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  • American Association for Cancer Research (AACR)  (10)
  • Liu, Yan  (10)
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  • American Association for Cancer Research (AACR)  (10)
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  • 1
    Online Resource
    Online Resource
    Abstract 4983: Integrative analysis of DNA copy number and gene expression identifies G3BP1 and HIRA as potential therapeutic targets against metastatic oral squamous cell carcinoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4983-4983
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4983-4983
    Abstract: The presence of lymph node metastasis is associated with a 50% reduction of 5-year survival in patients with oral squamous cell carcinoma (OSCC). We set out to combine DNA copy number aberrations (CNAs) with gene expression profiles, to identify CNAs-associated genes dysregulated in metastatic OSCC, and determine whether these genes can be targeted to selectively kill metastatic OSCC tumor cells. Toward this end, we interrogated DNA and RNA of the same OSCC cell populations laser micro-dissected from non-metastatic primary tumors (n=17) and metastatic lymph nodes (n=20) using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR) & lt; 5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Out of these, 114 transcripts showed significant correlation between their DNA copy number alternations (estimated using SNPs within 250 kb upstream and downstream of the transcript) and gene expression (FDR & lt; 0.01). Among these CNA-correlated transcripts, 95 had significantly different DNA copy numbers between metastatic and non-metastatic OSCC (FDR & lt;0.01 by Wilcoxon rank test). These 95 transcripts (representing 87 genes) mainly clustered around three genomic locations: 3p25.3-22.1, 9p24.1- 22.3 and 18q21.1-22.3. Among these 87 genes, we selected 28 of the 58 genes that were over-amplified and over-expressed in metastatic OSCC and conducted a high-throughput siRNA-mediated gene knockdown screen in five cell lines derived from primary and lymph node metastatic OSCC. The expression-knockdown of 18 genes showed 30% or more growth suppression in at least one cell line as compared to mock controls in which the cells were treated with transfection reagent only without the siRNA (P & lt; 0.01). In particular, knocking-down G3BP1 and HIRA selectively suppressed the growth of all OSCC cell lines derived from lymph node metastases when compared to non-metastatic lines. Further investigation is warranted to confirm these findings and to examine the biological role of G3BP1 and HIRA in OSCC metastasis and their potential as therapeutic targets. 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 4983. doi:10.1158/1538-7445.AM2011-4983
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-4983
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
    Online Resource
    Online Resource
    Abstract 2209: Integrative analysis of DNA copy number and gene expression in metastatic tumor cells from oral squamous cell carcinoma for the identification of genes associated with survival
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2209-2209
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2209-2209
    Abstract: To examine the impact of copy number aberrations (CNA) on gene expression in oral squamous cell carcinoma (OSCC) metastasis, we used Affymetrix 250K Nsp single nucleotide polymorphism arrays and U133 Plus 2.0 expression arrays, respectively, to interrogate the DNA and RNA from metastatic OSCC cells isolated using laser capture microdissection from lymph nodes of 20 patients. Overall, CNA accounted for expression changes in about 30% of the transcripts studied. With a false discovery rate & lt; 1%, 530 transcripts (461 genes) were identified as to have significantly correlated CNA and expression. When tested using an independent dataset with expression profiles for 148 primary OSCC and 45 normal oral mucosa, the genes were enriched with candidates associated with OSCC (vs. normal oral mucosa) (n=174 transcripts differentially expressed) and OSCC-specific survival (n=32 transcripts associated), as compared to a random gene set of the same size (p & lt; 0.001). We then fit two Cox models using the first two principal components derived from these two gene sets (‘174-transcript PCA’ or ‘32-transcript PCA’), and two other models that combined stage with either the 174- or the 32-transcript PCA score. The Area Under the Curve (AUC) for a model combining stage with 174-gene PCA was significantly higher than that for a model with stage alone (AUC=0.80 vs. 0.72, p = 0.042). Further investigation is warranted to confirm these findings and to examine the biologic role of these copy number-associated transcripts in OSCC metastasis and their potential as therapeutic targets. 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 2209.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-2209
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
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    Abstract 1925: Establishment and characterization of 3D cancer organoids as clinically relevant ex vivo drug screening tools for cancer translational research and drug discovery
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1925-1925
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1925-1925
    Abstract: Patient derived cancer organoids (PDO), a form of comprehensive 3D spheroid cultures that harbor cancer multicellular components and mimic cancer lesion structures and tumor heterogeneity, have been proven to be innovative preclinical model system for use in both academic research and industrial cancer drug development. It has been demonstrated by a large amount of independent literature reports that 3D PDOs can better predict drug response than 2D cell line settings due to their clinical relevant tumor micro-environment. We have the world’s largest patient derived xenograft (PDX) tumor model collection (~2500 models), which were annotated and validated genomically and phenotypically. However, there appears to be limitations when using PDX models to evaluate compounds in large scale fashion with narrow time windows and limited budget allocation. To address these limitations and to fully leverage preclinical values of these PDX model assets, we have established and characterized a series of PDX-derived cancer organoid (PDXO) models so that they could be used as scalable and high throughput compatible drug screening platforms. As first phase of development, we started with low passage PDX primary tumors from 5 major cancers types, including colorectal, lung, breast cancer, gastric and pancreatic carcinoma. The PDX tumor tissues were mechanically and enzymatically dissociated and the digested tumor fragments were cultured and passaged in Matrigel containing culture medium supplemented with stem cell niche factors. Technical protocols for 3D cultures including culture propagation procedures and medium optimization have been established. Characterization and QC of these PDXO models were done by gross morphology, histopathology, and genomic profiling. Histopathological analysis showed cellular/structural similarities (ductal, mucous or carcinoid) between PDXO models and original PDX tumor tissues, suggesting that tissue specific structural features were maintained in the 3D organoids. Moreover, ~10 PDXO models were tested for ex vivo cytotoxicity with SOC drugs. The preliminary data indicated that majority of (73%, 24/33) the PDXO ex vivo drug sensitivity IC50 datasets correlated with the in vivo PDX drug sensitivity TGI data. The negative and positive predictive values for PDXO are 94% and 53%, respectively. Genomic characterization including RNAseq and WES, is in progress. In summary, we successfully established PDXO models that were stably passaged from PDX primary tumors and resembled original PDX tumors both morphologically and histopathologically. In addition, the PDXOs apparently had encouraging predictive values for SOC drug response. Further in-depth model validation/characterization is warranted. Citation Format: Xiaoxi Xu, Satya Pathi, Limei Shang, Yan Liu, Peng Han, Likun Zhang, Binchen Mao, Davy Ouyang, Henry Li, Wenqing Yang. Establishment and characterization of 3D cancer organoids as clinically relevant ex vivo drug screening tools for cancer translational research and drug discovery [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 1925.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1925
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
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    Abstract B068: The establishment of a large tumor organoid biobank using a well characterized/annotated patient-derived xenograft (PDX) library to enable drug discovery and translational research
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Therapeutics Vol. 18, No. 12_Supplement ( 2019-12-01), p. B068-B068
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 18, No. 12_Supplement ( 2019-12-01), p. B068-B068
    Abstract: Background: Patient derived xenograft (PDX), a cancer stem cell (CSC) derived in vivo model, is an accepted model of choice for preclinical and translational research due to its proven predictive power. Patient derived cancer organoids (PDOs), also CSC-derived 3D culture of carcinoma with defined structures, harbor carcinoma’s multicellular components and mimics cancer lesion structures/heterogeneity, both genomicly and histopathologically. PDO was first described by Hans Clevers Lab and proven to be a predictive model for preclinical research, similar to PDX. Method: We have used the Hubrecht organoid technology (HUB approach to systematically create the worlds-first biobank of organoids derived from a well annotated PDX library (the world’s largest with & gt;2,500, covering a variety of carcinomas, with extensive pathology, genomic and treatment information), referred to as PDXOs. We then systematically profiled these PDXOs by WES (whole exome sequencing)/RNAseq (transcriptome sequencing), histopathology and standard of care (SOC) treatment. Results: At present, we have established & gt; 100 PDXOs covering & gt; 9 cancer types, including bladder, breast, colorectal, gastric, liver, lung, ovarian and pancreatic cancer, cholangiocarcinoma, etc. Histopathological analysis showed cellular/structural similarities (ductal, mucous or carcinoid) between PDXO and original PDX, suggesting that tissue specific structural features were maintained in the 3D organoids. A high throughput screening (HTS in 384 well) format was established using the PDXOs and SOC sensitivity testing was conducted. The preliminary results largely correlated to the SOC response seen in vivo for the corresponding PDXs. Conclusion: In summary, we have successfully established a large biobank of the PDXOs that mirror the original PDXs, creating a unique library of matched in vitro/in vivo models with high translational power and enabling HTS, thus likely become an important tool for the future oncology drug discovery and development tools. Citation Format: Xiaoxi Xu, Limei Shang, Lili Wang, Chunmei Li, Yan Liu, Peng Han, Zhongman Sun, Yaping Qu, Likun Zhang, Bonnie Xiaobo Chen, Davy Xuesong Ouyang, Yujun Huang, Henry Qixiang Li. The establishment of a large tumor organoid biobank using a well characterized/annotated patient-derived xenograft (PDX) library to enable drug discovery and translational research [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B068. doi:10.1158/1535-7163.TARG-19-B068
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-19-B068
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
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    Abstract 3861: 3D ex vivo PDX cell model screening to better predict in vivo outcome
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3861-3861
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3861-3861
    Abstract: Patient-derived xenograft (PDX) models have been highly demanded in preclinical drug discovery and development due to several advantages over conventional 2D cell culture system: 1) reflection of the heterogeneity, molecular and histopathologic signatures of the original tumor than cell lines or genetically engineered mouse models, and 2) certain degree of correlation of their drug-response profiles with clinical response. Certain limitations of using PDX models, however, do exist, including low throughput in candidate drug screening, lack of dose-response curves, high cost and time-consuming studies, and progressive loss of human-derived stromal elements over passages. To overcome these disadvantages, we sought to develop ex vivo 3D assay format on cells isolated from early passage PDX models, and provide genetic mutation information to better interpret results. Moreover, we attempted to incorporate immunotherapy strategy into the 3D system as well. We have recently built up an ex vivo cell bank containing more than 300 frozen ex vivo tumor cells dissociated from freshly isolated PDX tumor tissues. We have collected five panels of such frozen ex vivo cells, each panel representing more than 50 models in a specific tumor type. SOC compounds corresponding to each unique tumor panel were tested, and will be discussed. Moreover, we have established a 3D immune cell and ex vivo somatic tumor cell co-culture system to evaluate drug efficacy of immune checkpoint inhibitors aPD1, aPDL1 and CTLA4 antibodies either as single agent or in combination with small-molecule inhibitors. The data will be presented. In summary, we have developed a robust and reproducible 3D ex vivo assay platform for medium-throughput compound screening with bioinformatics information for data interpretation. Citation Format: Xiaoxi Xu, Zhongliang Li, Yan Liu, Fanxiu Meng, Yu Lu, Songling Zhang, Chunlan Dong, Frank Xing, Qian Shi. 3D ex vivo PDX cell model screening to better predict in vivo outcome [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 3861.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3861
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8 ( 2013-04-15), p. 2574-2586
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8 ( 2013-04-15), p. 2574-2586
    Abstract: mTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival, and autophagy. Deregulation of the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clinical evaluation. Here, we report the characterization of Torin2, a second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORC1-dependent T389 phosphorylation on S6K (RPS6KB1) with an EC50 of 250 pmol/L with approximately 800-fold selectivity for cellular mTOR versus phosphoinositide 3-kinase (PI3K). Torin2 also exhibited potent biochemical and cellular activity against phosphatidylinositol-3 kinase–like kinase (PIKK) family kinases including ATM (EC50, 28 nmol/L), ATR (EC50, 35 nmol/L), and DNA-PK (EC50, 118 nmol/L; PRKDC), the inhibition of which sensitized cells to Irradiation. Similar to the earlier generation compound Torin1 and in contrast to other reported mTOR inhibitors, Torin2 inhibited mTOR kinase and mTORC1 signaling activities in a sustained manner suggestive of a slow dissociation from the kinase. Cancer cell treatment with Torin2 for 24 hours resulted in a prolonged block in negative feedback and consequent T308 phosphorylation on Akt. These effects were associated with strong growth inhibition in vitro. Single-agent treatment with Torin2 in vivo did not yield significant efficacy against KRAS-driven lung tumors, but the combination of Torin2 with mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitor AZD6244 yielded a significant growth inhibition. Taken together, our findings establish Torin2 as a strong candidate for clinical evaluation in a broad number of oncologic settings where mTOR signaling has a pathogenic role. Cancer Res; 73(8); 2574–86. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-1702
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 7
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    Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1 -Mutant Lung Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Discovery Vol. 3, No. 8 ( 2013-08-01), p. 870-879
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 8 ( 2013-08-01), p. 870-879
    Abstract: The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non–small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1–wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. Significance: Using cell lines derived from the lung cancers occurring in genetically engineered mice, we conducted an integrative genome-wide short hairpin RNA and metabolite screen to identify DTYMK as a potential therapeutic target in Kras/Lkb1–mutant lung cancer. We believe that DTYMK is tractable for the development of novel therapeutics, and show an integrative approach to target identification that reduces false-positive candidates and should have broad applicability for the development of targeted therapeutics. Cancer Discov; 3(8); 870–9. ©2013 AACR. See related commentary by Marcus and Khuri, p. 843 This article is highlighted in the In This Issue feature, p. 826
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-13-0015
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 8
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    TMTP1, a Novel Tumor-Homing Peptide Specifically Targeting Metastasis
    American Association for Cancer Research (AACR) ; 2008
    In:  Clinical Cancer Research Vol. 14, No. 17 ( 2008-09-01), p. 5494-5502
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 17 ( 2008-09-01), p. 5494-5502
    Abstract: Purpose: Tumor metastasis continues to be the major obstacle to cancer therapy and the leading cause of cancer-related death. Methods used to detect metastasis, especially occult metastases, have received a great deal attention. In this study, a novel selective peptide was assessed for its specific binding to metastasis. Methods: The FliTrx bacterial peptide display system, an alternative to phage peptide display, was used to identify a 5-amino acid peptide termed TMTP1 (NVVRQ), which binds to the highly metastatic prostate cancer cell line PC-3M-1E8. The synthetic TMTP1 was tested in vitro for its binding specificity and affinity to highly metastatic cancer cells. The tumor targeting assays were done in vivo by i.v. injection of FITC-conjugated TMTP1 into tumor-bearing mice. Results: TMTP1 specifically bound to a series of highly metastatic tumor cells, including prostate cancer PC-3M-1E8, breast cancer MDA-MB-435S, lung cancer PG-BE1, and gastric cancer MKN-45sci, in vitro and in vivo but not to the poorly metastatic or nonmetastatic cell line, including prostate cancer PC-3M-2B4, breast cancer MCF-7, lung cancer PG-LH7, or murine fibroblast cell NIH/3T3. FITC-TMTP1 strongly and specifically targeted the metastasis foci in tumor-bearing mice 24 h after i.v. peptide injection. Moreover, the occult metastases were specifically detected by FITC-TMTP1. Conclusion: Our results suggest that TMTP1 is a potential strategy for the development of new diagnostic tracers or alternative anticancer agents for tumor metastasis.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-0233
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 9
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    Abstract 3950: Optimization of a method for FACS analysis of checkpoint receptor expression on tumor infiltrating lymphocytes in clinical tumor samples
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3950-3950
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3950-3950
    Abstract: While immune checkpoint therapies against CTLA-4, PD-1 and PD-L1 have achieved promising clinical outcome recently, the dynamic therapeutic responses spanning individual patients and different cancer types warrant exploration and validation of additional therapeutic strategies. Since the expression of immune checkpoints in tumor infiltrating lymphocytes (TIL) has been of interest to the field, we attempted to analyze the expression of several checkpoint receptors on TILs in clinical tumor samples. Unexpectedly, a number of markers were subject to time-dependent degradation during the tissue disaggregation process. This degradation could be due to the proteolytic activity of a proteinase, which has been used commonly in various tissue disaggregation protocols. Analysis of the protein sequences verified the presence of the proteinase recognition sequences in the affected receptors. Using PHA-stimulated hPBMCs, we found and demonstrated that a specific protease was responsible for either partial or total degradation of these markers. To overcome this issue, we developed a protease-free tissue disaggregation method, which showed no adverse effect on protease affected cell membrane receptors, thus allowing for more reliable flow cytometric analysis of various TIL subpopulations. With this method, we analyzed these checkpoint receptors positivity of both CD4+ and CD8+ TILs and revealed a high degree of heterogeneity of these immune checkpoints in a number of tumor types, including lung, breast and gastric cancers. Analysis of the magnitude of lymphocyte infiltration to the tumor and expression of prominent immune checkpoints on CD4+ or CD8+ TILs will help understand the subtle interaction between tumor and the immune system in the tumor microenvironment and may provide guidance for clinical trials of novel combinatorial immuno-therapeutic strategies. Citation Format: Norman Zhang, Qiyao Zhang, Yan Liu, Juntao Yu, Jingjing Wang, Jie Xu, Qunsheng Ji, Keith Wilcoxen, Jonathan Graves. Optimization of a method for FACS analysis of checkpoint receptor expression on tumor infiltrating lymphocytes in clinical tumor samples. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3950.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3950
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 10
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    Abstract 5345: A novel small molecule, XZH-5 inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5345-5345
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5345-5345
    Abstract: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite the fact the improved treatment for Rhabdomyosarcoma has resulted in a remarkable increase of overall survival, the children with metastatic Rhabdomyosarcoma still have only a 3-year failure-free survival rate of less than 30%. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in most types of cancer including human RMS. STAT3 is considered to be an oncogene due to its ability to promote malignancy in mice. Given the oncogenic functions of STAT3 and the promise of inhibiting it, directly targeting STAT3 signaling represents a potential therapeutic approach to treating Rhabdomyosarcoma. Using structure-based drug design, we developed a novel small molecule, named XZH-5. In this study, we characterized the inhibitory effects of XZH-5 on STAT3 phosphorylation in four Rhabdomyosarcoma cell lines. XZH-5 competes with/inhibits the STAT3-SH2 dimerization through phosphorylated Tyr705 in all four Rhabdomyosarcoma cell lines. We also demonstrated a similar inhibition of STAT3 phosphorylation and induction of apoptosis by a previously known small molecular STAT3 inhibitor Stattic in Rhabdomyosarcoma cells. These results supporting Rhabdomyosarcoma cell lines are sensitive to STAT3 inhibition. In addition, XZH-5 inhibited STAT3 DNA binding activity and the expression of STAT3 downstream genes including Bcl-2, Bcl-xl, Cyclin D1 and Survivin. The inhibition of STAT3 in Rhabdomyosarcoma cells resulted in the induction of apoptosis, reduction of colony forming ability, and inhibition of cell migration. Furthermore, XZH-5 inhibited IL-6-induced STAT3 phosphorylation and STAT3 nuclear translocation. In contrast, it had no effect on IFN-γ-induced STAT1 phosphorylation, indicating the more selective effects on STAT3. These results demonstrated that Rhabdomyosarcoma cells are sensitive to STAT3 inhibition and STAT3 is a therapeutic target. Our results also suggested that XZH-5 may serve as a potential therapeutic agent for targeting STAT3 for Rhabdomyosarcoma treatments. 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 5345. doi:10.1158/1538-7445.AM2011-5345
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5345
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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