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  • American Association for Cancer Research (AACR)  (36)
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  • 1
    Online Resource
    Online Resource
    Abstract 4498: CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4498-4498
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4498-4498
    Abstract: PURPOSE: CKD-516 is a benzophenone analog with a modification of the B ring, which is replaced by a carbonyl group. The aim of this study is to assess the antivascular effects and the inhibition of cell proliferation of CKD-516. MATERIALS AND METHODS: To assess the effect of CKD-516 on vascularization, we analyzed the effect on endothelial cells (HUVECs). To determine the inhibition of cell proliferation of CKD-516, we used a lung carcinoma cell line (H460). The alteration of microtubule analyzed using immunoblot, RT-PCR and confocal image. To evaluate the anti-tumor effects of gemcitabine and/or CKD-516, H460 xenograft mice were treated with CKD-516 (2.5 mg/kg) or gemcitabine (40 mg/kg) or CKD-516 + gemcitabine, and tumor growth was compared with vehicle-treated control. For histologic analysis, liver, spleen and tumor tissues were taken at 12 and 24 hours after CKD-516 injection from H460 xenograft mice. RESULTS: We determined that cytoskeletal changes of HUVECs treated with 10 nM CKD-516 were assessed by immunoblot and confocal imaging. CKD-516 disrupts tubulin assembly and results in microtubule dysfunction inducing cell cycle arrest (G2/M). CKD-516 markedly enhanced the depolymerization of microtubules which may be related to vascular disrupting properties of CKD-516. Interestingly, CKD-516 decreased amount of total tubulin protein in HUVECs. Especially, CKD-516 decreased mRNA expression α-tubulin (HUVECs only) and β-tubulin (HUVECs and H460) at early time point (4 h). Immunocytochemical analysis showed that CKD-516 changed the cellular microtubule network and inhibited the formation of polymerized microtubules. We also showed extensive central necrosis of tumor by 24 h after treated with CKD-516 (2.5 mg/kg, i.p.). In H460 xenograft, CKD-516 combined with gemcitabine significantly delayed tumor growth as compared to control and gemcitabine alone. CONCLUSION: These results suggest that CKD-516 is a novel agent with vascular disrupting properties, and enhances anti-tumor activity in combination with chemotherapy. Citation Format: Young Joo Min, Chang Hoon Moon, Seung Ju Lee, Sang Ryun Ryu, Wha Ja Cho, Nal Ae Yoon, Sungchan Park, HeeJeong Cha. CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4498. doi:10.1158/1538-7445.AM2013-4498
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4498
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
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    Abstract 6219: WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6219-6219
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6219-6219
    Abstract: As the representative targeted anticancer drug for colon cancer patients, cetuximab is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild type cancers. Even some patient with KRAS wt gene did not respond cetuximab. However, there is no treatment available for cetuximab-resistant patient group, which is almost 50% of KRAS WT gene holders. Recently, our team identified cetuximab primary resistant related proteins named as mtRTK (mutant receptor tyrosine kinase) by array analysis based cetuximab responder or non-responder colon cancer patient tissues. We investigated mtRTK’s oncogenic potential as a novel anti-cancer target. A large proportion of colon cancer patients (36.2% Caucasian, 56.9% Korean) expressed the mtRTK was identified, using the sequencing analysis of patient samples. Based on these results, our efforts have led to the discovery of WM-S1, mtRTK inhibitor, which is the first mtRTK inhibitor in clinical development. The potent enzyme inhibitor showed a high anticancer activity confirmed in Patient-Derived Cells (PDC) and Patient-Derived Xenograft (PDX) animal models expressing the mutation. In preclinical studies demonstrate that WM-S1 is well tolerated in rats and dogs. Furthermore, WM-S1 has potent anticancer activities for various solid tumor (NSCLC, cholangiocarcinoma, etc.) including activated mtKRAS colon cancer expressing the mtRTK. Currently we are investigating WM-S1 in a phase 1a trial in AUS, which is the first mtRTK inhibitor in clinical development. Meanwhile, the mtRTK inhibitor WM-S1 drives antitumor immunity (with anti-PD-L1) in NSCLC. Combinational approaches with immunotherapy showed that synergistic effect of WM-S1 and anti-PD1 monoclonal antibody, suppressing tumor growth by 75% in anti-PD1 resistance NSCLC-derived humanized mouse model. A phase 1b trial is expected to develop WM-S1 through not only indication expansion but also combination therapy with immuno-checkpoint inhibitors in the USA, AUS and KOR from Q2 2022. In conclusion, mtRTK is a potential oncogenic driver mutation in various solid tumor. A first-in-class anticancer agent WM-S1 targeting mtRTK can be promising therapeutic agents for cetuximab-resistant colon cancer patients regardless of KRAS mutation status and other cancers. Citation Format: Joseph Kim, Jai-Hee Moon, Kyung-Mi Lee, Hyun Ryu, Eun Hye Park, Sang Hee Kim, Jeong Seok Kim, Young Ok Ko, Yong Seok Kim, Hyo Jin Kim, Tae Young Kim Kim, Moon Seong Yoo, Soll Jin, Seongrak Kim, Yoon Sun Park, Min Ki Lee, Mi So Lee, Ji Hyun Go, Yu Geun Ji, Jun Hyung Lee, Haneul Lee, Min Hwa Kim, Eun Hee Ko, Yeo Jin Lee, Seung-Mi Kim, Joon-yee Jeong, Yeon-seoung Choi, Seung-geon Bae, Jinwoo Lee, Won Jun Lee, Min-Kyeong Kim, Ji min Shin, Dong-in Koh, Sun-Chul Hur, Chun-Ho Park, Hyun Ho Lee, Dong-Hoon Jin. WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6219.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6219
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
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    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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  • 4
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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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  • 5
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    Abstract P2-05-07: Feasibility and sensitivity of fine-needle aspiration biopsies for the detection of somatic mutations using next-generation sequencing in breast cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P2-05-07-P2-05-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P2-05-07-P2-05-07
    Abstract: Background/Purpose: Next-generation sequencing (NGS) is being incorporated rapidly into clinical practice. Fine-needle aspiration biopsy (FNAB) specimens have been used feasibly in molecular analysis including direct sequencing and microarrays. They are readily available and enriched in malignant cells, thus providing opportunities for genomic analysis for more clinical samples. In this study, we assessed the feasibility and sensitivity of FNAB for the detection of somatic mutations by NGS compared to bulk tissue. Methods: Bulk tissue and FNAB was sampled via skin superficial to the palpable tumor from surgically resected breast cancer specimen. DNA was extracted from the bulk tissues and FNAB samples obtained from twelve patients. Somatic mutations detected from whole exome sequencing (WES) by next-generation sequencing (NGS) (HiSeq 2500, Illumina) were analyzed for corresponding pairs of bulk tissue and FNAB. Verification of somatic mutations detected exclusively from FNAB and known to be clinically relevant to breast cancer was carried out by Sanger sequencing. Invasive tumor percentages of bulk tissues were evaluated using hematoxylin and eosin (H & E)-stained sections. Results: Average depth of coverage were 158.8x and 158.3x for bulk tissue and FNAB, respectively. Number of detected somatic mutations ranged from 2 to 153 (median 18.5) and 19 to 210 (median 39.5) for bulk tissue and FNAB, respectively. Ten specimens had more mutations detected exclusively from FNAB than from bulk tissue. Allele fractions plotting of corresponding pairs of bulk tissue and FNAB showed good, intermediate, and poor correlation in five, two, and five specimens, respectively. H & E-stained sections of bulk tissue from the five specimens with good correlation contained an invasive tumor percentage of 45 to 98%, whereas those from five specimens with poor correlation contained 0 to 25%. Three of the poorly correlated bulk tissues were judged to have 0% of invasive tumor. Among mutations detected exclusively from FNAB, eighteen different genes of interest in 22 foci were evaluated for both FNAB and corresponding bulk tissue by Sanger sequencing. In the results, three mutations (PIK3CA, TP53 x2) were verified in FNAB samples but not in the bulk tissue. Conclusion: WES was successfully carried out in all pairs of bulk tissue and FNAB from twelve breast cancer patients. In samples with high tumor content somatic mutation profiles showed high correlation between the two samples whereas samples with low tumor content failed to show correlation. The failure was mostly due to the scarcity of tumor portions in the bulk tissues, indicating that FNAB more reliably retained malignant tumor portion. This study suggests that FNAB is an easy and feasible method, and furthermore, provides a more reliable specimen for NGS analysis where somatic mutations could be identified for potential prognostic or therapeutic benefits. Citation Format: Han-Byoel Lee, Jisun Kim, Kyung-Min Lee, Je-Gun Joung, Hae-ock Lee, Min Kyoon Kim, Eunshin Lee, Jongjin Kim, Tae-Kyung Yoo, Yun-Gyoung Kim, Young Joon Kang, Han Suk Ryu, In-Ae Park, Hyeong-Gon Moon, Dong-Young Noh, Woong-Yang Park, Wonshik Han. Feasibility and sensitivity of fine-needle aspiration biopsies for the detection of somatic mutations using next-generation sequencing in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P2-05-07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 6
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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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  • 7
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    Aberrant L1 Cell Adhesion Molecule Affects Tumor Behavior and Chemosensitivity in Anaplastic Thyroid Carcinoma
    American Association for Cancer Research (AACR) ; 2012
    In:  Clinical Cancer Research Vol. 18, No. 11 ( 2012-06-01), p. 3071-3078
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 11 ( 2012-06-01), p. 3071-3078
    Abstract: Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most invasive human cancers and has a poor prognosis. Molecular targets of ATC that determine its highly aggressive nature remain unidentified. This study investigated L1 cell adhesion molecule (L1CAM) expression and its role in tumorigenesis of ATCs. Experimental Design: Expression of L1CAM in thyroid cancer was evaluated by immunohistochemical analyses of tumor samples from patients with thyroid cancer. We investigated the role of L1CAM in proliferation, migration, invasion, and chemoresistance using short hairpin RNA (shRNA) knockdown experiments in human ATC cell lines. Finally, we evaluated the role of L1CAM on tumorigenesis with ATC xenograft assay in a nude mouse model. Results: L1CAM expression was not detectable in normal follicular epithelial cells of the thyroid or in differentiated thyroid carcinoma. In contrast, analysis of ATC samples showed specifically higher expression of L1CAM in the invasive area of the tumor. Specific knockdown of L1CAM in the ATC cell lines, FRO and 8505C, caused a significant decrease in the proliferative, migratory, and invasive capabilities of the cells. Suppression of L1CAM expression in ATC cell lines increased chemosensitivity to gemcitabine or paclitaxel. Finally, in an ATC xenograft model, depletion of L1CAM markedly reduced tumor growth and increased the survival of tumor-bearing mice. Conclusions: We report that L1CAM is highly expressed in the samples taken from patients with ATCs. L1CAM plays an important role in determining tumor behavior and chemosensitivity in cell lines derived from ATCs. Therefore, we suggest that L1CAM may be an important therapeutic target in patients with ATCs. Clin Cancer Res; 18(11); 3071–8. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-2757
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 8
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    Abstract B149: Yes-associated protein (YAP) is associated with aggressive characteristics of BRAFV600E thyroid cancer.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. B149-B149
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. B149-B149
    Abstract: Up regulation of Yes-associated protein (YAP), a transcriptional co-activator regulated by Hippo (MST-LAST-YAP) pathway, has been reported to mediate oncogenic transformation in animal models of hepatocellular carcinomas. However, the expression status and molecular biological role of YAP in thyroid cancer remained to be investigated. We evaluated YAP expression and identified increased nuclear YAP expression in PTC and ATC. Interestingly, we could observe nuclear YAP staining more frequently in BRAFV600E(+) PTC. We also performed immunofluorescence staining to verify intracellular localization of YAP in TPC1 (harboring RET/PTC1), 8505C (harboring BRAFV600E) and BRAFV600E stably transfected HEK293T cells. Consistently, we could detect nuclear YAP in 8505C and BRAFV600E expressed cells, but not in TPC1. Although cell viability assays did not show any difference between YAP knockout cells and control cells generated by using shYAP in 8505C and shCTL (control) 8505C, YAP knockout cells showed remarkably decreased migration ability in the scratch assays. Using orthotopic mice models, shYAP 8505C injected mice showed decreased local invasion ability and less frequent lung metastasis. In conclusions, Nuclear YAP could be more frequently detected in BRAFV600E(+) thyroid cancer compared to BRAFV600E(−) thyroid cancer. Furthermore, nuclear YAP in BRAFV600E(+) thyroid cancer was associated with local invasiveness and distant metastasis, presenting that YAP could affect the aggressive phenotype of BRAFV600E(+) thyroid cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B149.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-B149
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 9
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    Abstract A005: Ultra-rapid and precise measurement of HER2 copy number alteration by next-generation digital PCR capable of real-time analysis in patients with breast cancer: A multicenter retrospective study
    American Association for Cancer Research (AACR) ; 2024
    In:  Cancer Research Vol. 84, No. 3_Supplement_1 ( 2024-02-01), p. A005-A005
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 84, No. 3_Supplement_1 ( 2024-02-01), p. A005-A005
    Abstract: The HER2 diagnostics is necessary for selection of patients harboring HER2 gene amplification or protein overexpression who will benefit from anti-HER2 therapies in breast cancer. However, HER2 testing is still challenging due to the subjective natures of immunohistochemistry (IHC) and in situ hybridization (ISH), standard methods for determining HER2 status. Thus, a new method is needed to accurately quantify HER2 levels. Here, we developed a clinically reliable HER2 testing method enabling ultra-fast detection of HER2 gene amplification with high accuracy by using the digital real-time PCR (drPCR) system, a potential new diagnostic platform with improved performance by integrating both real-time and digital PCR technologies. For drPCR-based HER2 copy number (CN) measurement, primer-probe sets specific to HER2 gene and a genomic region adjacent to chromosome 17 centromere (CEP17) were designed, and the optimal drPCR condition was determined in clinical breast tumor specimens. To test the clinical validity and standardize procedures of drPCR-based HER2 status evaluation, three independent breast cancer cohorts from different institutions were enrolled, which assigned as a training (SCHU hospital, n = 103) and two validation sets (SNU hospital, n = 170; CNUH hospital, n = 45), and the drPCR assay was compared with current standard HER2 testing methods. In the training cohort, the HER2/CEP17 ratio values from FISH and drPCR tests were highly correlated (r2 = 0.81; P & lt; 0.001), and the drPCR results displayed 98.1% concordance to HER2 status defined by IHC and/or FISH with 92.6% sensitivity and 100% specificity. Eight samples further verified by targeted NGS showed 100% concordance of dPCR to NGS. Consistently, two validation cohorts also showed high concordance of drPCR to IHC and/or ISH results (accuracy = 97.1% and 97.8% in SNU and CNUH cohorts, respectively). The optimal cutoff for HER2 positivity in the drPCR assay was set as a HER2/CEP17 ratio ≥ 1.9 with AUC of 0.963 based on the results from training cohort, and the same cut-off for drPCR was applicable to two independent validation cohorts, supporting the clinical validity of our drPCR-based HER2 assessment. In some discordant cases, low tumor purity (≤ 25%) was observed and microdissection partly improved the drPCR results. The discordance between drPCR and ISH results was also found in marginal HER2+ cases with HER2/CEP17 ratio 2-3, but these cases showed inter-observer variability when re-evaluating the ISH/IHC data due to intratumoral HER2 heterogeneity. Of note, in HER2 IHC3+ cases with negative drPCR results, re-evaluation of IHC using an artificial intelligence (AI)-based HER2 scoring system revised the HER2 IHC 3+ score to 2+, and ISH assessment also confirmed that these cases are indeed HER2-negative, proving the high accuracy of HER2 CN drPCR assay. In conclusion, given the advantages of drPCR-based HER2 assessment with high accuracy, sensitivity, and simplicity, the drPCR assay could be a complementary or alternative method to IHC and ISH to greatly improve current HER2 testing. Citation Format: Jin hyuk Chang, YoonSik Kim, Hee-Joo Choi, Soo Young Park, Ji-Hye Park, Hee-Young Won, Min Ji Song, Da Sol Kim, Hayeon Kim, Sohyeon Yang, Nam Hun Heo, Minsik Song, Seung-Shick Shin, Do Young Lee, Han Suk Ryu, Si-Hyong Jang, Jeong-Yeon Lee. Ultra-rapid and precise measurement of HER2 copy number alteration by next-generation digital PCR capable of real-time analysis in patients with breast cancer: A multicenter retrospective study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A005.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.ADVBC23-A005
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2024
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract 5094: Mutant specific mitochondrial localization of BRAFV600E: Clinically used BRAF kinase inhibitors are not able to block mitochondrial actions of BRAFV600E
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5094-5094
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5094-5094
    Abstract: Oncogenic mutation in BRAF kinase (BRAFV600E) results active structural conformation characterized with greatly elevated ERK activities. However, other cellular effects which are specifically influenced by mutation in BRAF kinase remains to be identified. We investigated differences in subcellular localizations of wild type and mutant BRAFV600E and observed the effects of the BRAF inhibitors on subcellular compartment-specific effects of BRAFV600E. We found that significant portion of endogenous and exogenous BRAFV600E, but not wild type BRAF, was detected in mitochondrial fraction. The other BRAF mutants, BRAFV600D, BRAFV600K and BRAFV600R which shows higher kinase activities were able to localize in mitochondria. The localization of BRAFV600E onto mitochondria provides anti-apoptotic activities against staurosporine and TNFα/cycloheximide. In addition, inducible expression of BRAFV600E increases glucose uptake rate, decreased O2 consumption, suggesting reduced mitochondrial oxidative phosphorylation which are signature features found in cancer cells. Interestingly, suppression of MEK activities using U0126 did not affect both mitochondrial localization and anti-apoptotic activities of BRAFV600E. The BRAF inhibitor such as Sorafenib was effective to inhibit MEK/ERK activation, however, they did not block the mitochondrial localization of BRAFV600E. Therefore, these inhibitors did not block the antiapoptotic activities and not reduce high glucose uptake rate and glycolytic activities induced by BRAFV600E. We found oncogenic BRAF mutants are able to localize in mitochondria and these actions might be related to altered responses to apoptotic stimuli and to characteristic metabolic phenotypes. In addition, currently BRAFV600E inhibitors were not sufficient to block mitochondrial localization of BRAFV600E and it may explain the limited efficacy of these drugs in clinically advanced BRAFV600E-positive tumors. These observations provide new mutation- specific roles of BRAFV600E which is potentially important for the development of therapeutics. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5094.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-5094
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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