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  • American Association for Cancer Research (AACR)  (23)
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  • American Association for Cancer Research (AACR)  (23)
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  • 1
    Online Resource
    Online Resource
    Abstract 709: AST-301, a pDNA-based therapeutic cancer vaccine encoding HER2 ICD, improves the efficacy of checkpoint blockade therapy in CD34+ humanized gastric cancer mouse model
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 709-709
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 709-709
    Abstract: PD-1/PD-L1 play a crucial role in modulating immune response and promoting self-tolerance through activating apoptosis of antigen-specific T cells and suppressing apoptosis of regulatory T cells. Although immunotherapy to block this may provide a greater survival benefit for some patients, the therapeutic effect shown in clinical trials is limited by shortage of pre-existing CD8+ T cells infiltrating the tumor. AST-301 is a pDNA-based therapeutic cancer vaccine encoding HER2 ICD sequence. It was effective in eliciting HER2-specific T cells and antibody immunity in the majority of breast and ovarian cancer patients who completed the vaccine regimen and has proven safety as well as long-term immunological memory efficacy of T-cell immune by the phase 1 study (PN 109, NCT00436254). Our previous study has shown that AST-301 has anti-tumor effects by mediating NK cells in human HER2+ gastric cancer cell (NCI-N87) xenograft athymic mice. Here, we aimed to determine whether combined administration of AST-301 can enhance the anti-tumor effect of immune checkpoint inhibitor (ICI) using NCI-N87 xenograft humanized mouse. To confirm the tumor suppressive effect of pembrolizumab (anti-PD-1) treatment combined with AST-301 in the hu-CD34+ hematopoietic stem cell-engrafted NSG mice that formed tumors with NCI-N87, AST-301 (100 μg) and pembrolizumab (5 mg/kg) were administered into mice once a week for a total of 3 times and one booster doses of AST-301 was injected at week 4. Pembrolizumab low dose (5 mg/kg) test group administered with AST-301 had a relatively higher tumor growth inhibition (TGI) effect than the same concentration of Pembrolizumab alone group. TGI effect (%) of G2 (a combination of AST-301 and Pembrolizumab 5 mg/kg), G3 (Pembrolizumab 5 mg/kg), and G4 (Pembrolizumab 10 mg/kg) were 54%, 47%, and 78%, respectively. To evaluate the mechanism underlying the enhanced anti-tumor effect due to the combined administration of AST-301 and pembrolizumab, we measured the ratio of immune cells isolated from spleen and tumor in mice. in G2, the ratio of helper T cells and cytotoxic T cells in splenocytes higher than the vehicle-treated control group (G1), and the ratio of cytotoxic T cells infiltrated the tumor was also detected high in some subjects compared to those in all the other three groups. These results suggest that AST-301 can improve HER2+ gastric cancer treatment outcomes of immune checkpoint blockade therapy by inducing a robust cytotoxic CD8+ T cell response to tumor cells. Currently, we are ongoing study to prove the anti-tumor synergistic effects of the combination of AST-301 and various FDA-approved Antibody Drug Conjugates (ADCs). This effort is focused on narrowing the administration doses to low levels to resolve the safety issue of ADC or ICI, and it will strongly support the diverse applicability of the cancer therapeutic vaccine. Citation Format: Hyo-Hyun Park, Hye-Ran Kim, Jin Kyeong Choi, Jee Hyun Choi, JinHo Kang, Jinback Lim, Hyo Jung Lim, Jong Yeong Lee, Eunkyo Joung, Hun Jung. AST-301, a pDNA-based therapeutic cancer vaccine encoding HER2 ICD, improves the efficacy of checkpoint blockade therapy in CD34+ humanized gastric cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 709.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-709
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Online Resource
    Abstract 2594: Exosomes co-expressing aquaporin-5-targeting miRNAs and IL-4 receptor-binding peptide inhibit the migration of human breast cancer cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2594-2594
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2594-2594
    Abstract: Water channel aquaporins (AQPs) play a critical role in transcellular water transport. Recent studies revealed that dysregulation of AQPs is highly correlated with the migration of cancer cells and metastasis of tumor in vitro and in vivo models. In particular, we have demonstrated that increased expression of aquaporin-5 (AQP5) is associated with breast cancer cell migration, metastasis, and poor prognosis in human patients. We aimed to identify novel AQP5-targeting miRNAs and to examine the strategy for the post-transcriptional regulation of AQP5 using exosome-mediated microRNA (miRNA) delivery. Multiple tools of bioinformatics were used to identify AQP5-targeting miRNAs and miRNA target enrichment analysis revealed the cellular signaling pathways associated with the identified miRNAs. To examine the exosome-mediated miRNA delivery systems, exosomes containing both AQP5-targeting miRNAs and a peptide (CRKRLDRNC: IL-4RPep1) targeting the interleukin-4 receptor (IL-4R), which is highly expressed in breast cancer cells, were applied to triple-negative breast cancer cell line MDA-MB-231. Putative AQP5-targeting miRNAs were identified using DIANA Tool. Thereafter, three additional bioinformatic tools (TargetScan, miRDB and MiRanda Tools) were applied to select the miRNAs that were commonly identified from at least 3 different programs. Three miRNAs, miR-1226-3p, miR-19a-3p and miR-19b-3p, were identified as putative regulators of AQP5. Protein expression of AQP5 was decreased when mimic of each miRNA was transfected into MDA-MB-231 cells. Quantitative real-time PCR demonstrated a decrease of AQP5 mRNA expression by miR-1226-3p mimic and luciferase reporter assay revealed a reduction of AQP5 translation by miR-19b mimic in MDA-MB-231 cells. Consistently, cell migration was inhibited by mimic of each miRNA. miRNA target enrichment analysis showed that target genes of three miRNAs were predominantly enriched in the gap junction regulatory pathway. This suggested that these miRNAs are associated with breast cancer cell migration and, also, they might be involved in cell-cell adhesion. For the delivery of AQP5-targeting miRNAs to MDA-MB-231 cells, exosomes containing both AQP5-targeting miRNAs and a peptide (IL-4RPep1) were constructed in HEK293T cells. Both AQP5 protein expression and cell migration were significantly decreased in MDA-MB-231 cells when they were incubated with the exosome-containing culture media obtained from the culture of HEK293T cells expressing both AQP5-targeting miRNAs and IL-4RPep1. In conclusion, AQP5-regulating miRNAs are identified and their target genes are found to be mainly involved in the gap junction regulatory pathway. The exosome-mediated delivery of AQP5-targeting miRNAs could be exploited for the inhibition of breast cancer cell migration associated with AQP5. Citation Format: Eui-Jung Park, Hyun Jun Jung, Hyo-Jung Choi, Hyo-Ju Jang, Hye-Jeong Park, Tae-Hwan Kwon. Exosomes co-expressing aquaporin-5-targeting miRNAs and IL-4 receptor-binding peptide inhibit the migration of human breast cancer cells [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 2594.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2594
    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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    Online Resource
    Abstract P3-05-07: Primary neuroendocrine carcinoma of the breast: A case series by WHO classfication in 2019
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P3-05-07-P3-05-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P3-05-07-P3-05-07
    Abstract: Introduction Neuroendocrine tumours (NET) are thought to arise from cells throughout the diffuse endocrine system and can occur almost everywhere in the body. Most NETs arise from the gastrointestinal tract, lung, thymus, and pancreas. Primary neuroendocrine carcinoma (NEC) of the breast is a rare and under-recognized subtype, accounting for less than 1% of breast carcinomas. Only a few small studies and case reports have been reported and there are no clear diagnostic criteria and established treatment options. World Health Organization (WHO) classification of tumor series’ fifth edition was published in 2019 and adopted ‘Neuroendocrine neoplasm (NEN)’ as a term encompassing all tumour classes with predominant neuroendocrine differentiation. NENs of the breast are classified into invasive ductal carcinoma (IDC) with neuroendocrine differentiation (NED), NET, and NEC of small cell or large cell types. Thus we aim to report pathologic reviews and treatment outcomes of patients with NENs of the breast at a single center. Methods We retrospectively screened the medical record of 34,370 patients diagnosed with breast cancer from 2007 to 2022 by Corporate Data Warehouse (CDW) and revealed there were 22 patients diagnosed with primary breast NEN. The pathologist reviewed the pathology slides and reclassified the diagnosis according to the WHO classification of tumor series’ fifth edition. Clinical characteristics, treatment modalities, and therapeutic outcomes were reviewed retrospectively. Results We reviewed pathology slides of 22 patients with histologically proven diagnoses of primary breast NEN from 2007 to 2022. We found only 8 patients meet the criteria of primary breast NEC (large cell 2, small cell 6), 3 patients with NET, and 3 patients with IDC with NED. We excluded 8 patients who did not fulfill the criteria of NEN. The median age of NEN was 48.5 years (range, 31-70) and 6 patients (42.9%) were postmenopausal women. The median follow-up duration was 25.3 months (Interquartile range(IQR), 15.0-54.7). All patients underwent surgery, 3 patients underwent a mastectomy and 11 patients underwent breast-conserving surgery (BCS) with a curative aim. Five patients had lymph node metastasis. There was no expression of the human epidermal growth factor receptor 2 (HER2) in all 14 cases. Hormone receptor expression was shown in 4 of NECs (50%) and all NETs or IDC with NED patients. Patients with primary breast NEC had a median recurrence-free period (RFP) of 14.6 months (95% confidence interval (CI), 11.0-18.2) and median overall survival (OS) of 52.1 months (95% CI, 0.0-120.0). Patients with NET or IDC with NED had an overall favorable outcome, none of the patients died and only one patient with IDC with NED experienced disease progression. The median PFS and OS were not reached in NET or IDC with NED subgroups. Conclusion NETs are rare tumours with a wide range of clinical presentations according to the site of involvement. Primary breast NENs are extremely rare and there are no specific guidelines for treatment. NENs are often underdiagnosed, as neuroendocrine markers are not routinely tested in breast cancer. In this retrospective single-center study, the incidence of primary breast NENs was 0.04% (14 of 34,370 patients) and primary breast NEC was associated with poor prognosis compared with breast NET or IDC with NED. Identifying innovative treatment strategies is needed to overcome poor outcomes of primary breast NEC. Citation Format: Young Kyung Jeon, Ji-Yeon Kim, Jin Seok Ahn, Young Hyunk Im, Kyue-Hee Choi, Sun Young Jeong, Yeji Jung, Jae Yeon Jang, Daeho Choi, Joohyun Hong, Hyo Jung Kim, Soo Youn Cho, Yeon H. Park. Primary neuroendocrine carcinoma of the breast: A case series by WHO classfication in 2019 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-07.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P3-05-07
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Herbal Compound Farnesiferol C Exerts Antiangiogenic and Antitumor Activity and Targets Multiple Aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) Signaling Cascades
    American Association for Cancer Research (AACR) ; 2010
    In:  Molecular Cancer Therapeutics Vol. 9, No. 2 ( 2010-02-01), p. 389-399
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 9, No. 2 ( 2010-02-01), p. 389-399
    Abstract: Farnesiferol C (FC) is one of the major compounds isolated from Ferula assafoetida, an Asian herbal spice used for cancer treatment as a folk remedy. Here, we examined the hypothesis that novel antiangiogenic activities of FC contribute to anticancer efficacy. In human umbilical vein endothelial cells (HUVEC), exposure to the 10 to 40 μmol/L concentration range of FC inhibited vascular endothelial growth factor (VEGF)–induced cell proliferation, migration, invasion, tube formation, and the expression of matrix metalloproteinase-2. In addition, FC inhibited the angiogenic sprouting of VEGF-treated rat aorta in an ex vivo model. Furthermore, FC inhibited the in vivo growth of mouse Lewis lung cancer allograft model by 60% (P & lt; 0.001) at a daily i.p. dosage of 1 mg/kg body weight without any negative effect on the weight of the host mice. Immunohistochemistry staining showed decreased microvessel density (CD34) and proliferative index (Ki-67) without affecting the apoptotic (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) index. Mechanistically, FC decreased the binding of VEGF to VEGFR1/Flt-1, but not to VEGFR2/KDR/Flk-1. In terms of early signaling, FC exerted a rapid inhibitory action (examined within 10 minutes) on VEGF-induced autophosphorylation of VEGFR1 without affecting that of VEGFR2. Nevertheless, FC decreased the phosphorylation of most of the kinases downstream of VEGFR2: focal adhesion kinase, Src, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-jun-NH2-kinase without affecting AKT. Computer simulation suggests that FC may inhibit Src or focal adhesion kinase protein activities directly through its docking to their ATP-binding sites. Taken together, the multitargeting actions of FC, particularly VEGFR1 inhibition, may make it a novel drug candidate to complement current VEGF/VEGFR2-targeting antiangiogenic modalities for cancer. Mol Cancer Ther; 9(2); 389–99
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-09-0775
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 5
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    Expression of a Peroxisome Proliferator-Activated Receptor γ1 Splice Variant that Was Identified in Human Lung Cancers Suppresses Cell Death Induced by Cisplatin and Oxidative Stress
    American Association for Cancer Research (AACR) ; 2007
    In:  Clinical Cancer Research Vol. 13, No. 9 ( 2007-05-01), p. 2577-2583
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 9 ( 2007-05-01), p. 2577-2583
    Abstract: Purpose: The activation of peroxisome proliferator-activated receptor γ (PPARγ) has been implicated in the inhibition of tumor progression in lung cancers through the induction of differentiation and apoptosis. Recently, we identified a novel splice variant of human PPARγ1 (hPPARγ1) that exhibits dominant-negative activity in human tumor-derived cell lines. This study aimed to examine the expression and pathophysiologic roles of a truncated splice variant of hPPARγ1 (hPPARγ1tr) in primary human lung cancer tissues. Experimental Design: The expression and localization of hPPARγ1tr was surveyed in human primary lung cancer tissues using immunohistochemistry and Western blot analysis. Using transfectants stably expressing wild-type hPPARγ1 (hPPARγ1wt) and hPPARγ1tr, we also analyzed the pathophysiologic roles of hPPARγ1tr. Results: We showed that PPARγ is expressed predominantly in the nucleus of nontumorous tissues, whereas it is present in both the nucleus and the cytoplasm of tumorous tissues in squamous cell carcinoma (SCC) of the lung. Western blot analysis confirmed the presence of PPARγ1tr in primary lung SCC tissue but not in nontumorous tissue. Expression of PPARγ1tr in Chinese hamster ovary cells attenuated their susceptibility to cell death induced by oxidative stress or cisplatin, whereas their susceptibility was completely recovered by down-regulation of PPARγ1tr with small interfering RNA. Conclusions: hPPARγ1tr is expressed strongly in tumorous tissues of primary human lung SCC and its overexpression renders transfected cells more resistant to chemotherapeutic drug- and chemical-induced cell death. These data suggest that the decreased drug sensitivity of PPARγ1tr-expressing cells may be associated with increased tumor aggressiveness and poor clinical prognosis of patients.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-2062
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 6
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    Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species–mediated damage
    American Association for Cancer Research (AACR) ; 2007
    In:  Molecular Cancer Therapeutics Vol. 6, No. 8 ( 2007-08-01), p. 2178-2187
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 6, No. 8 ( 2007-08-01), p. 2178-2187
    Abstract: We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf−/− murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)–transduced Ink4a/Arf−/− astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr–transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr–transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr–transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. [Mol Cancer Ther 2007;6(8):2178–87]
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-07-0111
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 7
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    HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 18 ( 2017-09-15), p. 5039-5053
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 18 ( 2017-09-15), p. 5039-5053
    Abstract: Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types. Cancer Res; 77(18); 5039–53. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-0072
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
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    Targeting Cyclin D-CDK4/6 Sensitizes Immune-Refractory Cancer by Blocking the SCP3–NANOG Axis
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 10 ( 2018-05-15), p. 2638-2653
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 10 ( 2018-05-15), p. 2638-2653
    Abstract: Immunoediting caused by antitumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen–specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like cells. In this study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immunoedited cells and upregulates NANOG by hyperactivating the cyclin D1–CDK4/6 axis. The SCP3–cyclin D1–CDK4/6 axis was preserved across various types of human cancer and correlated negatively with progression-free survival of cervical cancer patients. Targeting CDK4/6 with the inhibitor palbociclib reversed multiaggressive phenotypes of SCP3high immunoedited tumor cells and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3high immune-refractory cancer. Significance: These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3high immune-refractroy cancer. Cancer Res; 78(10); 2638–53. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-2325
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 9
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    Polymorphisms in Telomere Maintenance Genes and Risk of Lung Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 18, No. 10 ( 2009-10-01), p. 2773-2781
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 18, No. 10 ( 2009-10-01), p. 2773-2781
    Abstract: This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C & gt; T and rs2736098 g.G & gt; A, and TNKS1 rs6985140 g.A & gt; G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (Ptrend & lt; 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2773–81)
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-09-0323
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 10
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    Abstract CT171: Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT171-CT171
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT171-CT171
    Abstract: Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study Background: There are several things needed to be resolved for successful efficacy when NK cell therapy is applied for solid tumor; improvement of NK cell invasion into tumor, activation and production of a large number of NK cells, etc. Basically, in human, NK cell number is relatively small compared to other immune cells such as T cell and the number becomes severely low when NK cell is obtained from cancer patients. For these reasons, allogeneic NK cell has been used for clinical studies against various cancer types. Recently, we also have finished a phase1 study of allogeneic NK cell therapy for cholangiocarcinoma, enrolling 9 patients at inoperable and no chemotherapy favorable stage due to side effects. Four of nine patients (44%) showed SD (stable disease) after six NK cell injections and no severe AE (adverse event) was found. In this following phase 2a study, to bring out immuno-synergetic effect of NK cell therapy against the inoperably advanced bile duct cancer, we have designed a combinatorial protocol with using Pembrolizumab. Methods: Enrollment of 40 bile duct cancer patients has been finished for a combinatorial study of allogeneic NK cell therapy with Pembrolizumab at two different sites in Korea (ClinicalTrials gov, NCT03937895). Patients were eligible for the enrollment when they were inoperable and no chemotherapy favorable stage due to side effects, and also when they had PD-L1-positive score. For treatment, the most favorable method for highly activated allogeneic NK cell production has been determined from our previous study, resulting that 3x106 NK cells per kg are injected for each dose along with Pembrolizumab injection. Pembrolizumab (200mg) was given every 3 weeks for up to 9 times and NK cell injection was given for up to 18 times during the maximum injection period of Pembrolizumab. Results: Six patients (pts) were first enrolled for the pilot combinatorial study, dosing 6 times of NK cells and 3 times of Pembrolizumab. The result showed no severe AE from the injections. Among the five pts finished the injections, 2 pts showed SD (Stable Disease) and continued the treatment, being enrolled into the Phase 2a in which 34 more pts were enrolled. Among the 20 pts finished 6 NK cell and 3 Pembrolizumab injections (1st RECIST), 65% of pts showed SD. When 12 NK cell and 6 Pembrolizumab injections finished (2nd RECIST), pts had 40% and 20% of SD and PR (Partial remission). Of the 3 pts at 3rd RECIST (18 NK cell and 9 Pembrolizumab), 1 and 2 pts showed SD and PR, respectively. Finding pts experienced AE, a total of 6 AEs has been reported: no treatment-related AE, one grade 3 (Encephalopathy), and five grade 1-2 with common AE. In a recent safety and efficacy study of pembrolizumab alone (10mg/kg, every 2 weeks for up to 2 years) with 28 pts of advanced bile duct cancer showing PD-L1 expression, 17% pts showed PR, 17% pts and 52% had SD and PD (progressive disease), respectively. Although our study is still ongoing, continuing the combinatorial treatment gives rise to PR, suggesting that NK cell therapy with Pembrolizumab shows an immuno-synergetic effect for the cancer. Biomarker experiments with the injected NK cells supports our finding and we will discuss this at presentation. Citation Format: Yong Yoon Chung, Seung Woo Park, Jung-Min Im, Da-Kyung Yoo, Hyo-Cheon Cheon, Jae-Eun Kim, Kyeong-Pill Lim, Eun-Hee Yang, Hye-Jin choi, Hyo-Sun Chung, Seo-Yeon Kim, Ju-Yong Lee, In-Hye Jung, Seung Min Bang, Moon Jae Chung, Sung Ill Jang, Jae Hee Cho, Hee Seung Lee, Jung Youp Park, Jung Hyun Jo. Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT171.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT171
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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