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  • American Association for Cancer Research (AACR)  (10.324)
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  • American Association for Cancer Research (AACR)  (10.324)
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  • 1
    Online-Ressource
    Online-Ressource
    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
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6219
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 2
    Online-Ressource
    Online-Ressource
    Abstract 1036: Establishment and molecular profiling of patient-derived xenograft models of Korean patients with primary lung cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1036-1036
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1036-1036
    Kurzfassung: Non-small cell lung cancer is the most prevalent type of lung cancer, and one of its subtype, squamous cell carcinoma (SCC) has the genomic complexity and high overall mutation due to the chemical carcinogens so that limited therapeutic options are available in comparison with adenocarcinoma. We constructed the patient-derived xenograft models of Korean primary lung cancer and then focused on the SCC PDX models for this particular ethnic subgroup. PDX models were established using the tissues of patients who underwent surgery as primary lung cancer at Samsung Medical Center during the period between October, 2014 and September, 2017. Briefly, tumor tissues from patients were subcutaneously engrafted and passaged two more times in NOD-scid-IL2Rγnull mouse. Models were selected whose tumor tissues showed the histopathology and genomics similar to the patient tumor tissues. Statistics of established PDX models are summarized in the Table. Successful engraftmentSuccess rate (%)Primary lung cancer (n=532)19937.41Histology--Non-small cell lung cancer (n=524)19437.02- Adenocarcinoma (n=355)8925.07- Squamous cell carcinoma (n=135)8361.48- Other NSCLC (n=34)2264.71Small cell carcinoma (n=8)562.5Type of resection--Curative lung resection (n=458)17437.99Biopsy (n=74)2533.78Pathologic staging of ADC (n=355)--I (n=162)4024.69II (n=58)1525.86III (n=68)1927.94IV (n=67)1522.39 In order to help facilitate the target drug development of SCC, we concentrated on the construction of comprehensive database of fourteen SCC PDX models integrating the information from whole exome sequencing, whole transcriptome sequencing and clinical profiles. We detected mutations commonly reported in SCC genes including EGFR, BRAF, CUL3, DDR2, TP53, MYD88, PIK3CA, PTEN, MED12, SMAD4, AKT1, CTNNB1, IDH1, HRAS, KRAS, NRAS, SMARCA4, GNAS, CDKN2A, APC, CDKN2A and RRAS2. Specifically potential therapeutic targets such as EFGR, BRAF, CUL3, DDR2, TP53 and KRAS which are currently under several clinical trials were found in our SCC PDX models, and intriguingly one model had five mutations in CUL3, KRAS, TP53, and EGFR simultaneously. We expect these SCC PDX models could be valuable resource for target drug development and interpretation of their therapeutic responses in the pre- or co-clinical trials. Detailed information on pathology and genomic information on all PDX models will be available at DNA Link PDX webpage. Citation Format: Tae Ho Kim, Hyunjin Heo, Soo Jung Lee, Seungje Lee, Eunjoo Hwang, Jinseon Lee, Heekyoung Lee, Kevin Koo, Hanna Lee, Seungjae Lee, Hwanseok Rhee, Jong Eun Lee, Jhingook Kim. Establishment and molecular profiling of patient-derived xenograft models of Korean patients with primary lung 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 1036.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1036
    RVK:
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    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 3
    Online-Ressource
    Online-Ressource
    Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 3 ( 2016-02-01), p. 686-699
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 3 ( 2016-02-01), p. 686-699
    Kurzfassung: The Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention. The natural rotenoid deguelin was identified as an Hsp90 inhibitor, but concerns about neurotoxicity have limited prospects for clinical development. In this study, we report progress on deguelin analogues that address this limitation, focusing on the novel analogue SH-1242 as a candidate to broadly target human lung cancer cells, including those that are chemoresistant or harboring KRAS mutations. In a KRAS-driven mouse model of lung cancer, SH-1242 administration reduced tumor multiplicity, volume, and load. Similarly, in human cell line–based or patient-derived tumor xenograft models, SH-1242 induced apoptosis and reduced tumor vasculature in the absence of detectable toxicity. In contrast to deguelin, SH-1242 toxicity was greatly reduced in normal cells and when administered to rats did not produce obvious histopathologic features in the brain. Mechanistic studies revealed that SH-1242 bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the ability to interact with its co-chaperones and clients and triggering a degradation of client proteins without affecting Hsp70 expression. Taken together, our findings illustrate the superior properties of SH-1242 as an Hsp90 inhibitor and as an effective antitumor and minimally toxic agent, providing a foundation for advancing further preclinical and clinical studies. Cancer Res; 76(3); 686–99. ©2015 AACR.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-1492
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2016
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 4
    Online-Ressource
    Online-Ressource
    Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 14 ( 2013-07-15), p. 4267-4277
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 14 ( 2013-07-15), p. 4267-4277
    Kurzfassung: Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated β-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated β-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity. Cancer Res; 73(14); 4267–77. ©2013 AACR.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-3516
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2013
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 5
    Online-Ressource
    Online-Ressource
    USP8 Is a Novel Target for Overcoming Gefitinib Resistance in Lung Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 14 ( 2013-07-15), p. 3894-3904
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 14 ( 2013-07-15), p. 3894-3904
    Kurzfassung: Purpose: Common treatment modalities for non–small cell lung cancer (NSCLC) involve the EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due, in large part, to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non–small cell lung cancer (NSCLC). Experimental Design: Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model. Results: Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs while having little toxicity toward normal cells. Genetic silencing of USP8 led to the downregulation of several receptor tyrosine kinases (RTK) including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells. Conclusions: Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells. Clin Cancer Res; 19(14); 3894–904. ©2013 AACR.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-3696
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2013
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
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  • 6
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    Abstract P1-16-01: Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer: A randomized, open-label, multicenter, phase II trial (KCSG-BR15-17)
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P1-16-01-P1-16-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P1-16-01-P1-16-01
    Kurzfassung: Background: Anthracyclines and taxanes are the preferred regimens for patients with advanced breast cancer and are usually introduced in earlier lines. Tumors refractory to anthracycline and taxanes are aggressive and often show rapid progression. Although single sequential chemotherapy is standard of care, combination chemotherapy is required for patients with rapid progression. Development of effective and tolerable combination regimens focused on these patients is clinically relevant. Methods: This randomized, open-label, phase II trial was conducted in 16 centers in Korea. Eligible patients were women aged 18 years or older with advanced or metastatic breast cancer previously treated with anthracycline and taxanes. A maximum of three previous chemotherapy regimens for metastatic disease were allowed. Patients were randomly assigned in a 1:1 ratio to receive vinorelbine monotherapy (25 mg/m2 days 1 and 8) or pemetrexed (500 mg/m2 day 1) plus vinorelbine (25 mg/m2 days 1 and 8) in a 21-day cycle until disease progression or unacceptable toxicity. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of life (QoL). Results: From March 2017 through August 2019, a total of 125 patients were enrolled. Sixty-two patients were assigned to pemetrexed plus vinorelbine and 63 were assigned to vinorelbine monotherapy. Baseline characteristics and demographics were well-balanced between the two treatment groups. Overall, hormone receptor was positive in 58.4% of patients and HER2 was positive in 6.4% of patients. Fifty-six percent of patients received 2 or 3 line of previous palliative chemotherapy and 41% of patients received previous endocrine therapy of palliative purpose. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine monotherapy (5.7 vs. 1.5 months, hazard ratio 0.542 [95% CI 0.374 - 0.786], p & lt; 0.001). Prolonged PFS with pemetrexed plus vinorelbine compared to vinorelbine monotherapy was consistent across all patient subgroups, regardless of patient’s hormone receptor status, prior capecitabine use, prior lines of palliative chemotherapy, and metastases sites. ORR was numerically higher (15.0% vs. 9.8%) and disease control rate was significantly higher (78.3% vs. 45.9%) in patients treated with pemetrexed plus vinorelbine compared to vinorelbine monotherapy. Febrile neutropenia (16.1% vs. 4.9%, p = 0.043), liver enzyme elevation (25.8% vs. 11.5%, p = 0.042), and anemia (29.0% vs. 9.8%, p = 0.007) was more frequent in the combination arm, but the toxicities were generally manageable. There was no treatment related death and only one patient in the monotherapy arm discontinued the treatment due to febrile neutropenia. There was no difference in QoL as measured by EORTC QLC-C30 and QLQ-BR23. Conclusions: Pemetrexed plus vinorelbine led to longer progression-free survival compared to vinorelbine monotherapy with manageable toxicities. We believe pemetrexed plus vinorelbine could be considered as a treatment option in patients with advanced breast cancer. Table 1.Best tumor responseTotal (N = 123)Vinorelbine single (N = 61)Pemetrexed plus vinorelbine (N = 62)P-ValueComplete response0 (0.0%)0 (0.0%)0 (0.0%)0.001Partial response15 (12.4%)6 (9.8%)9 (15.0%)Stable disease60 (49.6%)22 (36.1%)38 (63.3%)Progressive Disease46 (38.0%)33 (54.1%)13 (21.7%) Citation Format: Dae-Won Lee, Yeon Hee Park, Kyung-Hae Jung, Kyung-Hun Lee, Keun Seok Lee, Joohyuk Sohn, Hee Kyung Ahn, Jae Ho Jeong, Su-Jin Koh, Jee Hyun Kim, Han Jo Kim, Kyoung Eun Lee, Hee-Jun Kim, Ki Hyeong Lee, Kyong Hwa Park, Jieun Lee, Hye Sung Won, Tae-Yong Kim, Seock-Ah Im. Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer: A randomized, open-label, multicenter, phase II trial (KCSG-BR15-17) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-01.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P1-16-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 7
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    Abstract P3-03-05: Not presented
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P3-03-05-P3-03-05
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P3-03-05-P3-03-05
    Kurzfassung: This abstract was not presented at the conference. Citation Format: Jung S-Y, Han JH, Park SJ, Lee E-G, Lee MH, Lee ES, Kang H-S, Lee KS, Park IH, Sim SH, Jeong HJ, Kwon Y, Lee D-E, Joo J, Kim S-K, Lee S. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-05.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P3-03-05
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2019
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 8
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    Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Discovery Vol. 9, No. 10 ( 2019-10-01), p. 1388-1405
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 9, No. 10 ( 2019-10-01), p. 1388-1405
    Kurzfassung: The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RICTOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. Significance: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility. This article is highlighted in the In This Issue feature, p. 1325
    Materialart: Online-Ressource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-19-0442
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2019
    ZDB Id: 2607892-2
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  • 9
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    Abstract 2215: Use of peptide nucleic acid(PNA)-mediated PCR clamping method for detection EGFR mutation in patients with non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2215-2215
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2215-2215
    Kurzfassung: Introduction : Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with nonsmall cell lung cancer (NSCLC). Direct sequencing is known to be the standard for detecting EGFR mutations; however, it has limited sensitivity. Peptide nucleic acids (PNA)-mediated Real-Time PCR clamping method is a newly introduced method for analyzing EGFR mutations with increased sensitivity and stability. Methods : Clinical specimens from 240 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21. All clinical data and tumor specimens were obtained from 8 centers of Korean Molecular Lung Cancer Group (KMLCG). After genomic DNA extracted from paraffin-embedded tissue specimens, both PNA-mediated Real-Time PCR clamping and direct sequencing were performed. The results and clinical response to EGFR-TKIs were compared. Results : Sequencing revealed a total of 63(26.3%) mutations and PNA-mediated RT PCR clamping detected EGFR kinase mutation in 83(34.6%) samples. 61 mutations were consistent by both of direct sequencing and PNA-mediated RT PCR, however PNA-mediated RT PCR detected additional 22 mutations; 10 in exon 19, 9 in exon 21 and 3 in both of them. Furthermore, patients whose tumors expressed EGFR mutations exhibited an excellent response to EGFR-TKIs by more than 88%. Conclusion : PNA-mediated Real-Time PCR clamping is a simple and rapid, as well as a more sensitive method for screening of genomic alterations in EGFR gene compared to direct sequencing. This data suggests that PNA-mediated Real-Time PCR clamping should be implemented as a useful screening tool for detection of EGFR mutations in clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2215. doi:10.1158/1538-7445.AM2011-2215
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2215
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2011
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 10
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    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
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-3007
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2019
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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