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  • American Association for Cancer Research (AACR)  (16)
  • 1
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    D-501036, a novel selenophene-based triheterocycle derivative, exhibits potent in vitro and in vivo antitumoral activity which involves DNA damage and ataxia telangiectasia–mutated nuclear protein kinase activation
    American Association for Cancer Research (AACR) ; 2007
    In:  Molecular Cancer Therapeutics Vol. 6, No. 1 ( 2007-01-01), p. 193-202
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 6, No. 1 ( 2007-01-01), p. 193-202
    Abstract: D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is herein identified as a novel antineoplastic agent with a broad spectrum of antitumoral activity against several human cancer cells and an IC50 value in the nanomolar range. The IC50 values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were & gt;10 μmol/L. D-501036 exhibited no cross-resistance with vincristine- and paclitaxel-resistant cell lines, whereas a low level of resistance toward the etoposide-resistant KB variant was observed. Cell cycle analysis established that D-501036 treatment resulted in a dose-dependent accumulation in S phase with concomitant loss of both the G0-G1 and G2-M phase in both Hep 3B and A-498 cells. Pulsed-field gel electrophoresis showed D-501036–induced, concentration-dependent DNA breaks in both Hep 3B and A-498 cells. These breaks did not involve interference with either topoisomerase-I and topoisomerase-II function or DNA binding. Rapid reactive oxygen species production and formation of Se-DNA adducts were evident following exposure of cells to D-501036, indicating that D-501036–mediated DNA breaks were attributable to the induction of reactive oxygen species and DNA adduct formation. Moreover, D-501036–induced DNA damage activated ataxia telangiectasia–mutated nuclear protein kinase, leading to hyperphosphorylation of Chk1, Chk2, and p53, decreased expression of CDC25A, and up-regulation of p21WAF1 in both p53-proficient and p53-deficient cells. Collectively, the results indicate that D-501036–induced cell death was associated with DNA damage–mediated induction of ataxia telangiectasia–mutated activation, and p53-dependent and -independent apoptosis pathways. Notably, D-501036 shows potent activity against the growth of xenograft tumors of human renal carcinoma A-498 cells. Thus, D-501036 is a promising anticancer compound that has strong potential for the management of human cancers. [Mol Cancer Ther 2007;6(1):193–202]
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-06-0482
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 2
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    Abstract 4626: Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4626-4626
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4626-4626
    Abstract: Developing realistic preclinical models using clinical samples that reflect complex tumor biology is critical to advancing cancer research. Patient-derived preclinical tumor models are the optimal tool for understanding drug action patterns and resistance mechanisms. In order to improve the capability of drug R & D in our institute (NHRI-IBPR), we have generated several patient-derived xenograft (PDX) models and characterized the genomic signature and responsiveness to standard-of-care (SOC) therapy. DBPR216, an orally bioavailable multikinase inhibitor, showed potent effect for treatment of gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML) through targeting of c-KIT and FLT-3, respectively. In order to further discover other indications of DBPR216 for clinical application, we investigated the anti-tumor effect of DBPR216 in several in-house PDX models. Among them, we found that DBPR216 was effectively to suppress PDX tumor growth in the immuno-deficient mice in two colorectal adenocarcinoma PDX models, C008 and C015. These PDX models showed similar genomic features with original tumor samples from patients when test using targeted sequencing of cancer related genes. To further identify if DBPR216 is superior to other kinase inhibitors and SOC therapy, we used in vitro PDX cell proliferation assay to quickly examine the anti-tumor effect of DBPR216 compared to a panel of therapeutic drugs. The result demonstrated that DBPR216 appeared to be superior in potency to kinase inhibitors (Regorafenib, Afatinib, Sunitinib, and Imatinib) and SOC therapy (Irinotecan, 5-FU, and Oxaliplatin). Combining the kinase profiling of DBPR216 and mutational analysis of C008 and C015 PDX models, we proposed that DDR2, FLT1, PDGFRα, PDGFRβ, RET, and SRC may be the potential targets of DBPR216 in these PDX models, and need further elucidation. Taken together, we found that DBPR216 exhibits potent anticancer effect against colorectal cancer and may bring the better opportunity than Regorafenib, a therapeutic agent for metastatic colorectal cancer in clinical. DBPR216 is now under preclinical development for further IND submission. Citation Format: Ching-Chuan Kuo, Weir-Torn Jiaang, Jing-Jim Ou, Chiung-Tong Chen, Shu-Ching Hsu, Chuan Shih, Li-Mei Lin, Manwu Sun, Yi-Hsin Wang, Zih-Ting Huang, Jang-Yang Chang, Shau-Hua Ueng. Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216 [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 4626.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4626
    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 A83: 4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. A83-A83
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A83-A83
    Abstract: The Nrf2/ARE pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins, and has been considered as a potential target for cancer chemoprevention by eliminating harmful reactive oxygen species (ROS) or reactive intermediates generated from carcinogens. The objectives of this study were to identify a novel Nrf2/ARE activator and to investigate the mechanistic signaling pathway involved in the activation of Nrf2-mediated cytoprotective effects against oxidative-induced cell injury. A stable ARE-driven luciferase reporter cell line was established to screen the potentially cytoprotective compound. 4-Ketopinoresinol (4-KPR), the (−) double cyclized type of lignan obtained from adlay (Coix lachrymal-jobi L. var. ma-yuen Stapf), more effectively activates ARE-driven luciferase activity than the classical ARE activator, tert-butylhydroquinone. 4-KPR treatment resulted in a transient increase in AKT phosphorylation and subsequent phosphorylation and nuclear translocation of Nrf2, along with increased expression of ARE-dependent cytoprotective genes, such as heme oxygenase-1 (HO-1), aldo-keto reductases, and glutathione synthetic enzyme, and their protein products. 4-KPR suppresses oxidative stress-induced DNA damage and cell death via up-regulation of HO-1. Inhibition of PI3K/AKT signal by chemical inhibitors or RNA interference suppressed Nrf2 activation and HO-1 up-regulation. These observations in an ARE-regulated gene system suggest that 4-KPR is a novel Nrf2/ARE-mediated transcription activator, activates the Nrf2/HO-1 axis, and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling. These results may have relevance to the clinical application of 4-KPR and its significance in cancer chemoprevention. The study was supported by grants of DOH100-TD-C-111-004, NSC98-2320-B-400-003-MY3, and NSC99-2323-B-400-006. 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 A83.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-A83
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 4
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    Abstract 1528: Activation of NRF2/ABCC1 axis confers resistance to topoisomerase II poisons in human oral malignancies
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1528-1528
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1528-1528
    Abstract: Etoposide (VP-16), a DNA topoisomerase II poison, is an important clinical used chemotherapeutic agent for human oral malignancies. An etoposide-resistant cell line, KB-7D, has been generated from human oral epidermoid carcinoma KB cells to investigate the mechanism of action of drug resistance in oral malignancies. Previous studies revealed that KB-7D cells were approximately 50-fold more resistant to etoposide as compared to parental KB cells. It also exhibited cross-resistant to chemotherapeutic agents such as doxorubicin. This multi-drug resistance may be caused by the over-expression of ABCC1, leading to the decrease in drug accumulation in KB-7D cells. Our current work continues the effort to investigate the mechanism of regulation of ABCC1 expression in the etoposide-derived drug resistant cells and subsequently find the molecular target that can be used to restore therapeutic efficacy in chemo-refratory cancers. Down-regulation of ABCC1 by RNA interference and a selective inhibitor, MK-571, significantly enhanced the chemosensitivity to etoposide and doxorubicin in KB and KB-7D cells. To further determine the possible transcriptional factors that regulate the ABCC1 transactivation, the promoter region of ABCC1 was examined. A NRF2 binding sequence, antioxidant responsive element (ARE), has been found locate in the ABCC1 promoter at -470 to -458 upstream from the transcription start site. Real-time RT-PCR and Western blot analyses showed that expression of NRF2 mRNA and protein in KB-7D cells was 1.4 to 1.8 folds higher than those expressed in the parental cells. In addition, Chromatin Immunoprecipitation (ChIP) analysis revealed that NRF2 directly targeted to the ARE sequence in the ABCC1 promoter region. Interestingly, down-regulation of NRF2 decreased the expression of ABCC1 and also increased the chemosensitivity of KB-7D cells against selected anti-cancer drugs. In addition, cells incubated with an NRF2 activator, tBHQ, induced nucleus accumulation of NRF2 and over-expression of ABCC1, resulting in the enhancement of drug-resistance against etoposide or doxorubcin in KB and KB-7D cells. In summary, constitutive activation of NRF2-dependent ABCC1 contributed to the causation of chemoresistance in etoposide-derived drug resistant cells. Blockage of ABCC1 expression by manipulation of the NRF2 signaling pathway enhanced the chemotherapeutic efficacy in cells. Therefore, targeting NRF2 may be able to reverse chemoresistance in chemo-refractory oral malignancies. In addition, development of NRF2 inhibitors may be a new strategy to overcome chemoresistance in human cancers. (The study was supported by grants of Department of Health DOH99-TD-C-111-004, Taiwan.) 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 1528. doi:10.1158/1538-7445.AM2011-1528
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1528
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 5
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    Abstract 3944: Blockage of EGFR signaling repurposes tumor metabolism through suppression of glycolysis and Kreb cycle in head and neck cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3944-3944
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3944-3944
    Abstract: Head and neck squamous cell carcinoma (HNSCC), the most common malignant neoplasm arising in the mucosa of the upper aerodigestive tract, remains a significant cause of morbidity worldwide. With respect to the cancer treatment, HNSCC has a moderately good survival rate, however, the disease often recurs, leading to a poor prognostic disease course and tends to fail in treatment. The metabolic properties of cancer cells diverge significantly from those of normal cells. Emerging evidence suggests these metabolic alterations are also linked to therapeutic resistance in cancer treatment. EGFR targeted agents currently approved or under investigation for HNSCC. We recently identified a novel EGFR tyrosine kinase inhibitor (EGFR-TKI), BPR3K007S0, and found that this compound significantly inhibited EGFR phosphorylation in EGFR-overexpressing HNSCC cells in vitro and in vivo than that of gefitinib. BPR3K007S0 significantly suppressed the expression of a wide range of metabolic genes, including metabolic-related transcription factors, glycolysis, TCA cycle, and pentose phosphate pathway genes. Collectively, we also found that BPR3K007S0 significantly decreased glycolytic and mitochondria respiratory capacity. Pharmacological and genetic manipulation demonstrated that c-Myc/hexokinase 2 axis was one of downstream effector in response to EGFR inhibition. Furthermore, we found that EGFR-TKIs were able to suppress succinate dehydrogenase A leading to reduce fumarate, an oncometabolite generates from Kreb cycle, and contributed to EGFR-TKIs mediated antitumor effect. Taken together, these results revealed that blockage of EGFR signaling repurposes tumor metabolism through suppression of hexokinase 2 and succinate dehydrogenase A, in glycolysis and Kreb cycle, respectively, and demonstrated added benefits to treatment of HNSCCs. Citation Format: Ching-Chuan Kuo, Jang-Yang Chang, Hsing-Pang Hsieh, Hsing-Jien Kung, Hsih-Huei Chang, Chih-Hsiang Huang, Cheng-Chin Kuo, Yi-Yu Ke. Blockage of EGFR signaling repurposes tumor metabolism through suppression of glycolysis and Kreb cycle in head and neck 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 3944.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3944
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 6
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    Abstract 1701: Activation of Akt/FoxO axis confers resistance to cisplatin in human nasopharyngeal carcinomas
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1701-1701
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1701-1701
    Abstract: Nasopharyngeal carcinoma (NPC) is one of the predominant cancers found in Southeastern China and Taiwan. Chemotherapy is one of the major treatment modalities, and the cisplatin-based regimen is the front-line treatment. However, NPC patients failing to cisplatin treatment will have a compromised survival. To explore the resistance spectrum and mechanisms of cisplatin resistance in NPC, two cisplatin-resistant sublines (cis6 and cis15) derived from the parental NPC cell line HONE-1 were obtained. Compared with HONE-1 cells, cis6 and cis15 cells showed upto 18-fold resistance to cisplatin in each, and also possessed a cross-resistance to oxaliplatin and arsenic trioxide. The level of platinum-DNA-adduct and γH2AX were significantly decreased in cis6 and cis15 cells. To unravel the behind details, the systems of DNA repair and cisplatin detoxification were examined and found to be more active in both resistant cells. In terms of the DNA repair proteins, the levels of p-DNA-PK and XRCC1 were increased; in terms of cellular localization of cisplatin, the level of copper transporter ATP7A was upregulated; in terms of Nrf2/antioxidant/detoxifizing enzyme, the resistant cells had a higher Nrf2 activity and an increased intracellular level of GSH, GR, NQO1, AKR1C1 and AKR1C2. Moreover, as compared with HONE-1 cells, our results showed that the resistant cells spared the cisplatin-induced cell death via the suppression of pro-apoptotic proteins and the enhancement of anti-apoptotic proteins. Since the members of ErbB family could be overexpressed in NPC and the ErbB/Akt/FoxO axis could involve in the actions of apoptosis, DNA damage repair and detoxification of reactive oxygen species, the ErB/Akt/FoxO were investigated. Indeed, the phosphorylations of Akt, FoxO1, and FoxO3 were upregulated in cis6 and cis15 cells. Thus, the resistance to cisplatin in cis6 and cis15 cells was partially explained by the Akt/FoxO pathway. Surprisingly, EGFR was downregulated in the resistant cells, whereas ErbB2 was upregulated. The elevations of the negative regulators of EGFR, including c-Cbl, GCF and LRIG1, were observed in cis6 and cis15 cells, indicating that the negative regulation of EGFR could be at the levels of transcription and protein degradation. Since LRIG1 could be upregulated and negatively feedback to control the level of ErbB after the ErbB was activated, it was plausible that the overexpression of ErbB2 upregulated the expression of LRIG1 and subsequently, caused the downregulation of EGFR. Nevertheless, the hypothesis which both overexpression of ErbB2 and LRIG1 contributes to the resistance to cisplatin in our cell model awaits experimental verification. Taken together, our results suggested that the mechanism responsible for cisplatin resistance in NPC, at least in part, through Akt/FoxO pathway. (The study was supported by grants of Department of Health DOH99-TD-C-111-004, Taiwan, R.O.C.) 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 1701. doi:10.1158/1538-7445.AM2011-1701
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1701
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 7
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    Abstract A16: Establishment and characterization of CCGL007, a novel human chronic lymphocytic leukemia cell line
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 16_Supplement ( 2016-08-15), p. A16-A16
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 16_Supplement ( 2016-08-15), p. A16-A16
    Abstract: Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. However, lack of immortalized cell line representative of the CLL disease has hampered a full understanding of disease pathogenesis and development of novel therapeutic agents for treatment. There were very few representative CLL cell lines are available now. To this end, we have tested different culture condition with addition of growth factor supplements to generate CLL cell lines from highly purified peripheral blood B cells of CLL patients. Recently, we have successfully established a new CLL cell line, named CCGL007. CCGL007 cells grow as suspension in liquid culture. Surface marker analysis with a panel of monoclonal antibodies revealed that CCGL007 cell line expresses B cell markers. The chromosomal, immunophenotypic, molecular biologic characteristics, and in vivo tumorigenesis potential of CCGL007 is under investigation. We have used this cell model to test the efficacy of selected standard chemotherapy drugs and new therapeutic agents, such as ibrutinib and several novel in-house BTK inhibitors, against CLL cell growth, and CCGL007 represents as a suitable preclinical model for testing pharmacological agents. Citation Format: Ching-Chuan Kuo, Chih-Cheng Chen, Chih-Hsiang Huang, Lin Li-Mei. Establishment and characterization of CCGL007, a novel human chronic lymphocytic leukemia cell line. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A16.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.PDX16-A16
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 8
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    Abstract 4194: The hereditary genetic polymorphism of mir-608 predicts the clinical outcome and expression of IL-6 in patients with esophageal squamous cell carcinoma .
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4194-4194
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4194-4194
    Abstract: PURPOSE: To investigate the effect of the single nucleotide polymorphisms (SNPs) in microRNA-related genes on the prognosis of patients with esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A total of 504 patients with a diagnosis of ESCC were enrolled in the study. The genotypes of miRNA-related SNPs were analyzed from the genomic DNA of peripheral leukocytes and were correlated with the clinical outcome of patients, which was first evaluated in a randomly assigned training set (n=129) and subsequently verified by a replication set (n= 375). RESULTS: In training group, the heterozygous CG genotype of mir-608 rs4919510 was associated with reduced risk for adverse clinical outcomes (HR [95% CI] =0.47 [0.27-0.82] for death; HR [95% CI] =0.47 [0.29-0.77] for recurrence). In contrast, both homozygous CC and GG genotypes showed unfavorable for prognosis. The associations were confirmed in an independent replication group (GG+CC vs. CG, HR [95% CI] =1.36 [1.07-1.73] , P=0.013 for death; HR [95% CI] = 1.26 [1.00-1.59] , P=0.048 for recurrence). The prognostic effect was more pronounced among patients with advanced tumor stages and in those treated with concurrent neoadjuvant chemo- radiotherapy (CCRT). Functional relevance of rs4919510 was correlated with the serum IL-6 levels. GG variant was significantly associated with IL-6 over-expression in advanced ESCC patients. CONCLUSION: The hereditary genetic variants in mir-608 can serve as an independent predictor for the clinical outcome of ESCC patients. The prognostic effect of rs4919510 may be partially mediated by impairing the ability in regulating IL-6 expression. Citation Format: Pei-Wen Yang, Ching-Yueh Hsieh, Yu-Ting Huang, Ya-Chuan Huang, Tzu-Hsuan Chiang, Jang-Ming Lee. The hereditary genetic polymorphism of mir-608 predicts the clinical outcome and expression of IL-6 in patients with esophageal squamous cell carcinoma . [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 4194. doi:10.1158/1538-7445.AM2013-4194
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4194
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
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  • 9
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    Abstract 3991: The genetic variants of growth factor-related genes associate with the prognosis of patients with advanced esophageal squamous cell carcinoma .
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3991-3991
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3991-3991
    Abstract: PURPOSE: To investigate the association between the genetic polymorphisms of growth factor-related genes and the prognosis of patients with advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A total of 336 ESCC patients with advanced tumor stages (stage 2b+3+4) were enrolled in the study. These subjects were randomly assigned to a training set (n=95) and a replication set (n=241).The genotypes of candidate single nucleotide polymorphism (SNPs) were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes, and were correlated with the clinical outcome of patients in training, replication, and combined groups. Serum levels of growth factors were examined by enzyme-link immunosorbent assay (ELISA). RESULTS: In training group, the genotyping of 16 candidate SNPs was successfully performed. Seven SNPs, rs4444903, rs2010963, rs2272037, rs713646, rs3025039, rs3025040, rs2016347, significant or borderline significant correlated with mortality or disease progression and were further evaluated in an independent replication group. In replication group, GG of rs4444903 at EGF gene and CC of rs2010903 at VEGF showed unfavorable trend for the mortality (P=0.286 for rs4444903; P=0.215 for rs2010963). These 2 SNPs showed significant effects on overall survival of the patients in combing group (GG vs. AA, adjusted [HR] = 1.29, 95% CI=1.01-1.66, P=0.045 for rs4444903; CC vs. GG, adjusted [HR] = 1.53, 95% CI=1.07-2.18, P=0.020 for rs2010963). Meanwhile, GA genotype of rs2272037at IGF1R gene also show unfavorable trend among all subjects (GA vs. GG, [HR] = 1.24, 95% CI=0.96-1.60, P=0.108). Combing these 3 SNPs, patients with 3 unfavorable genotypes showed 2-fold risk for mortality compared to patients without any of the unfavorable genotypes (accumulated unfavorable genotypes 3 vs. 0, [HR] = 2.00, 95% CI=1.10-3.64, P=0.023). Additionally, GG genotype of EGF_rs4444903 correlated with increase serum levels of EGF in patients with advanced ESCC. Finally, both EGF and VEGF expression levels significant associated with the mortality of patients. CONCLUSION: The genetic variants in growth factor-related can serve as prognostic predictors of the patients with advanced ESCC, and thus provide more information for the personalized therapies for the patients with ESCC. Citation Format: Jang-Ming Lee, Pei-Wen Yang, Ya-Chuan Huang, Min-Shu Hsieh, Ching-Yueh Hsieh, Pei-Ming Huang, Hsao-Hsun Hsu, Jin-Shing Chen, Shuenn-Wen Kuo. The genetic variants of growth factor-related genes associate with the prognosis of patients with advanced esophageal squamous cell carcinoma . [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 3991. doi:10.1158/1538-7445.AM2013-3991
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3991
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
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  • 10
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    Abstract 1400: Extended concurrent gene signatures of ER, HER2 and disease-free survival in breast cancers
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1400-1400
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1400-1400
    Abstract: Our recent work had identified concurrent gene signatures which highlighted the interplay between copy number variation (CNV) and differential gene expression (GE) for Han Chinese breast cancers. The merit of the approach is the discovery of biomarkers not readily identified by conventional GE only data, for which phenotype-correlation or gene variability is the criteria of gene selection. A total of 31 array CGH and 83 GE arrays (29 samples with data from both platforms) were performed. Potential targets of cancer therapy were revealed by Genomic Identification of Significant Targets in Cancer (GISTIC) from 31 array CGH. We used these concurrent genes as well as genes with significant GISTIC scores to derive signatures associated with clinical ER, HER2 status, and disease-free survival. The most common gain regions were 1q21.2 and 17q12-q21.1 while the most common lost region was 22q11.23. In subgroup analysis, recurrent gains for ER positive cancers were 8p23.1, and 8p11.23-11.21. For HER2 overexpressing tumors, recurrent gain was 17q12-21.1 and recurrent losses were 8p11.22, 8p12, and 8p23.1. We identified 1,584 concurrent genes from 29 samples assayed for both array CGH and GE microarrays, and enriched concurrent gene sets for ER, HER2 and disease-free survival were identified independently from our 83 GE arrays (GSE48391) and two series with Han Chinese origin (GSE5460 and GSE20685) as well as three studies of Western countries (GSE7390, GSE2034 and GSE3494). Signature genes were consensus genes from leading edge analysis across all studies, and we used supervised partial least square (PLS) regression to derived predictive model of clinical ER, HER2 and disease-free survival with each signature gene further weighted by the coefficient of concurrence as an additive tuning parameter. The predictive accuracy was 92.3% for ER and 84.6% for HER2 in 208 Han Chinese breast cancers and was 87.3% for ER in 735 breast cancers in Western countries. For five studies with disease-free survival data (no survival data for GSE5460), prognostic discrepancy was observed in four studies except GSE3493 between high-risk and low-risk patients predicted with the concurrent signature. We conclude that parallel analysis of CGH and microarray data, in conjunction with known gene expression patterns, can be used to identify biomarkers with prognostic values in breast cancer. Citation Format: Chi-Cheng Huang, Shih-Hsin Tu, Ching-Shui Huang, Heng-Hui Lien, Liang-Chuan Lai, Eric Y. Chuang. Extended concurrent gene signatures of ER, HER2 and disease-free survival in breast cancers. [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 Su ppl):Abstract nr 1400. doi:10.1158/1538-7445.AM2014-1400
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1400
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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