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  • American Association for Cancer Research (AACR)  (38)
  • 1
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    Abstract 2372: Predictive markers in patients with non-small cell lung cancer with pemetrexed treatment.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2372-2372
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2372-2372
    Abstract: Background: This study is desiged to evaluate biomarkers that are correlated with the efficacy of pemetrexed in patients with non-small-cell lung cancer (NSCLC). Methods: Patients with stage III or IV NSCLC who received pemetrexed monotherapy after failure of one or more chemotherapy regimen between January 2003 and August 2011 were included. Polymorphism of reduced folate carrier gene (SLC19A, rs1051298), 5,10-methylenetetrahydroflate reductase (MTHFR, rs1801133) and thymidylate synthase (TS, rs45445694, rs16430) gene were analyzed by PCR and direct sequencing method using peripheral blood. Results: Total 123 patients were included. The median age was 61 years (range 35-82). Fifty eight (47.2%) patients were female. Predominant histology was adenocarcinoma (92.7%). Metastatic diseases were 114 (80.5%) patients. Patients received one or more lines of systemic therapy before pemetrexed therapy, one line in 53 (43.1%) patients, two in 51(41.5%), three in 14 (11.02%), and four in 4 (3.3%). Median 4 cycles of chemotherapy were given (range 1-44). Response rate was 22.7% (CR, n=2, PR, n=26) and stable disease was detected in 54 patients (43.9%). Median follow up duration was 28.7months (range 4.07-84.33months). Median progression free survival (PFS) was 4.2 months (95% CI: 2.9-5.6) and median overall survival (OS) was 18.9 months (95% CI: 13.3-24.6). Clinical factors like, sex, histology of tumor (adenocarcinoma vs, nonadenocarcinoma), differentiation, smoking status and EGFR mutation status (active mutation vs. other mutation vs. wild type) did not have any significant difference on response and PFS. Only polymorphisms of TS promoter enhancer region (TSER) were related with PFS. 2R/2R repeat in the TSER (2R/2R vs 2R/3R, 3R/3R 1.0m vs 4.3m, p & lt;0.01) and CC homozygote variant in second repeat of the 3R allele (CC vs GC, GG 2.8m vs 5.0m, p=0.04) had poor PFS. All polymorphism did not have effect on response rate and overall survival. Conclusions: This study suggests that polymorphisms of TSER associated PFS in pemetrexed treatment. Further prospective studies will be needed to validate these polymorphism as a useful biomarker of pemetrexed treatment in NSCLC patients. Citation Format: Hiun S. Chae, Yoon Ho Ko, Eun Kyoung Jeon, Sook Hee Hong, Jeong-Oh Kim, Seung Joon Kim, Kyo Young Lee, Young Kyoon Kim, HoonKyo Kim, Seok young Park, In Sook Woo, Jin Hyoung Kang. Predictive markers in patients with non-small cell lung cancer with pemetrexed treatment. [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 2372. doi:10.1158/1538-7445.AM2013-2372
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2372
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 2
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    Abstract 2357: Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2357-2357
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2357-2357
    Abstract: Background: Placental growth factor (PIGF) is a proangiogenic factor, belonging to the VEGF family. It binds to VEGF receptor 1(VEGFR-1) and stimulates the growth, migration and survival of endothelial cells. PIGF also activates and attracts macrophages that release angiogenic molecules. Increased expression of PIGF has correlated with poor survival of patients in several solid tumors. However, PIGF expression is not consistently elevated in all malignancies. No reports on the clinical implications of PIGF expression in metastatic or recurrent non-small cell lung cancer (NSCLC) are currently available. We investigate the clinical significance of PIGF expression in metastatic or recurrent NSCLC. Patients and methods: A retrospective review was done for seventy four patients with metastatic or recurrent NSCLC. Immunohistochemical staining for PIGF and its receptor VEGF-R1, neurophilin-1 was performed. Results: Of 74 patients with NSCLC, 73 patients were positive for PIGF, and 72 patients were positive for neurophilin-1. For PIGF expression, significant correlations were demonstrated with female (p=0.007) and nonsquamous histology (p=0.045). Thirty five patients (47%) were classified into low PIGF expression groups, whereas 38 patients (51%) were grouped as showing high PIGF expression. Survival time for patients with high PIGF expressing NSCLC was significantly longer than that for patients displaying low PIGF expression (median survival time, 15.1 months vs. 9.0 months[log-rank, p=0.01]). However, the difference in time to progression between two groups was not statistically significant (median time to progression, 5.1 months vs. 3.9 months [log-rank, p=0.24] ). Conclusions: Low expression of PIGF is associated with poor prognosis in patients with metastatic or recurrent NSCLC. Further studies on larger patients populations are warranted to validate the utility of PIGF as a prognostic biomarker in lung cancer. Citation Format: Jung Hoon Kim, Tae Jung Kim, Kyu Sang Lee, Yun Hwa Jung, In Sook Woo, Sook Hee Hong, Chi Wha Han, Jae Kil Park, Jae Ho Byun. Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer. [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 2357. doi:10.1158/1538-7445.AM2013-2357
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2357
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 3
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    Abstract 1192: Increased regulatory T cells induced by glycolytic metabolic change in EGFR mutant NSCLC after EGFR TKI therapy
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1192-1192
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1192-1192
    Abstract: Background. Studies on the immune microenvironment of EGFR mutant lung cancer have been limited. We analyzed the effect of immune microenvironments on the development of EGFR-TKI resistance in EGFR-mutated lung cancer. Methods. The EGFR mutant lung cancer cell line was co-cultured with activated PBMC for 72 hours with EGFR-TKI. Changes of cytokines/chemokines in the media, PD-1 expression of CD8+ T cells, regulatory T cells fraction and transcriptome analysis of tumor cells were analyzed. We also performed immune profile analysis of fresh tissues of 21 surgically resected NSCLC (7 EGFR mutant and 14 EGFR wild) by multicolor FACS. Results. The Cytotoxicity of EGFR-TKI (elrotinib) in EGFR mutant HCC827 and H4006 lung cancer cell lines co-cultured with active PBMC tended to decrease. IL-6, IL-8, VEGF, TGF-B1, CXCL1, and CXCL10 were significantly increased after co-culture with activated PBMC but did not decrease after addtional EGFR-TKI treatment. IFN gamma increased after co-culture with activated PBMC but decreased after EGFR-TKI treatment. PD-L1 expression on tumor cells increased after co-culture with activated PBMC (p = 0.08 in HCC827 and p = 0.09 in H4006) but did not decrease after co-culture with activated PBMC and EGFR-TKI treatment (p = 0.36 in HCC827 and p = 0.45 in H4006). PD-L1 expression of A549 (EGFR wild type) did not change with co-culture or EGFR-TKI treatment. PD-1 expression of CD8 T cell co-cultured with HCC827 or H4006 did not change, however proportion of regulatory T cell increased after co-culture with HCC827 or H4006 (p=0.05 and p=0.08, respectively) and did not decrease during co-culture and EGFR-TKI treatment. Proportion of regulatory T cell in co-cultures with A549 or H1975 (erltinib resistant cell line) did not change during co-culture or EGFR-TKI treatment. Transcriptome analysis by RNA sequencing showed 1747 gene sets were differentially expressed in EGFR-TKI treated EGFR mutant cell line co-cultured with activated PBMC compared to EGFR-TKI treatment alone. Interferon gamma response pathway (NES 2.65, FDR q & lt;0.1) and glycolytic pathway (NES 2.15, FDR & lt;0.1) were most significantly changed. Immune profile analysis of human EGFR mutant lung cancer showed that CD4+/CD3+ T cells in EGFR mutant groups was increased compared to EGFR wild group. Proportion of FOXP3+CD25+CD4+ T reg in EGFR mutant group tended to increase compared to EGFR wild group (1.352±0.4 vs 0.74 ± 0.16%, p=0.256). Conclusion. The regulator T cell is considered to be important in EGFR mutant NSCLC in induction of immuno suppressive microenvrionement and EGFR-TKI resistance. Study on glycolytic pathway mediated immuno suppressive microenvionment and EGFR-TKI resistance is currently ongoing Citation Format: Sook-hee Hong, Nahyeon Kang, Seung joon Kim, Okrane Kim, Jin-hyoung Kang, Sook Whan Sung. Increased regulatory T cells induced by glycolytic metabolic change in EGFR mutant NSCLC after EGFR TKI therapy [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 1192.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1192
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 4
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    Abstract 3618: Synergistic anti-tumor efficacy of a multi kinase inhibitor, Sorafenib combined with Paclitaxel in vitro and in vivo lung cancer models
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3618-3618
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3618-3618
    Abstract: Sorafenib (BAY 43-9006), a multi-kinase inhibitor, targets a serine-threonine kinase, BRAF as well as several tyrosine kinases. Paclitaxel has been known to exhibit potent anti-tumor activity in non-small cell lung cancer (NSCLC). Our aim of this study was to examine anti-proliferation, anti-angiogenesis and apoptosis induction when Sorafenib combined with Paclitaxel in vitro and in vivo NSCLC models. We measured the inhibitory activities of Sorafenib or Paclitaxel single and their sequential combinations(PS: Paclitaxel 24h → Sorafenib 48h and SP: Sorafenib 48h → Paclitaxel 24h) on cell proliferation in A549 (KRAS mutation), H1666 (BRAF mutation), and Calu-3 (p53 mutation) by SRB assay. We evaluated phosphorylation of ERK, AKT and BRAF proteins using Western bloting and analyzed the cell cycle distribution in A549 cell line. Xenograft tumor model was established with A549 tumor cells implanted in the Balb/c nu/nu mice. Together with single treatments, two different combination schedules of Sorafenib with Paclitaxel were examined. PPS, 20mg/kg of paclitaxel IP at 2 times in 1st wk followed by 40mg/kg of Sorafenib PO during 5 consecutive days in 2nd wk, PSS, 20mg/kg of Paclitaxel IP one time at 1st day followed by 40mg/kg of Sorafenib PO during 5 consecutive days in 1st week. Intratumoral molecular changes were studied on paraffin-embedded tumor tissue obtained from xenograft mice using immunohistochemistry and the apoptotic induction was evaluated with TUNEL assay. Single Sorafenib or Paclitaxel showed active cytotoxicities with dose-dependent manner in three cell lines. Their IC50s at 72hrs were as follows: A549, 5.7 ± 1.3 µM and 1.6 ± 0.1 nM; H1666, 3.7 ± 0.2 µM and 2.2 ± 0.6 nM; Calu-3, 8.8 ± 1.0 µM and 1.4 ± 1.3 nM, respectively, and the combination effect of PS was superior to SP in the three cell lines. A549 cells were treated with Paclitaxel (24h/48h), Sorafenib (24h/48h), PS and SP. Sorafenib significantly reduced the expressions of pBRAF, pERK and pAKT. PS showed greater reduction of pBRAF, pERK and pAKT compared to Sorafenib. However, downregulation of pERK expression was not detected in SP. Sorafenib induced G0/G1 arrest of cell cycle (54.5% at baseline vs. 61.9% at 48hr). PS demonstrated greater increase of G0/G1 arrest than SP (66.8% vs. 50.8%). In xenograft tumor model, Sorafenib combined with Paclitaxel (PPS or PSS) more effectively suppressed tumor growth compared to their single treatments. In immunohistochemistry study, greater inhibition of Ki-67 as well as pAKT, pERK, and CD31 were observed in two sequential combinations compared to single treatment. Additionally, significant increase of apoptotic change was also found in these two combinations. Taken together, sequential combination of Sorafenib with Paclitaxel demonstrated synergistic interaction and potent anti-tumor efficacy compared to their single treatment in vitro and in vivo NSCLC models. 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 3618.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3618
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
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  • 5
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    Abstract 2609: Overexpression of YAP1 of EGFR-mutant lung adenocarcinoma before tyrosine kinase inhibitor is associated with poor survival
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2609-2609
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2609-2609
    Abstract: Purpose: EGFR tyrosine kinase inhibitor (EGFR TKI) was approved as a first line treatment for EGFR mutant lung adenocarcinoma (LADC) with advanced stage. YAP1 (Yes-associated protein 1) is a main effector of hippo pathway, related with adverse prognosis and EGFR TKI modulation of non-small cell lung cancer. This study aimed to clarify a prognostic role of YAP1 in EGFR mutant LADC and efficacy for EGFR TKI through the course of EGFR TKI. Materials and Methods: 41 patients with paired lung cancer specimen before and after EGFR TKI were enrolled in this study. The expression of YAP1 protein was evaluated by immunohistochemistry. Results: 15 cases (36.6%) with high YAP1 expression was found in pre-EGFR TKI LADC, while high YAP1 expression in 21 cases (52.5%) was detected after EGFR-TKI. The transitional level of YAP1 between pre- and post-EGFR TKI was significantly upregulated (P=0.002). High YAP1 before EGFR TKI was related with shorter OS (P=0.023) and PFS (P=0.041). In addition, high YAP1 before EGFR TKI in T790M mutant LADC was related with poor OS (P & lt;0.001). Conclusion: YAP1 burden before EGFR TKI was crucial role in prognosis of EGFR mutant LADC treated by EGFR TKI. Citation Format: Soon Auck Hong, Jin-Hyoung Kang, Sook Hee Hong. Overexpression of YAP1 of EGFR-mutant lung adenocarcinoma before tyrosine kinase inhibitor is associated with poor survival [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 2609.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2609
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
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  • 6
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    Abstract 4663: Markers of anaerobic glycolysis as predictive factor in neoadjuvant chemoradiotherapy of rectal cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4663-4663
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4663-4663
    Abstract: Background: Growing tumors adapt to a hypoxic environment and increase anaerobic glycolysis. This metabolic switch is related to resistance of radiotherapy and chemotherapy. We investigate the relationship between biomarkers related to anaerobic glycolytic metabolism (glucose transpoter-1(GLUT-1), lactate dehydrogenase (LDH)-5 and pyruvate dehydrogenase kinase (PDK)-1) and prognosis. Methods: GLUT-1, LDH-5, PDK-1 expression determined by immunohistochemistry were assessed in 109 patients with rectal cancer treated with 5 flurouracil and leucovorin neoadjuvant chemoradiotherapy. Results: This study included 74 male and 35 female patients with a median age of 63 (range 53-70 years). Stage I, II and III accounted for 7.3%, 43.1% and 49.5%. All patients had 45 Gy (1.8 Gy/day in 25 fractions) over five weeks, plus 5-fluorouracil (425 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33 and surgery was done on 7 to 10 weeks after completion of all therapies. The down staging rate of this neoadjuvant therapy was 53% and pathologic complete response rate is 18.3%. High expression of GLUT-1, LDH-5, PDK-1 was observed in 34 (31.2%), 62 (56.9%) and 45 (41.3%) patients, respectively. A negative GLUT-1 was associated with a significantly higher rate of pathologic complete response compared to positive GLUT-1 (25.3% vs. 0.02%, p=0.006). LDH-5, PDK-1 was not correlated with down staging and complete response of chemoradiotherapy. Conclusions: The GLUT-1 expression is the predictive factor of pathologic complete response in rectal cancer patients treated with 5 flurouracil and leucovorin neoadjuvant chemoradiotherapy. 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 4663.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-4663
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 7
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    Abstract B41: Different clinical outcomes of systemic chemotherapy in non-small cell lung cancer without EGFR and K-ras mutation according to smoking status.
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 11_Supplement ( 2013-11-01), p. B41-B41
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. B41-B41
    Abstract: Background: The current treatment strategy in non-small cell lung cancer (NSCLC) adenocarcinoma without epidermal growth factor receptor (EGFR) activating mutation or anaplastic large cell kinase gene (ALK) rearrangement does not differentiate between genotype or smoking status even though resent advances in molecular study in NSCLC. In terms of second line treatment, pemetrexed is considered as a standard treatment in non-squamous NSCLC without EGFR activating mutation or ALK rearrangement. We retrospectively analyzed clinical outcomes of systemic chemotherapy according to molecular characteristics. Methods: Between 2006 and 2012, 131 patients with stage 4 NSCLC adenocarcinoma patients who were enrolled in a Seoul St. Mary's hospital lung cancer multidisciplinary center registry were available for molecular pathology regarding EGFR and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. Results: Among 131 patients, the frequency of EGFR mutations, KRAS mutations, and no mutations in both genes (double negative [DN]) was 28.2%, 5.3% and 66.4% respectively. Among the DN genotype, 47.1%were never smoker and 37.9% were female. The median progression free survival (PFS) with 1st line platinum based combination chemotherapy was 5.4 months (95% CI: 3.7-7.02) for DN genotype and 7.4 months (95% CI: 5.73-9.06) for EGFR mutation group (p=0.047). According to smoking status, the median PFS with 1st line platinum based combination chemotherapy for never smokers in EGFR mutation group was significantly longer than the DN group (DN-N) (8.4 vs 6.7 months: p=0.018). However among the smokers, no significant difference in median PFS with 1st line chemotherapy between EGFR mutation and DN group (DN-S) were found (6.7 vs 4.6 months: p=0.515). In terms of second line treatment except EGFR tyrosine kinase inhibitors (EGFR-TKI), 64% of DN group and 70.3% of EGFR mutation group received pemetrexed, 21% of DN group and 29.7% of EGFR mutation group received docetaxel. 15.1% of DN group received EGFR-TKIs. The median PFS with second line treatment in DN-N group was 7.7 months (95% CI: 2.1-18.9), 3.1 months (95% CI: 1.4-4.8) and 4.4 months (95% CI: 2.2-6.5) for pemetrexed, docetaxel and EGFR-TKI respectively (p=0.009). However, no significant differences in median PFS between second line treatments was found in DN-S group [3.0 vs 2.8 vs 1.7 months for pemetrexed, docetaxel and EGFR-TKI respectively (p=0.100)] . In EGFR mutation group, no significant difference between pemetrexed and docetaxel was found according to the smoking status. Conclusions: NSCLC without EGFR and K-ras mutation (DN group) had different clinical outcomes according to smoking history. Smoking history could be a useful clinical marker to choose a second-line treatment. However, further genomic study to find a druggable target in this group should be conducted. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B41. Citation Format: Sook Hee Hong, JinHyoung Kang, Eun kyung Jeon, Seung Joon Kim, Kyo-Young Lee, Sang young Roh. Different clinical outcomes of systemic chemotherapy in non-small cell lung cancer without EGFR and K-ras mutation according to smoking status. [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 B41.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-13-B41
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 8
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    Abstract B195: Immune microenvironment change after acquiring resistance to EGFR TKI therapy in EGFR mutant non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B195-B195
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B195-B195
    Abstract: Introduction: The efficacy of anti-programmed death-1 therapy in EGFR mutant NSCLC is limited. We hypothesized that immune microenvironment was different before and after developing acquired resistance to EGFR-TKI (tyrosine kinase inhibitor) therapy. We evaluated the change of the tumor proportion score (TPS) of programmed death-ligand 1 (PD-L1) and intratumoral CD8+ tumor-infiltrating lymphocyte (TIL) in EGFR mutant NSCLC. Materials and Methods: We identified 44 patients with sufficient paired tumor tissues before and after EGFR-TKI therapy available for analysis. PD-L1 expression on tumor cells was defined by immunohistochemical (IHC) stain with 22C3 pharmDx assay. Intratumoral CD8+ TIL score was also defined by IHC stain. Results: According to paired pre- and post-TKI biopsies comparison, the degree of PD-L1 expression was consistent in both biopsies in 26 (59.1%) patients, but varied upon the development of resistance in 18 (40.9%), with 10 showing higher levels of PD-L1 expression in the resistant biopsy. The score of CD8+ TIL was consistent in both biopsies in 15 (34.1%) patients, but varied upon the development of resistance in 29 (65.9%), with 11 (25%) showing higher levels CD8+ TIL score in the resistant biopsy. Regarding exon 20T790M acquired mutation, only 2 (14.2%) of 14 specimens observed higher TPS of PD-L1 in post-TKI biopsies. We defined high post-TKI TPS of PD-L1 group who observed high TPS of PD-L1 in post-TKI compared to paired pre-TKI biopsies or post- TKI TPS of PD-L1 ≥50%. The post-TKI high TPS of PD-L1 group tended to decrease CD8+ TIL score . 8 observed post-TKI TPS of PD-L1 ≥50% and 7 of 8 observed low CD8+ TIL score. The median progression-free survival of first-generation EGFR-TKI in these 7 patients was statistically significantly lower than the others (6.6 months vs 14.0 months, respectively; P=0.0105). Conclusions: The TPS of PD-L1 and CD8+ TIL score changed after EGFR-TKI therapy. High TPS of PD-L1 and low CD8+ TIL in post-TKI EGFR mutant NSCLC could be related to EGFR-TKI resistance. Before considering anti-PD-1 therapy, reevaluation of PD-L1 should be considered. Citation Format: Tae-Jung Kim, Jin-Hyoung Kang, Sook-hee Hong. Immune microenvironment change after acquiring resistance to EGFR TKI therapy in EGFR mutant non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B195.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B195
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 9
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    Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 1 ( 2018-01-01), p. 59-73
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 1 ( 2018-01-01), p. 59-73
    Abstract: Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59–73. ©2017 AACR. See related commentary by Carugo and Draetta, p. 17. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-17-0461
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    Abstract 185: Alteration of microRNA expression profiles in HPV-associated squamous cell carcinoma of the head and neck (SCCHN)
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 185-185
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 185-185
    Abstract: Background High-risk type of human papillomavirus (HPV) has recently been found to be etiologically associated with 20 to 25% of SCCHN, particularly common in or pharyngeal tumors. We investigated the protein expression of PTEN/PI3K/AKT/mTOR signal pathway on HPV 16 +/− tonsillar squamous cell carcinomas. And, we analyzed microRNA expression profile in tongue cancer cell line transfected with HPV 16 E6/E7 oncogene. Method Tonsil cancer patients who had been treated at Seoul St. Mary's Hospital between 2000 and 2009 were reviewed. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded tumor tissues of 65 surgical specimens, and stained with antibodies against PTEN, PIK3CA, phosphorylated AktSer473, and phosphorylated mTORSer2448. High-risk HPV infection status was determined by in situ hybridization. The protein expression of EGFR, PIK3CA, pAkt, mTOR, and PTEN was assessed by immunohistochemistry. MicroRNA expression was studied using microarrays (PANArray™ miRNA expression profiling kit) in two tongue cancer cell lines (YD8 and YD10B) transfected with HPV 16 E6/E7 oncogene. Results Of the 65 pts, 26 (40%) pts were HPV positive. Overall survival and relapse-free survival were significantly different between two groups (P = 0.05 and P = 0.036, respectively). PTEN expression was significantly higher in HPV-positive- than in HPV-negative patients (P = 0.02). PIK3CA, phosphorylated AktSer473, and phosphorylated mTORSer2448 expression was negatively correlated with HPV status, yet not significantly. HPV status (P = 0.03) and nodal stage (P = 0.05) were found to significantly affect overall survival, as determined by multivariate analysis. The expression profile of miRNAs was different in HPV 16 E6/E7 transformed cells compared with vector alone cells. In the final round, 8 of 158 miRNAs were selected to be most differently expressed miRNAs; let-7b, miR-1, miR-107, miR-122, miR-127-5p, miR-95, miR-23b and miR-370 ( & gt;1.2-fold). Conclusion We observed the higher expression of PTEN in HPV 16 positive tonsil tumor than HPV 16 negative tumor. Our data suggest that some microRNAs induced by E6/E7 oncogene might directly affect PTEN expression level independent of p53. We are underway on the experiments confirming that PTEN is regulated by which among these miRNAs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 185. doi:1538-7445.AM2012-185
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-185
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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