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  • American Association for Cancer Research (AACR)  (12)
  • Ryu, Min-Hee  (12)
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  • American Association for Cancer Research (AACR)  (12)
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  • 1
    Online Resource
    Online Resource
    Abstract A13: Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A13-A13
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A13-A13
    Abstract: BACKGROUND: The prognosis of gastrointestinal stromal tumor (GIST) has been dramatically improved after introduction of imatinib which can inhibit the driver mutated oncoproteins,KIT or PDGFRa. However, most patients eventually develop resistance to the tyrosine kinase inhibitors (TKIs) targeting these oncoproteins including imatinib, sunitinib, or regorafenib. The paucity of TKIs-resistant commercially available GIST cell lines hampers development of effective therapy for drug-resistant GIST. Therefore, we established patient-derived xenograft (PDX) models that faithfully recapitulate the genetic and phenotypic features of drug-resistant GIST. METHODS: PDXs have been established in NOD-SCID mice with tumor fragments of patients with metastatic and/or unresectable GIST after failure of at least imatinib and/or sunitinib. The histological and genomic similarities between all xenografts and the parental tumors have been confirmed using H & E and KIT staining, and short tandem repeat (STR) analysis, respectively. Mutation was detected by whole exome sequencing of patients' tumors on a HiSeq2000 and validated by Sanger sequencing of patients tumors and PDXs. After sequential passaging to BALB/c nude mouse, drug sensitivity assay (imatininb, sunitinib, and regorafenib) was conducted in established PDX models along with Western blotting regarding to KIT and FGFR signaling pathway. As an imatinib-sensitive control model, a xenograft established with GIST-T1 cell line was used. RESULTS: Three GIST PDX models were established from an imatinib/sunitinib/sorafenib-resistant GIST harboring KIT exon 11 (p.Y570-L576del) and 17 (p.D816E) mutations (AMC-GX1), an imatinib-resistant GIST harboring KIT exon 11 (p.K550_K558del) and 14 (p.T670I) mutations (AMC-GX2), and an imatinib/sunitinib-resistant GIST harboring KIT exon 11 (p.565-577GNNYVVIDPTQLP & gt;Q) and 17 (p.D820Y) mutations (AMC-GX3). Histologic and genetic similarities were confirmed between primary patients' tumors and PDXs. The mutation status of GIST PDXs was consistent with primary tumors. The GIST PDX models showed TKI sensitivity profiles comparable to clinical responses in patients. At day 21 after treatmemt with imatinib, tumor growth was inhibited by 17.8, 53.9, and 12.6% in AMC-GX1, GX2, and GX3, respectively, while by 80.0% in GIST-T1 xenografts. Western blotting analysis showed that KIT phosphorylation was inhibited by imatinib treatment in AMC-GX1 similar to GIST-T1, but not in AMC-GX2 and AMC-GX3. In contrast to GIST-T1, PI3K downstream of KIT was not inhibited with imatinib in AMC-GX1, GX2, and GX3. In addition, TKIs-resistant PDX models showed FGFR1 activation at baseline which was not evident in GIST-T1 xenografts. CONCLUSION: We have established 3 TKI-resistant GIST PDX models harboring variable KIT mutations which show different KIT and FGFR signaling features from imatinib-sensitive models. The established GIST PDX models will play a role for further studies on mechanisms of resistance to TKI and evaluation of novel targeted therapies in GIST. Citation Format: Young-Soon Na, Min-Hee Ryu, Sook Ryun Park, Ju-Kyung Lee, Hanui Kim, Chae-Won Lee, Sun Young Lee, Young-Kyoung Shin, Ja-Lok Ku, Sung-Min Ahn, Yoon-Koo Kang. Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A13.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-A13
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    SSG: 12
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  • 2
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    Abstract 1058: Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: Analyses of clinopathological characteristics related with success
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1058-1058
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1058-1058
    Abstract: BACKGROUND: The gastrointestinal stromal tumor (GIST) has activating mutations in either KIT or platelet-derived growth factor receptor alpha (PDGFRa) gene, and tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib and regorafenib remain the mainstay of anti-GIST treatment. Patient-derived xenografts (PDXs) are useful preclinical models in cancer research, owing to their demonstration of more real tumor heterogeneity and complexity, compared with cell lines and cell line-based xenograft models. PDX models have been established using numerous tumor types, however, there are only a few PDX models of GIST because of its very low success rate. As we have been establishing PDXs from GIST patients since 2012, in this study, we report the established PDXs and the clinopathological characteristics related to the successful establishment of GIST PDXs. MATERIALS and METHODS: PDXs have been established in NOD-scid Il2rg-/- (NSG) mice by implanting GIST tumor fragments from 185 patients who underwent surgical resection prior to and after tyrosine kinase inhibitors from July, 2012 to July, 2017. The established PDXs passaged greater than F2 generation. Chi-square test and logistic regression were used for comparison. RESULTS: Of a total of 185 patients, 66 (35.7%) patients were TKI-naïve, 21 (11.4%) had residual disease after control with TKIs, and the remaining 98 (53.0%) showed disease progression after TKIs at the time of surgical resection. The success rate of establishment of GIST PDXs was 16.8% (31/185). In univariate analyses, a higher engraftment rate was observed for tumors derived from patients with disease progression after TKIs (TKI-naïve vs residual disease vs progressive disease; p & lt;0.001), larger tumor size (≤50 mm vs 50-100 mm vs & gt;100 mm; p & lt;0.001), more mitotic count (≤10/50 HPFs vs & gt;10/50 HPFs; p & lt;0.001), higher Ki-67 index ( & lt;1/3 vs ≥1/3; p & lt;0.001), higher cellularity (low vs high; p & lt;0.001), or tumor necrosis (absence vs presence; p=0.001). In addition, PDX engraftment success rate was higher with tumors harboring primary mutation in KIT exon11 (vs other mutations; p=0.025) or with metastatic tumor lesions (vs primary site; p & lt;0.001). In multivariate analysis including significant factors in the univariate analyses, Ki-67 index (p=0.001) and largest tumor size (p=0.058) were independent factors for success of PDX establishment. CONCLUSION: Clinicopathologic factors such as disease progression after TKIs, larger tumor size, more mitotic count, higher Ki-67 index, higher cellularity or tumor necrosis were associated with higher success rate of PDX establishment. Especially, largest tumor size and Ki-67 index were independent factors for successful PDX engraftment. These findings will be helpful to establish PDX models more efficiently in GIST. Citation Format: Young-Soon Na, Min-Hee Ryu, Young Soo Park, Chae-Won Lee, Ju-Kyung Lee, Yangsoon Park, Jung Min Park, Jungeun Ma, Yoon-Koo Kang. Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: Analyses of clinopathological characteristics related with success [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 1058.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1058
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    Abstract 1269: P-glycoprotein expression in refractory gastrointestinal stromal tumors and its implication in the efficacy of paclitaxel as a salvage treatment
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1269-1269
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1269-1269
    Abstract: BACKGROUND: KIT-targeting tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib and regorafenib are the standard treatment for patients with gastrointestinal stromal tumor (GIST). However, most patients eventually develop treatment resistance to these standard therapies, and new agents must be introduced upon disease progression. Before TKIs were available, most of the conventional cytotoxic agents did not show sufficient clinical activity in GIST patients. However, a recent preclinical study demonstrated that 37 of the 89 FDA-approved anti-tumor drugs including paclitaxel (PTX) possess antitumor effect in at least one GIST cell line. Therefore, in this study, we aimed to evaluate the efficacy of PTX as a salvage treatment for GIST patients who exhibited treatment failure after standard TKI therapy using in-vitro/vivo models. MATERIALS and METHODS: The effect of PTX in GIST was examined by cell viability assay and rhodamine 123 (Rho123) efflux assay using GIST cells including established patient-derived GIST cell lines, and in animal models with patient-derived xenografts (PDXs) established from patients with GIST tumors refractory to TKIs. Multidrug resistance 1 (MDR1) mRNA expression by reverse transcription-PCR (RT-PCR) and P-glycoprotein (Pgp) expression by Western blotting or immunohistochemistry were evaluated in 20 patients’ tumor tissues, 9 GIST cell lines and 21 PDXs. To investigate the role of Pgp on PTX treatment, a stable MDR1-expressing GIST T1 cell line (GIST-T1-ABCB1#17) was prepared and compared with parent GIST T1 cell line. Verapamil was used as a Pgp inhibitor. RESULTS: Compared to imatinib-sensitive GIST-T1 harboring KIT exon 11 mutation and imatinib-resistant GIST-T1/816 harboring KIT exon 11 and 17 mutations, the patient-derived imatinib- and sunitinib-resistant GIST-R3 cell line harboring KIT exon 11 and 17 mutations was more resistant to PTX. Higher Rho123 efflux was observed in GIST-R3 which had high Pgp expression than in GIST-T1 and GIST-T1/816 which had low Pgp expression. The tumor growth inhibition of PTX was greater in xenografts with low Pgp expression (GIST-T1/816 xenografts and GIST-RX10 PDXs) than in xenografts with high Pgp expression (GIST-R3 xenografts and GIST-RX4 PDX). The GIST-T1-ABCB1#17, a stable MDR1-expressing GIST T1 cell line, exhibited a higher Pgp activity and a less sensitivity to PTX than the parent GIST-T1 cell line. The resistance of GIST-T1-ABCB1#17 to PTX was overcome by verapamil. CONCLUSION: Pgp expression was an important mechanism of resistance to PTX in preclinical GIST models. PTX is worth being tried clinically as a salvage treatment in patients with refractory GISTs with low Pgp expression. Citation Format: Young-Soon Na, Min-Hee Ryu, Young Soo Park, Chae-Won Lee, Ju-Kyung Lee, Jung Min Park, Yangsoon Park, Yoon-Koo Kang. P-glycoprotein expression in refractory gastrointestinal stromal tumors and its implication in the efficacy of paclitaxel as a salvage treatment [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 1269.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1269
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
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    Abstract CT175: Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human study
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT175-CT175
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT175-CT175
    Abstract: Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. Here we assessed SHR-A1811 in HER2-expressing/mutated unresectable, advanced, or metastatic solid tumors. Methods: Pts were eligible if they had HER2 positive breast cancer (BC), HER2 positive gastric/GEJ carcinoma, HER2 low-expressing BC, HER2-expressing/mutated NSCLC, or other HER2-expressing/mutated solid tumors, and were refractory or intolerant to standard therapy. SHR-A1811 at doses of 1.0-8.0 mg/kg was given Q3W (IV). The primary endpoints were DLT, safety, and the RP2D. Results: From Sep 7, 2020 to Sep 28, 2022, 250 pts who had undergone a median of 3 prior treatment lines in the metastatic setting received at least one dose of SHR-A1811 in dose escalation, PK expansion, and indication expansion part. As of data cutoff on Sep 28, 2022, 1 pt experienced DLT. Treatment-related adverse events (TRAEs) were reported in 243 (97.2%) pts. Grade ≥3 TRAEs, serious TRAEs, and treatment-related deaths were reported in 131 (52.4%), 31 (12.4%), and 3 (1.2%) pts, respectively. Interstitial lung disease (AESI) was reported in 8 (3.2%) pts. Exposures of SHR-A1811, total antibody, and the payload were generally proportional to dose from 3.2 to 8.0 mg/kg. ORR was 61.6% (154/250, 95% CI 55.3-67.7) in all pts. Objective responses were observed in pts with HER2 positive BC (88/108, ORR 81.5%, 95% CI 72.9-88.3), HER2-low BC (43/77, ORR 55.8%, 95% CI 44.1-67.2), urothelial carcinoma (7/11), colorectal cancer (3/10), gastric/GEJ carcinoma (5/9), biliary tract cancer (5/8), NSCLC (1/3), endometrial cancer (1/2), and H & N cancer (1/1). Subgroup analyses of ORR are shown in Table 1. The 6-month PFS rate was 73.9% in all pts. Conclusions: SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors. Table 1. Subgroup analyses of ORR No. of prior treatment lines in metastatic setting in all pts (N=250) HER2 positive BC (N=108) HER2-low BC (N=77) Other tumor types (N=65) ≤3 81.8% (45/55) 58.7% (27/46) 36.7% (18/49) & gt;3 81.1% (43/53) 51.6% (16/31) 31.3% (5/16) Prior anti-HER2 therapies in pts with BC (N=185)* HER2 positive BC (N=108) HER2-low BC (N=77) All BC (N=185) Any 82.2% (88/107, 73.7-89.0) 68.8% (11/16, 41.3-89.0) 80.5% (99/123, 72.4-87.1) Trastuzumab 81.9% (86/105, 73.2-88.7) 75.0% (9/12, 42.8-94.5) 81.2% (95/117, 72.9-87.8) Pertuzumab 83.0% (39/47, 69.2-92.4) 100% (5/5, 47.8-100) 84.6% (44/52, 71.9-93.1) Pyrotinib 86.9% (53/61, 75.8-94.1) 71.4% (5/7, 29.0-96.3) 85.3% (58/68, 74.6-92.7) Lapatinib 80.0% (28/35, 63.1-91.6) 100% (1/1, 2.5-100) 80.6% (29/36, 64.0-91.8) T-DM1 82.4% (14/17, 56.6-96.2) 100% (3/3, 29.2-100) 85.0% (17/20, 62.1-96.8) Other HER2-ADC (except T-DM1)** 60.0% (9/15, 32.3-83.7) 50.0% (2/4, 6.8-93.2) 57.9% (11/19, 33.5-79.8) ORR in pts with tumor types other than BC (N=65) HER2 IHC3+ or IHC2+/ISH+ (N=36) HER2 IHC2+/ISH- or IHC1+ or unknown (N=29) All other tumor types (N=65) % (n/N) 38.9% (14/36) 31.0% (9/29) 35.4% (23/65) ORR was shown as % (n/N, 95% CI) or % (n/N). *ORR is calculated using the number of subjects previously treated with anti-HER2 cancer therapy in advanced/metastatic setting as denominator; 2-sided 95% CIs are estimated using Clopper-Pearson method. **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103, and BAT8001. Citation Format: Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, Jee Hyun Kim, John Park, Yahua Zhong, Weiqing Han, Caigang Liu, Mark Voskoboynik, Qun Qin, Jian Zhang, Minal Barve, Ana Acuna-Villaorduna, Vinod Ganju, Seock-Ah Im, Changsheng Ye, Yongmei Yin, Amitesh C. Roy, Li-Yuan Bai, Yung-Chang Lin, Chia-Jui Yen, Hui Li, Ki Young Chung, Shanzhi Gu, Jun Qian, Yuee Teng, Yiding Chen, Yu Shen, Kaijing Zhao, Shangyi Rong, Xiaoyu Zhu, Erwei Song. Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human study [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT175.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT175
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract 3986: Digital droplet PCR measurement for plasma HER2 amplification in patients with AGC
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3986-3986
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3986-3986
    Abstract: Introduction: With the recent introduction of human epidermal growth factor receptor 2 (HER2) targeted therapies for patients with advanced gastric cancer (AGC), determining HER2 status is essential to select the patients who may benefit from this treatment. The current standard method assessing HER2 positivity is immunohistochemistry (IHC) or in situ hybridization assays, but this way of HER2 assessment has weaknesses especially when considering tumor heterogeneity. Using digital droplet polymerase chain reaction (ddPCR) technique, we evaluated HER2 amplification in both tissue and plasma samples collected from AGC patients and analyzed clinical implication of HER2 amplification in circulating tumor DNA. Method: Biopsied tissue and plasma samples were collected from patients with metastatic or recurrent AGC who were enrolled in AGC biomarker study conducted at Asan Medical Center. Samples were obtained before the start of anti-cancer treatment. HER2 amplification in DNA from tissue and cell-free DNA from plasma were determined by ddPCR, performed in Kindai University. Results: Samples of 63 patients with HER2 positive GC and 37 patients with HER2 negative GC enrolled between April 2014 and October 2017 were included in the analysis. As expected, the median HER2 copy number (CN) was higher in patients diagnosed as HER2 positive than negative, both for tissue (4.54 vs 0.95, P & lt; 0.001) and plasma (1.49 vs 1.07, P & lt; 0.001). ROC curve analysis showed 83.8% specificity and 69.8% sensitivity for tissue HER2 positivity at 1.17 CN of plasma HER2. In patients receiving anti-HER2 therapy (n=57), there was a trend for worse progression-free survival (PFS) outcome in patients with higher plasma HER2 CN ( & gt;1.5 vs ≤1.5), although no statistical significance was seen (median PFS 6.67 vs 8.19 months, P = 0.172). In multivariate Cox regression analysis including the age ( & gt;60 vs ≤60), HER2 IHC intensities (2+ vs 3+), and risk groups determined by Koo et al.’s prognostic model (Good vs Moderate vs Poor), higher plasma HER2 CN ( & gt;1.5 vs ≤1.5) was significantly associated with poor PFS (HR 2.22, 95% CI 1.14-4.32, P = 0.019). However, when tumor burden (sum of largest diameter of all measurable lesions) was combined as another factor in patients with measurable disease (n=39), plasma HER2 CN was no longer an independent factor (HR 1.38, 95% CI 0.58-3.27, P = 0.466) and larger tumor burden ( & gt;6.5cm vs ≤6.5cm) was found to be an independent prognostic factor for poor PFS (HR 2.63, 95% CI 1.12-6.21, P = 0.027), instead. Of note, plasma HER2 CN showed a positive relationship with tumor burden multiplied by tissue HER2 CN in linear regression (β=0.32, P = 0.002). Conclusion: Using the ddPCR technique, we found that plasma HER2 CN was significantly increased in HER2 positive GC patients compared to negative patients. However, plasma HER2 CN did not provide more information on predicting therapeutic effects than the tumor burden in patients receiving anti-HER2 therapy. Citation Format: Kyoungmin Lee, Kazuko Sakai, Min-Hee Ryu, Jae-Joon Kim, Young Soo Park, Young-Soon Na, Jungeun Ma, Hana Na, Kazuto Nishio, Yoon-Koo Kang. Digital droplet PCR measurement for plasma HER2 amplification in patients with AGC [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 3986.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3986
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
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    Abstract B211: Comparison of detection of FGFR2 amplification by quantitative real-time-PCR (qPCR) and fluorescent in situ hybridization (FISH) in gastric cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 11_Supplement ( 2013-11-01), p. B211-B211
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. B211-B211
    Abstract: Background: Fibroblast growth factor receptor 2 (FGFR2) amplification is associated with tumorigenesis of gastric cancer and can be a promising molecular target for the treatment of FGFR2-amplified gastric cancer. So far, the most optimal single method to screen patients with FGFR2 amplification has not been determined. To screen patients with gastric cancer harboring FGFR2 amplification, we aim to investigate whether qPCR can replace the FISH method which is the golden standard but less sensitive and much more expensive than qPCR. Methods: FISH (Abnova, #FG0018) and qPCR (Applied Biosystems, HS05182482_cn) method for FGFR2 amplification were performed with formalin-fixed paraffin-embedded (FFPE) tissues of patients with gastric cancer who were diagnosed from 2007 to 2012 in Asan Medical Center, Seoul, Korea, and whose FFPE tissues contained at least 70% of tumor cells. qPCR was conducted initially in 26 patients who had both endoscopic biopsy and surgical tissues in the diagnosis to figure out which samples are better between biopsy and surgical tissues. According to the results, 182 patients with endoscopic biopsy tissues were further included. FISH was defined as positive in case of FGFR2 to CEP10 ratio & gt; 2.0. Results: In 26 patients who had paired endoscopic biopsy and surgical samples, the qPCR-based copy number assay for FGFR2 amplification was more sensitive in biopsy samples; i.e., FGFR2 copy number by qPCR was higher in biopsy samples in 13 (50%) patients, while it was higher in surgical samples only in 3 (11.5%) patients. In a total of 208 endoscopic biopsy FFPE samples including 182 patients with biopsy tissues, copy number of FGFR2 ranged from 0.8 to 399.0 (median 15.9) by qPCR and from 0.7 to 166.9 (median 6.1) by FISH. 16 biopsy samples showing FGFR2 copy number & gt; 10 by qPCR were all FISH-positive, while 192 biopsy samples showing FGFR2 copy number & lt; 10 by qPCR were all FISH-negative. In cases of FGFR2 copy number & gt; 10 in biopsy tissues by qPCR, the copy numbers were very well correlated between qPCR and FISH in all patients, and were also over 10 in surgical tissues regardless of methods in 26 patients. The positive rate of FGFR2 amplification was 7.7% with a cut-off value of 10 by qPCR. Conclusion: This study suggests that it is better to use biopsy samples than surgical tissues to detect FGFR2 amplification by qPCR; and for patient screening in gastric cancer, the optimal cut-off value for definite FGFR2 amplification by qPCR is 10 in comparison with the results of FISH. Clinical relevance of intermediate FGFR2 copy number elevation & lt; 10 by qPCR needs to be addressed in future clinical trials using FGFR2 inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B211. Citation Format: Young-Soon Na, Young Soo Park, Min-Hee Ryu, Chae-Won Lee, Hye Jin Park, Ju-Kyung Lee, Sook Ryun Park, Baek-Yeol Ryoo, Yoon-Koo Kang. Comparison of detection of FGFR2 amplification by quantitative real-time-PCR (qPCR) and fluorescent in situ hybridization (FISH) in gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B211.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-13-B211
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 7
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    Abstract 2539: Antitumor effects of oral paclitaxel DHP107 on gastric cancer xenografts
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2539-2539
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2539-2539
    Abstract: Oral paclitaxel DHP107 (Daehwa, Seoul Korea), an antineoplastic agent, is effectively absorbed through the gastrointestinal tract via the lipid uptake mechanism, which is currently under clinical investigation. Oral capecitabine generates 5-fluorouracil (5-FU) by thymidine phosphorylase, preferentially in tumor tissue. Taxanes, such as paclitaxel and docetaxel, have the ability to up-regulate levels of thymidine phosphorylase which show the its increased activity in tumors compared with that of normal tissue. Accordingly, combination treatment using taxanes with capecitabine is effective in several tumors, especially in gastric cancer. In this study, we investigated the antitumor effect of DHP107 combined with capecitabine and compared the effects of DHP107 and Taxol in gastric cancer xenografts. DHP107 in combination with capecitabine dramatically inhibited tumor growth without additive toxicity compared with each agent used alone in gastric xenografts. The expression of the level of thymidine phosphorylase in tumor was markedly increased four hours after treatment with DHP107. The apoptotic effects, assessed using TUNEL and soft agar colony-formation assay on xenograft tumors, were greater with combined treatment than with either agent used alone. The antitumor effects of DHP107 were similar to those of Taxol in gastric cancer xenografts. These data indicate that DHP107 combined with capecitabine had enhanced antitumor effects in human gastric tumor xenografts and that DHP107 had antitumor effects in gastric cancer models, both of which provide support for future clinical trials of DHP107. 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 2539. doi:10.1158/1538-7445.AM2011-2539
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2539
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 8
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    Abstract 5371: Synergistic antitumor effect of HDAC inhibitor PXD101 in combination with irinotecan in colon cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5371-5371
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5371-5371
    Abstract: The histone deacetylase inhibitors (HDACi), such as PXD101 or SAHA, inhibit the proliferation and stimulate the apoptosis in tumors. The enhanced effect of HDACi combined with chemotherapy or radiotherapy has been reported in several cancers. In this study, we investigated the antitumor effect of HDACi PXD101 combined with irinotecan in colon cancer. PXD101 and SN38, active form of irinotecan, had a dose-dependent anti-proliferative activity in HCT116 and HT29 colon cancer cells. PXD101 combined with SN38 had a synergistic effect in colon cancer cell lines, as shown by combination index. The combination of PXD101 with SN38 had an effect on XIAP and p21 protein expressions with time- and dose-dependent manner, more prominently in HCT116 than HT29 cells. These effects were further enhanced by the addition of PXD101 than irinotecan alone in both cell lines. In xenograft mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without additive toxicity. In addition, antiumor effect was more prominent in HCT116 than HT29 xenografts. Apoptotic effects of tumor in xenografts treated with these combinations were better than irinotecan alone. Combination of PXD101 and irinotecan resulted in 63 % of relative SUV mean in [18F]FLT-PET in mice with established HCT116 xenograft. Early response to these agents can be detected with [18F] FLT-PET. These data suggest that PXD101 increases the cytotoxic activity of iriontecan in colon cancer and these drug combinations should be explored in the treatment of 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 5371.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-5371
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 9
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    Abstract 2874: A prospective study of a repeat endoscopic biopsy to identify HER2-positive tumors following an initial HER2-negative endoscopic biopsy in unresectable or metastatic gastric cancer patients: GASTHER1 study
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2874-2874
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2874-2874
    Abstract: Background: The intratumoral heterogeneity of HER2 expression in gastric cancer (GC) is a major challenge when identifying patients who will benefit from HER2-targeting therapy. The aim of this study is to evaluate the significance of re-evaluation of the HER2 status by repeat endoscopic biopsy in GC patients with an initial, HER2-negative endoscopic biopsy. Methods: Patients with unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma and who will receive first-line chemotherapy, were eligible if the HER2 was negative on the initial endoscopic biopsy. HER2 positivity was defined as immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH) + using the GC scoring system. A repeat endoscopic biopsy was performed in ≥6 different primary tumor sites immediately after obtaining initial HER2-negative results. Results: From May 2011 to April 2013, a total of 183 eligible patients were enrolled. Baseline characteristics at the time of the initial biopsy were as follows: tumor location, GEJ∼fundus/body/antrum/diffuse stomach=22(12.0%)/47(25.7%)/68(37.2%)/46(25.1%); Lauren classification, intestinal/diffuse/mixed=53(29.0%)/111(60.7%)/19(10.4%); and HER2 IHC score, 0/1/2=149(81.4%)/26(14.2%)/8(4.4%). The median number of biopsy pieces per patient was 5 (range, 1-15) and 10 (range, 1-15) on the initial and repeat biopsy, respectively (P & lt;0.0001). There was no difference in the median ratio of the number of cancer-containing pieces/total pieces; 0.86 (range, 0.13-1) vs. 0.89 (range, 0.10-1) (P=0.679). As the repeat biopsy identified 16 patients with HER2-positive tumor, the rate of rescued HER2 positivity was 8.7% (95% CI 4.6-12.8%). Rescued HER2 positivity was associated with tumor location (diffuse stomach vs. others=0% vs. 11.7%, P=0.013), Bormann type (IV vs. others=0% vs. 11.7%, P=0.013), and the HER2 IHC score on the initial biopsy (0 vs. 1 vs. 2 = 6.7% vs. 15.4% vs. 25.0%, P=0.028). In multivariate analysis, the HER2 IHC score (1/2 vs. 0, odds ratio=3.78; P=0.016) was an independent predictive factor for rescued HER2 positivity. Conclusions: Repeat endoscopic biopsy is recommended in order to check the HER2 status again even if the initial endoscopic biopsy is HER2 negative in metastatic or unresectable GC. Note: This abstract was not presented at the meeting. Citation Format: Sook Ryun Park, Young Soo Park, Baek-Yeol Ryoo, Chang Gok Woo, Hwoon-Yong Jung, Jeong Hoon Lee, Gin Hyug Lee, Min-Hee Ryu, Yoon-Koo Kang. A prospective study of a repeat endoscopic biopsy to identify HER2-positive tumors following an initial HER2-negative endoscopic biopsy in unresectable or metastatic gastric cancer patients: GASTHER1 study. [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 2874. doi:10.1158/1538-7445.AM2014-2874
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2874
    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 1392: Integrative biomarker analysis of regorafenib plus nivolumab (RegoNivo) in unresectable hepatocellular carcinoma (uHCC): A multicenter phase 2 RENOBATE trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1392-1392
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1392-1392
    Abstract: Regorafenib plus nivolumab (RegoNivo) combination has shown promising anti-cancer activity in multiple cancer types. REBNOBATE trial is a single-arm multicenter phase 2 trial of first-line RegoNivo in patients (pts) with uHCC (NCT04310709). Here we report the clinical outcomes of the RENOBATE study and integrative biomarker analysis using circulating tumor DNA (ctDNA) and single cell RNA sequencing (scRNA-seq) analysis. Method: Adult pts with ECOG PS 0 or 1, BCLC stage B or C, and no prior systemic therapy were eligible for the study. Pts received nivolumab 480 mg iv, every 4 wks, and regorafenib 80 mg daily po, 3 wks on/1 wk off, every 4 wks. Tumor response was assessed according to RECIST v1.1 every 8 wks. ctDNA analysis was performed using the Guardant 360 CDx (n=42). scRNA-seq was performed using PBMCs at baseline (e.g., C1D1) and on treatment (eg., C1D15) from early progression (EP) group (14 pts with PD or tumor burden increases towards PD on the 1st evaluation) and long-term response (LR) group (15 pts with PR or SD & gt; 6 months). Results: 42 pts were enrolled. Response rates were 31.0% and median progression-free survival (was 7.4 mo (95% CI, 4.2-13.0) and 1-year OS rate was 80.5% (95% CI, 63.0-90.3%). Aberrations of Wnt/β-Catenin and PI3K/mTOR pathways identified in ctDNA were not associated with efficacy outcomes. scRNA-seq revealed that genes upregulated in immune cells on C1D15 (vs. C1D1) were associated with immune activation and regulation of angiogenesis. Unsupervised clustering identified 13 immune subsets; among them, classical monocyte showed the most prominent changes in their proportion and gene expression profiles. After RegoNivo treatment, CD8 clusters had enhanced expressions of genes related to cytotoxicity, tissue homing (i.e., CXCR6, CX3CR1, and CXCR3) and proliferation (MKI67), and monocyte clusters showed an enrichment of the gene signatures representing polarization towards M1-related features. Importantly, the enrichment of cytotoxic features of the T cell clusters and M1-polarizing features of monocyte clusters were more pronounced in LR group than in EP group. From the analysis of differentially expressed genes monocyte clusters between the EP and LR groups, a surface molecule ‘X’ was identified as a potential biomarker involved in resistance to RegoNivo. RegoNivo showed promising efficacy outcomes in pts with uHCC. Through scRNA-seq of serial PBMCs, we identified enhanced cellular immune responses induced by RegoNivo and a potential predictive marker for immunotherapy in pts with uHCC. Our study highlighted that regorafenib might synergize with anti-PD-1 in pts with uHCC. Association between differential features of T cell and monocyte clusters induced by this combination and distinct clinical outcomes highlights the importance of immune-modulation in HCC pts suggesting a potential to further harness these signals Citation Format: Hyung-Don Kim, Seyoung Jung Jung, Baek-Yeol Ryoo, Min-Hee Ryu, Beodeul Kang, Hong Jae Chon, Jung Yong Hong, Ho Yeong Lim, Jeong Seok Lee, June-Young Koh, Changhoon Yoo. Integrative biomarker analysis of regorafenib plus nivolumab (RegoNivo) in unresectable hepatocellular carcinoma (uHCC): A multicenter phase 2 RENOBATE trial [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 1392.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1392
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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