. 565-575
    Abstract: Purpose: Bromodomain-containing protein 7 (BRD7), which is a subunit of SWI/SNF complex, has been recently suggested as a novel tumor suppressor in several cancers. In this study, we investigated the tumor suppressive effect of BRD7 in epithelial ovarian cancer. Experimental Design: We analyzed the expression of BRD7 in human ovarian tissues with real-time PCR. To investigate the functional role of BRD7, we transfected ovarian cancer cells (A2780 and SKOV3) with BRD7 plasmid and checked the cell viability, apoptosis, and invasion. The activities of BRD7 in the signaling pathways associated with carcinogenesis were also tested. In addition, we used the orthotopic mouse model for ovarian cancer to evaluate tumor growth-inhibiting effect by administration of BRD7 plasmid. Results: The BRD7 expression was downregulated in the ovarian cancer tissues compared with normal (P & lt; 0.05), high-grade serous cancer exhibited significantly decreased expression of BRD7 compared with low-grade (P & lt; 0.01) serous cancer. Transfection of BRD7 plasmid to A2780 (p53-wild) or SKOV3 (p53-null) ovarian cancer cells showed the tumor suppressive effects assessed by cell viability, apoptosis, and invasion assay and especially significantly decreased tumor weight in orthotopic mouse model (A2780). Moreover, we found that tumor suppressive effects of BRD7 are independent to the presence of p53 activity in ovarian cancer cells. BRD7 negatively regulated β-catenin pathway, resulting in decreased its accumulation in the nucleus. Conclusions: These results suggested that BRD7 acts as a tumor suppressor in epithelial ovarian cancers independently of p53 activity, via negative regulation of β-catenin pathway. Clin Cancer Res; 20(3); 565–75. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-1271
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
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    Linalool-Incorporated Nanoparticles as a Novel Anticancer Agent for Epithelial Ovarian Carcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Therapeutics Vol. 15, No. 4 ( 2016-04-01), p. 618-627
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 4 ( 2016-04-01), p. 618-627
    Abstract: Although cytotoxic chemotherapy is widely used against epithelial ovarian cancer (EOC), adverse side effects and emergence of resistance can limit its utility. Therefore, new drugs with systemic delivery platforms are urgently needed for this disease. In this study, we developed linalool-incorporated nanoparticles (LIN-NP) as a novel anticancer agent. We prepared LIN-NPs by the self-assembly water-in-oil-in-water (w/o/w) emulsion method. LIN-NP–mediated cytotoxicity and apoptosis was assessed in EOC cells, and the role of reactive oxygen species (ROS) generation as the mechanism of action was evaluated. In addition, therapeutic efficacy of LIN-NP was assessed in cell lines and patient-derived xenograft (PDX) models for EOC. LIN-NPs had significant cytotoxicity and apoptotic activity against EOC cells, including A2780, HeyA8, and SKOV3ip1. LIN-NP treatment increased apoptosis in EOC cells through ROS generation and a subsequent decrease in mitochondrial membrane potential and increase in caspase-3 levels. In addition, 100 mg/kg LIN-NPs significantly decreased tumor weight in the HeyA8 (P & lt; 0.001) and SKOV3ip1 (P = 0.006) in vivo models. Although treatment with 50 mg/kg LIN-NP did not decrease tumor weight compared with the control group, combination treatment with paclitaxel significantly decreased tumor weight compared with paclitaxel alone in SKOV3ip1 xenografts (P = 0.004) and the patient-derived xenograft model (P = 0.020). We have developed LIN-NPs that induce ROS generation as a novel anticancer agent for EOC. These findings have broad applications for cancer therapy. Mol Cancer Ther; 15(4); 618–27. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-15-0733-T
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    SSG: 12
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  • 3
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    Abstract 1106: BRAF and EGFR fusion as a novel mechanism of resistance mechanism to Lazertinib, 3rd- generation EGFR-TKI, in EGFR-mutant NSCLC
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1106-1106
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1106-1106
    Abstract: Background: EGFR-TKI is an established first-line therapy for NSCLC with activating EGFR mutations. Osimertinib, third-generation EGFR TKI, was investigated as a first-in-class drug, but lazertinib(YH25448) was also reported as an outstanding drug which had similar efficacy as osimertinib. Nevertheless, acquired resistance is inevitably developed by third-generation EGFR-TKIs in clinic. Even though EGFR C797S mutation has been identified as a major resistant mechanism, the remaining resistance mechanisms to these TKIs are largely unknown. Methods: To explore the mechanism of resistance to lazertinib, we firstly established drug-resistant cells to lazertinib in vitro using four NSCLC cells including the patient-derived cell line (PDC), patient-derived tumor xenograft cell line (PDTC), and ATCC cell lines. To analyze the changes in global genetic alterations and gene expression of established lazertinib-resistant cell lines(YH1R), whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed. The effect of EGFR/BRAF fusion was investigated in vitro using established YH1R cell line and various patient-derived tumor xenograft samples. Western blot study was used to investigate EGFR and MAPK cascade signaling pathway. We evaluated antitumor activity of MEK inhibitor and lazertinib combination treatment in lazertinib-resistant NSCLC cells with EGFR/BRAF fusion in vitro and in vivo. Results: RNA-seq data revealed a novel EGFR/BRAF fusion transcript (EGFR Exon 19-BRAF Exon 9, in-frame fusion) in lazertinib-resistant PC9GR_YH1R. The fusion gene consisted of EGFR (Exon 1-19) portion and BRAF kinase domain (Exon 9-18). The EGFR/BRAF fusion mRNA and protein were specifically upregulated in PC9GR_YH1R compared to parental cells. Intriguingly, we detected the EGFR/BRAF fusion gene expression in patient-derived xenografts (YHIM-1045 and YHIM-1035) obtained from patients who experienced acquired resistance to lazertinib. Compared with treatment with either single agent, combination treatment of lazertinib and MEK inhibitor, trametinib or selumetinib, was significantly effective at inhibiting cell proliferation as well as EGFR signaling pathways in PC9GR_YH1R in vitro and in vivo. Conclusion: We found a novel EGFR/BRAF fusion gene, as a key driver of acquired resistant mechanism of lazertinib, in NSCLC cell lines and patient-derived xenografts with acquired resistance to lazertinib. Combination treatment of lazertinib and MEK inhibitor showed a strong antitumor effect in lazertinib-acquired resistant NSCLCs, indicating that the combination therapy of EGFR and MEK inhibitors might be a promising therapeutic option for overcoming lazertinib-acquired resistant NSCLC patients in clinic. Citation Format: Seo-Yoon Jeong, Jiyeon Yun, San-Duk Yang, Soo-Hwan Lee, Sangbin Lim, Seok-Young Kim, Min Hee Hong, Sun Min Lim, Hye Ryun Kim, Hye Ryun Kim, Byoung Chul Cho. BRAF and EGFR fusion as a novel mechanism of resistance mechanism to Lazertinib, 3rd- generation EGFR-TKI, in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1106.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1106
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 4
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    Abstract CT171: Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT171-CT171
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT171-CT171
    Abstract: Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study Background: There are several things needed to be resolved for successful efficacy when NK cell therapy is applied for solid tumor; improvement of NK cell invasion into tumor, activation and production of a large number of NK cells, etc. Basically, in human, NK cell number is relatively small compared to other immune cells such as T cell and the number becomes severely low when NK cell is obtained from cancer patients. For these reasons, allogeneic NK cell has been used for clinical studies against various cancer types. Recently, we also have finished a phase1 study of allogeneic NK cell therapy for cholangiocarcinoma, enrolling 9 patients at inoperable and no chemotherapy favorable stage due to side effects. Four of nine patients (44%) showed SD (stable disease) after six NK cell injections and no severe AE (adverse event) was found. In this following phase 2a study, to bring out immuno-synergetic effect of NK cell therapy against the inoperably advanced bile duct cancer, we have designed a combinatorial protocol with using Pembrolizumab. Methods: Enrollment of 40 bile duct cancer patients has been finished for a combinatorial study of allogeneic NK cell therapy with Pembrolizumab at two different sites in Korea (ClinicalTrials gov, NCT03937895). Patients were eligible for the enrollment when they were inoperable and no chemotherapy favorable stage due to side effects, and also when they had PD-L1-positive score. For treatment, the most favorable method for highly activated allogeneic NK cell production has been determined from our previous study, resulting that 3x106 NK cells per kg are injected for each dose along with Pembrolizumab injection. Pembrolizumab (200mg) was given every 3 weeks for up to 9 times and NK cell injection was given for up to 18 times during the maximum injection period of Pembrolizumab. Results: Six patients (pts) were first enrolled for the pilot combinatorial study, dosing 6 times of NK cells and 3 times of Pembrolizumab. The result showed no severe AE from the injections. Among the five pts finished the injections, 2 pts showed SD (Stable Disease) and continued the treatment, being enrolled into the Phase 2a in which 34 more pts were enrolled. Among the 20 pts finished 6 NK cell and 3 Pembrolizumab injections (1st RECIST), 65% of pts showed SD. When 12 NK cell and 6 Pembrolizumab injections finished (2nd RECIST), pts had 40% and 20% of SD and PR (Partial remission). Of the 3 pts at 3rd RECIST (18 NK cell and 9 Pembrolizumab), 1 and 2 pts showed SD and PR, respectively. Finding pts experienced AE, a total of 6 AEs has been reported: no treatment-related AE, one grade 3 (Encephalopathy), and five grade 1-2 with common AE. In a recent safety and efficacy study of pembrolizumab alone (10mg/kg, every 2 weeks for up to 2 years) with 28 pts of advanced bile duct cancer showing PD-L1 expression, 17% pts showed PR, 17% pts and 52% had SD and PD (progressive disease), respectively. Although our study is still ongoing, continuing the combinatorial treatment gives rise to PR, suggesting that NK cell therapy with Pembrolizumab shows an immuno-synergetic effect for the cancer. Biomarker experiments with the injected NK cells supports our finding and we will discuss this at presentation. Citation Format: Yong Yoon Chung, Seung Woo Park, Jung-Min Im, Da-Kyung Yoo, Hyo-Cheon Cheon, Jae-Eun Kim, Kyeong-Pill Lim, Eun-Hee Yang, Hye-Jin choi, Hyo-Sun Chung, Seo-Yeon Kim, Ju-Yong Lee, In-Hye Jung, Seung Min Bang, Moon Jae Chung, Sung Ill Jang, Jae Hee Cho, Hee Seung Lee, Jung Youp Park, Jung Hyun Jo. Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT171.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT171
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Abstract 265: Epi-magnolin suppresses EGF-induced neoplastic cell transformation by inhibition of Akt/mTOR signaling pathway in JBC Cl41 cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 265-265
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 265-265
    Abstract: The phosphatidylinositol-3-kinase (PI3K)/Akt/the mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in human cancer and plays a pivotal role in cell proliferation and transformation. In this study, we reveal epi-magnolin, a phytochemical found in Magnolia flos, as an inhibitor of Akt/mTOR signaling pathway. Epi-magnolin inhibits EGF-induced Akt phosphorylation at Thr308 and Ser473, but not extracellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathway. Moreover, we demonstrate that epi-magnolin suppresses JB6 cell proliferation by impairing EGF-induced G1/S cell cycle transition in a dose-dependent manner. Notably, epi-magnolin abrogates phosphorylation of c-Jun at Ser63 and 73 as well as total c-Jun protein level, which leads to downregulation of AP-1 transactivation activity. The inhibition effect of Akt/mTOR signaling pathway and AP-1 transactivation activity by epi-magnolin suppressed EGF-induced anchorage-independent cell transformation. Based on these results, epi-magnolin might be a chemopreventive agent by targeting Akt/mTOR signaling pathway. Key words: chemoprevention, cell transformation, Akt/mTOR signaling pathway Citation Format: Cheol-Jung Lee, Sun-Mi Yoo, Seung-Min Kim, Seon-Yeon Cho, Juhee Park, Yu-Mi Shin, Yong-Yeon Cho, Hye Suk Lee. Epi-magnolin suppresses EGF-induced neoplastic cell transformation by inhibition of Akt/mTOR signaling pathway in JBC Cl41 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 265.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-265
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Abstract 1148: Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1148-1148
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1148-1148
    Abstract: Introduction: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents. Methods: Hu-PBL-NSG mouse model was established by engrafting human peripheral blood lymphocytes (PBLs) into NOD-scid (NSG) mice. The 6-7 week-old NSG mouse was transfused with 1 x 107 cells of PBL via tail vein, and human immune cells were characterized after 24 hours, and weekly thereafter. Cytokine array was performed to assess serological similarity between patient and the Hu-PBL-NSG mouse, and microscopic immune cell infiltration was observed in various organs mouse model. Human anti-PD-1 therapy was treated for assessing drug efficacy in patient-derived tumor. Results: hCD3+hCD45+ T-cells and antigen presenting cells (dendritic cells, macrophages, and MDSC) increased in the serum of Hu-PBL-NSG mouse 24 hour after the transfusion of human PBLs, and CD3+ T cells were observed in lung, liver, kidney, spleen sections. Cytokine arrays of human and Hu-PBL-NSG mouse revealed high similarity of Th1, Th2, Th17-related cytokines. A tumor xenograft was engrafted from an EML4-ALK patient, and Hu-PBL-NSG mouse was sacrificed for histological analyses. hCD3+ T cells were infiltrated within the tumor, and CD11c+ cells, which represent antigen-presenting capability, were seen in spleen, lung, liver and kidney. When anti-PD-1 Ab was treated intraperitoneally, xenograft tumor showed significant reduction in volume after day 6, and increased expression of immune response-related genes on microarray analysis in the tumor. Mostly IFN-gamma and its related gene sets were significantly changed (FDR & lt; 0.25, GSEA). Conclusion: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC. Citation Format: Sun Min Lim, Kyoung-Ho Pyo, Jae Hwan Kim, Ji Min Lee, Seong Keun Kim, Sung Eun Kim, Ha Ni Jo, Jae Soek Cho, Hye Ryun Kim, Byoung Chul Cho. Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models [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 1148.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1148
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    RhoGDI2 Expression Is Associated with Tumor Growth and Malignant Progression of Gastric Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 8 ( 2009-04-15), p. 2612-2619
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 8 ( 2009-04-15), p. 2612-2619
    Abstract: Purpose: Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of Rho family GTPase. However, there is currently no direct evidence suggesting whether RhoGDI2 activates or inhibits Rho family GTPase in vivo (and which type), and the role of RhoGDI2 in tumor remains controversial. Here, we assessed the effects of RhoGDI2 expression on gastric tumor growth and metastasis progression. Experimental Design: Proteomic analysis was done to investigate the tumor-specific protein expression in gastric cancer and RhoGDI2 was selected for further study. Immunohistochemistry was used to detect RhoGDI2 expression in clinical samples of primary gastric tumor tissues which have different pathologic stages. Gain-of-function and loss-of-function approaches were done to examine the malignant phenotypes of the RhoGDI2-expressing or RhoGDI2-depleting cells. Results: RhoGDI2 expression was correlated positively with tumor progression and metastasis potential in human gastric tumor tissues, as well as cell lines. The forced expression of RhoGDI2 caused a significant increase in gastric cancer cell invasion in vitro, and tumor growth, angiogenesis, and metastasis in vivo, whereas RhoGDI2 depletion evidenced opposite effects. Conclusion: Our findings indicate that RhoGDI2 is involved in gastric tumor growth and metastasis, and that RhoGDI2 may be a useful marker for tumor progression of human gastric cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-2192
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 8
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    Abstract 2855: Identification of optimal treatment sequence and acquired resistance mechanisms of ALK inhibitors using EML4-ALK transgenic mouse model
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2855-2855
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2855-2855
    Abstract: Introduction: EML4-ALK is a distinct molecular entity that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). While many trials have showed the superiority of ALK TKIs over cytotoxic chemotherapy, the optimal sequencing of ALK TKIs is still obscure. Acquired resistance to ALK TKIs remains a key challenge, and unknown mechanisms of resistance need to be resolved. In this study, we aimed to identify optimal treatment sequence and acquired resistance mechanisms of ALK TKIs using EML4-ALK transgenic mice model that recapitulates human EML4-ALK lung adenocarcinoma. Methods: The tumorigenesis of EML4-ALK transgenic mice was based on Cre-ERT2/Lox system, and intraperitoneal injection with tamoxifen induced lung tumors. When tumor nodules were observed, EML4-ALK transgenic mice were treated with either crizotinib (150mg/kg) followed by ceritinib (75mg/kg) upon progression (N=13) or with ceritinib followed by crizotinib (N=12) upon progression. Tumor response was evaluated weekly using magnetic resonance imaging. Progression-free survival (PFS) was measured to compare the efficacy between two ALK TKIs. For the analysis of acquired resistance mechanism, whole-exome sequencing, RNA sequencing, and targeted sequencing of ALK gene were performed. Results: Head-to-head comparison of crizotinib and ceritinib was performed in the first-line setting. A total of 13 mice were treated with upfront crizotinib, and mice that showed progressive disease (PD) were crossed over to ceritinib (n=9). A total of 12 mice were treated with upfront ceritinib, and mice that showed PD (n=8) were crossed over to crizotinib. Four mice in each group were sacrificed for analysis of resistance mechanism at the time of PD. The PFS of ceritinib was significantly longer than that of crizotinib [24 weeks (95% CI, 21.4-26.5) vs. 8 weeks (95% CI, 6.5-9.0), P & lt; 0.001]. Subsequent treatment with ceritinib following crizotinib resulted in significantly longer PFS than crizotinib following ceritinib [7 weeks (95% CI, 4.1-9.9) vs 3 weeks (95% CI, 2.5-3.5), P & lt; 0.001]. Altogether, treatment with ceritinib followed by crizotinib showed a prolongation of PFS, compared to crizotinib followed by ceritinib (27 weeks vs. 15 weeks, P & lt; 0.001). We noted that ALK-TKI resistant tumors harbored several copy number variations (CNVs), and nonsynonymous oncogenic mutations, but found no previously reported resistant mechanisms including secondary mutations, or CNVs. Wnt signaling related gene set was increased in both crizotinib- and ceritinib-resistant tumors, and Hippo signaling related gene set was increased in ceritinib-resistant tumors on KEGG pathway-based analysis. Conclusion: Our findings suggest that ceritinib is superior to crizotinib when used in the first-line setting. Novel mechanisms of acquired resistance such as increased Wnt and Hippo signaling need further validation. Citation Format: Kyoung-Ho Pyo, Lim Sun Min, Jae Hwan Kim, Ji Min Lee, Ha Ni Jo, Jae Soek Cho, Mi-Ran Yun, Sung Eun Kim, Hye Ryun Kim, Chun-Feng Xin, Tae-Min Kim, Byoung Chul Cho. Identification of optimal treatment sequence and acquired resistance mechanisms of ALK inhibitors using EML4-ALK transgenic mouse model [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 2855.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2855
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 9
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    Abstract 4076: Finding the optimal strategy of incorporating immune checkpoint inhibitor in ALK -positive non-small-cell lung cancer using EML4-ALK transgenic mouse model
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4076-4076
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4076-4076
    Abstract: Introduction: EML4-ALK is a distinct molecular entity that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). Although the role of oncogenic and native ALK in modulating the immune responses has been suggested, immune checkpoint inhibitors (ICIs) have not proved efficacy in ALK-positive non-small cell lung cancer (NSCLC) so far. In this study, we evaluated comprehensive immunomodulatory effect of ALK TKI and aimed to suggest optimal method of incorporating ICIs in ALK-positive NSCLC using an EML4-ALK transgenic mice model. Methods: Ceritinib or anti-PD-1 was treated in EML4-ALK transgenic mice, and tumor response was evaluated using magnetic resonance imaging. Progression-free survival (PFS) and overall-survival (OS) were measured to compare the efficacy in mice. To examine the dynamics of immune response, flow cytometry of tumor region, cytokine-ELISA of bronchoalveolar lavage (BAL) fluid were performed at baseline and at the time of disease progression. Sequencing of ALK kinase domain was performed to identify acquired ALK mutations. Results: Upfront ceritinib was clearly more efficacious than anti-PD-1 upfront, as shown by the median PFS was 139 days vs.13 days (P & lt; 0.05). Use of ceritinib in the first line resulted in a prolonged OS compared to the use in the second line (OS 203 days vs. 135 days, P & lt; 0.05). The efficacy of ceritinib and anti-PD-1 combination was not more effective than ceritinib alone in the first line. Of note, we identified 1 mouse which showed a complete response to anti-PD-1 after progression on 1st line ceritinib. Tumors which progressed on ceritinib showed increased proportion of CD8+ tumor infiltrating T cells among total CD3+ T cells, and increased expression of IFN-γ in BAL fluid, representing Th1-dominant immune phenotype. In tumors which acquired resistance to ceritinib, we identified known ALK kinase domain mutations such as G1202R with a concomitant increased tumor mutational burden compared to ceritinib-naïve tumors. Ceritinib-resistant tumors also had significantly increased memory cytotoxic T cells and PD-1-expressing helper T cells in total CD3+ population. On the contrary, we noted decreased expressions of central memory T cells, effector memory T cells, IFN-γ in tumors which progressed after ceritinib and anti-PD-1 combination therapy. Conclusion: Our study confirmed that combination of ALK inhibitor and ICI is not efficacious, as evidenced by low infiltrating T cells and memory T cells. We concluded that tumor progressing on ceritinib could be sensitive to anti-PD-1 due to increased neoantigens derived from acquired ALK mutations, increased tumor mutational burden and increased number of memory T cells and PD-1-expressing helper T cells. Citation Format: Kyoung-Ho Pyo, Sun Min Lim, Ha Ni Jo, Jae Seok Cho, Jae Hwan Kim, Ji Min Lee, Chun-Feng Xin, Sung Eun Kim, Chae Won Park, Wongeun Lee, Hye Ryun Kim, Byoung Chul Cho. Finding the optimal strategy of incorporating immune checkpoint inhibitor inALK-positive non-small-cell lung cancer usingEML4-ALKtransgenic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4076.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4076
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Abstract 5012: Mouse-human co-clinical trials demonstrate superior efficacy with combinational approach of BKM120 and erbitux over BKM120 monotherapy in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN)
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5012-5012
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5012-5012
    Abstract: Background: To investigate clinical activity, safety and biomarkers of a pan-PI3K inhibitor BKM120 in R/M-SCCHN and identify optimal combinational strategies by conducting mouse co-clinical trials mirroring the ongoing clinical study. Methods: Patients with R/M-SCCHN were eligible if they had progressed on platinum-based chemotherapy, and were treated with BKM120 100mg/day. The primary endpoint was disease control rate (DCR) at 8 weeks. Secondary endpoints included response rate (RR), progression-free survival rate (PFS), overall survival (OS) and safety. Patient-derived xenografts (PDXs) with genomic annotations were established directly from patients for evaluation of novel drug combinations and biomarkers. Based on the integrated clinical and preclinical data, study protocol had been revised to combine BKM120 and erbitux to explore whether erbitux increases the efficacy of BKM120 in R/M-SCCHN. Results: A total of 52 patients were enrolled. Patient characteristics included median age (55 years; range, 31-82); male (84.6%); ECOG performance status 0/1/2 (13.5%/73%/13.5%); locoregional/metastatic/both (30.8%/30.8%/38.4%); oral cavity/oropharynx/larynx primary (36.5%/30.8%/13.5%); prior chemotherapy regimens 1/≥2 (40%/60%). Seven patients were not evaluable due to rapid progression or withdrawal. DCR at 8 weeks was 60% (27/45) and RR was 2.2% (1/45) in BKM120 monotherapy. Median PFS and OS were 8.0 (95% CI, 5.3-9.5) and 30.7 weeks (95% CI, 11.8-26.6). After protocol revision, 11 patients were treated with BKM120 and erbitux after progression to BKM120. In combination phase, PR was observed in 18.1% (2/11) and SD was 45.5% (5/11) in patients who failed to BKM120. Toxicities were not increased in combination phase. In seven established PDXs, we tested BKM120 alone or in combination with erbitux. All PDXs showed strong resistance to single-agent BKM120, whereas three PDXs (3/7, 42.8%) demonstrated strong synergistic inhibition of tumor growth to combined BKM120 and erbitux, compared with single agent (vs. BKM120, P & lt;0.01; vs. Erbitux, P & lt;0.01), which resembled the responses of corresponding patients. We found several genetic alterations in F2 tumors including EGFR fusion, HRAS mutation (G12D), MYC amplification, KRAS mutation (G13D), and EGFR amplification. Interestingly, two PDXs with RAS mutations demonstrated synergistic effect of BKM120 and erbitux. Conclusions: Combining BKM120 and Erbitux would be effective treatment strategies with manageable toxicity in R/M-SCCHN based on strong rationale of co-clinical trial with PDXs (NCT01527877). Citation Format: Han Na Kang, Mi Ran Yun, Kyoung Ho Pyo, Myung-Ju Ahn, Jong-Mu Sun, Sun Min Lim, Soonmyung Paik, Byoung Chul Cho, Hye Ryun Kim. Mouse-human co-clinical trials demonstrate superior efficacy with combinational approach of BKM120 and erbitux over BKM120 monotherapy in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5012. doi:10.1158/1538-7445.AM2017-5012
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5012
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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