63 results on '"Jing Yuan"'
Search Results
2. Histone methyltransferase NSD2 activates PKCα to drive metabolic reprogramming and lenalidomide resistance in multiple myeloma
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Chong, Phyllis S.Y., primary, Chooi, Jing-Yuan, additional, Lim, Julia S.L., additional, Leow, Aaron C.Y., additional, Toh, Sabrina Hui Min., additional, Azaman, Irfan, additional, Koh, Mun Yee, additional, Teoh, Phaik Ju, additional, Tan, Tuan Zea, additional, Chung, Tae-Hoon, additional, and Chng, Wee Joo, additional
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- 2023
- Full Text
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3. Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma
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Yunlu Jia, Jianbiao Zhou, Tze King Tan, Tae-Hoon Chung, Yongxia Chen, Jing-Yuan Chooi, Takaomi Sanda, Melissa J. Fullwood, Sinan Xiong, Sabrina H.M. Toh, Kalpnaa Balan, Regina W.J. Wong, Julia S.L. Lim, Enfan Zhang, Zhen Cai, Peng Shen, Wee Joo Chng, School of Biological Sciences, Cancer Science Institute of Singapore, NUS, and Centre for Translational Medicine
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Cancer Research ,Oncology ,Carcinogenesis ,Biological sciences [Science] ,Medicine [Science] ,Apoptosis - Abstract
Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma. SIGNIFICANCE: A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets. Published version The work was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative (to W.J. Chng), the NMRC Clinician Scientist Investigator award (to W.J. Chng), the RNA Biology Center at CSI Singapore, NUS, from funding by the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3–1-006 (to W.J. Chng), the National Natural Science Foundation of China (grant no. 82000212 to Y. Jia), Natural Science Foundation of Zhejiang Province (grant no. LQ21H160022 to Y. Jia), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (grant no. 2021RC003 to Y. Jia). Y. Jia also thanks the China Scholarship Council (grant no. 201706320167) for financial support to visit National University of Singapore.
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- 2021
4. SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma
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Wee Joo Chng, Phyllis S.Y. Chong, Tuan Zea Tan, Jing Yuan Chooi, Julia S.L. Lim, and Sabrina Hui Min Toh
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0301 basic medicine ,Cancer Research ,Histone-modifying enzymes ,Chemistry ,Protein subunit ,medicine.disease ,Chromatin remodeling ,Chromatin ,Bromodomain ,Cell biology ,BET inhibitor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Stable isotope labeling by amino acids in cell culture ,medicine ,Multiple myeloma - Abstract
NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2–SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability. In vivo, treatment with PFI-3 reduced the growth of t(4;14) xenograft tumors. Together, our study reveals an interplay between histone-modifying enzymes and chromatin remodelers in the regulation of myeloma-specific genes that can be clinically intervened. Significance: This study uncovers a novel, SWI/SNF–independent interaction between SMARCA2 and NSD2 that facilitates chromatin remodeling and transcriptional regulation of oncogenes in t(4;14) multiple myeloma, revealing a therapeutic vulnerability targetable by BET inhibition.
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- 2021
5. Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma
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Jia, Yunlu, primary, Zhou, Jianbiao, additional, Tan, Tze King, additional, Chung, Tae-Hoon, additional, Chen, Yongxia, additional, Chooi, Jing-Yuan, additional, Sanda, Takaomi, additional, Fullwood, Melissa J., additional, Xiong, Sinan, additional, Toh, Sabrina H.M., additional, Balan, Kalpnaa, additional, Wong, Regina W.J., additional, Lim, Julia S.L., additional, Zhang, Enfan, additional, Cai, Zhen, additional, Shen, Peng, additional, and Chng, Wee Joo, additional
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- 2021
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6. TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling
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Xiaohong Wang, Yanquan Zhang, Ka Fai To, Huarong Chen, Rui Li, Jessie Qiaoyi Liang, Jun Yu, Jiafu Ji, Francis K.L. Chan, Jing-Yuan Fang, Joanna H.M. Tong, Joseph J.Y. Sung, Hongyan Gou, and Lijing Zhang
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Male ,0301 basic medicine ,Cancer Research ,Carcinogenesis ,Colorectal cancer ,Mice, Nude ,Apoptosis ,Wnt1 Protein ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cyclin D1 ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Viability assay ,beta Catenin ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Regulation of gene expression ,Mice, Inbred BALB C ,Protein Stability ,Chemistry ,Cell growth ,Wnt signaling pathway ,Cell migration ,LIM Domain Proteins ,Middle Aged ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Colorectal Neoplasms ,Transcription Factors - Abstract
Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal cancer from a Chinese cohort (n = 102), which was further validated by a The Cancer Genome Atlas (TCGA) cohort (n = 376). High expression of TTPAL was significantly associated with shortened survival in patients with colorectal cancer. TTPAL promoted cell viability and clonogenicity, accelerated cell-cycle progression, inhibited cell apoptosis, increased cell migration/invasion ability in vitro, and promoted tumorigenicity and cancer metastasis in vivo. TTPAL significantly activated Wnt signaling and increased β-catenin activation and protein expression of cyclin D1 and c-Myc. Coimmunoprecipitation followed by mass spectrometry identified thyroid receptor–interacting protein 6 (TRIP6) as a direct downstream effector of TTPAL. Depletion of TRIP6 significantly abolished the effects of TTPAL on cell proliferation and Wnt activation. Direct binding of TTPAL with TRIP6 in the cytoplasm inhibited ubiquitin-mediated degradation of TRIP6 and, subsequently, increased levels of TRIP6 displaced β-catenin from the tumor suppressor MAGI1 via competitive binding. This sequence of events allows β-catenin to enter the nucleus and promotes oncogenic Wnt/β-catenin signaling. In conclusion, TTPAL is commonly overexpressed in colorectal cancer due to copy number gain, which promotes colorectal tumorigenesis by activating Wnt/β-catenin signaling via stabilization of TRIP6. TTPAL overexpression may serve as an independent new biomarker for the prognosis of patients with colorectal cancer. Significance: TTPAL, a gene preferentially amplified in colorectal cancer, promotes colon tumorigenesis via activation of the Wnt/β-catenin pathway.
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- 2019
7. Abstract P6-20-06: Withdrawn
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Meirong Xu, Koleen Eisele, Douglas Carl Behenna, John Chionis, Sutton Scott Channing, Cathy Zhang, Ping Wei, Ravi Visswanathan, Stephen Dann, B Jessen, Robert M. Hoffman, Britton Boras, Kevin Daniel Freeman-Cook, Michael A. White, Qin Zhang, Brion W. Murray, Jing Yuan, Sacha Ninkovic, Scott L. Weinrich, Nanni Huser, Jim Solowiej, Nichol Miller, Todd VanArsdale, and Chaoting Liu
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Cancer Research ,Oncology - Abstract
This abstract was withdrawn by the authors. Citation Format: Dann S, Chionis J, Eisele K, Zhang Q, Liu C, Yuan J, Miller N, Murray B, Xu M, Solowiej J, Wei P, Weinrich S, Sutton S, Behenna D, Ninkovic S, Hoffman R, Freeman-Cook K, Jessen B, Huser N, Zhang C, Visswanathan R, Boras B, VanArsdale T, White MA. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-06.
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- 2019
8. Abstract CT544: Multi-omics analysis uncovers prognostic biomarkers and tumor ecosystem dynamics during toripalimab combined with nab-paclitaxel and s-1 as neoadjuvant therapy for esophageal squamous carcinoma: A single-center, open-label, single-arm phase 2 trial
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Guoqing Zhang, Jing Yuan, Chaohu Pan, Qing Xu, Xiaoli Cui, Jing Zhang, Minglu Liu, Zhigang Song, Liangliang Wu, Dongfang Wu, Bo Yang, Haitao Luo, Yi Hu, and Shunchang Jiao
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Cancer Research ,Oncology - Abstract
Background: Immune checkpoint inhibitor (ICI) combined with chemotherapy as a neoadjuvant therapy has been applied to the treatment of ESCC. However, the optimal regimen needs to be further explored, and the mechanisms by which the ICI combined with chemotherapy modulates the evolution of ESCC are unknown. Methods: In this single-arm phase 2 trial, patients received nab-paclitaxel 260 mg/m2 for 2 cycles and oral S-1 (d1-14, bid) for two weeks, combined with 240 mg intravenous toripalimab for 2 cycles before surgery. The primary outcome was the major pathological response (MPR). Biopsies and plasma before and after neoadjuvant therapy were analyzed for whole-exome sequencing, transcriptome sequencing, PD-L1 expression and 92 proteins using proximity extension assay technology. Results: After neoadjuvant therapy, 26 patients (48.15%) achieved MPR, 16 (29.63%) achieved pCR. 18.3% of the patients experienced grade ≥3 AEs. Compared to patients PD-L1-low, patients with PD-L1-high had a significant higher ratio of PR. During therapy, TMB and TNB were significantly decreased in PR patients, and the ratio of gained and increased clones were significantly lower in MPR patients than nonMPR patients, while the lost and decreased clones were significantly higher in MPR patients than nonMPR patients. Transcriptome analyses before and during therapy revealed CD8 and CD4 T cells were increased in all patients, however, the exhausted cells, nTreg and iTreg were significantly increased in nonMPR patients. Proteins analyses revealed the levels of TRAIL and MUC16 were significantly increased in MPR and PR patients, respectively, while the levels of IFN-γ and IL18 were significantly decreased in MPR and PR patients, respectively. And the expression of ADA, ARG1, CD83, TNFRSF4 and VEGFR2 in plasma were found to be related with serious adverse events. Conclusion: In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was well tolerated and showed promising antitumor activity in patients with resectable ESCC, and the changes of genomic, transcriptome, PD-L1 expression and proteins in plasma were comprehensively analyzed and correlated with clinical outcomes, which provided insight into the mechanism of action of Toripalimab combined with nab-Paclitaxel and S-1 in ESCC patients. Citation Format: Guoqing Zhang, Jing Yuan, Chaohu Pan, Qing Xu, Xiaoli Cui, Jing Zhang, Minglu Liu, Zhigang Song, Liangliang Wu, Dongfang Wu, Bo Yang, Haitao Luo, Yi Hu, Shunchang Jiao. Multi-omics analysis uncovers prognostic biomarkers and tumor ecosystem dynamics during toripalimab combined with nab-paclitaxel and s-1 as neoadjuvant therapy for esophageal squamous carcinoma: A single-center, open-label, single-arm phase 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT544.
- Published
- 2022
9. SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma
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Chong, Phyllis S.Y., primary, Chooi, Jing Yuan, additional, Lim, Julia S.L., additional, Toh, Sabrina Hui Min, additional, Tan, Tuan Zea, additional, and Chng, Wee-Joo, additional
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- 2021
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10. SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic
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Phyllis S Y, Chong, Jing Yuan, Chooi, Julia S L, Lim, Sabrina Hui Min, Toh, Tuan Zea, Tan, and Wee-Joo, Chng
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Transcriptional Activation ,Cell Survival ,Pyridines ,Histone-Lysine N-Methyltransferase ,Mice, SCID ,Chromatin Assembly and Disassembly ,Transfection ,Xenograft Model Antitumor Assays ,Translocation, Genetic ,Neoplasm Proteins ,Tumor Burden ,Repressor Proteins ,Mice ,Mice, Inbred NOD ,Cell Line, Tumor ,Gene Knockdown Techniques ,Animals ,Humans ,Female ,Protein Tyrosine Phosphatases ,Multiple Myeloma ,Azabicyclo Compounds ,Transcription Factors - Abstract
NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2-SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability.
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- 2020
11. IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma
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Jing Yuan Chooi, Wee Joo Chng, Qi Zeng, Julia S.L. Lim, Daniel D Waller, Michael Sebag, Jianbiao Zhou, Tae-Hoon Chung, Yan Ting Hee, Phyllis S.Y. Chong, and Zea Tuan Tan
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0301 basic medicine ,STAT3 Transcription Factor ,endocrine system ,Cancer Research ,Antineoplastic Agents ,Apoptosis ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Mice, SCID ,Biology ,Bortezomib ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,immune system diseases ,Mice, Inbred NOD ,hemic and lymphatic diseases ,medicine ,Tumor Cells, Cultured ,Gene silencing ,Animals ,Humans ,Phosphorylation ,Protein kinase B ,Multiple myeloma ,Cell Proliferation ,Regulation of gene expression ,Interleukin-6 ,medicine.disease ,Prognosis ,Xenograft Model Antitumor Assays ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,Oncology ,Proteasome ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Signal transduction ,Protein Tyrosine Phosphatases ,Multiple Myeloma ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Signal Transduction - Abstract
Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed “deactivation” of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify high-risk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma. Significance: IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn re-phosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma.
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- 2019
12. Correction: Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors
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Jing Qi, Robert C. Peery, Jianguo Liu, Jian Ting Zhang, Jing-Yuan Liu, Zizheng Dong, and Shaobo Zhang
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0301 basic medicine ,03 medical and health sciences ,Cancer Research ,030104 developmental biology ,Oncology ,Western blot ,medicine.diagnostic_test ,Interface (Java) ,Chemistry ,Survivin ,medicine ,Cancer research ,Small molecule - Abstract
In the original version of [this article][1] ([1][2]), the Western blot image in Fig. 4F was inadvertently taken from the results of a different experiment. The authors provided the Western blot image from the correct experiment and the error has been corrected in the latest online HTML and PDF
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- 2018
13. Abstract P3-06-01: Mechanisms of resistance to CDK4/6 inhibition in ER+ breast cancer
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Peter Olson, Koleen Eisele, Zhou Zhu, Valeria Fantin, Danan Li, David J. Shields, John Chionis, Todd VanArsdale, Chaoting Liu, Jing Yuan, Nathan V. Lee, and Kim Arndt
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Cyclin E ,Fulvestrant ,biology ,Cyclin D ,Palbociclib ,03 medical and health sciences ,Cyclin E1 ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cancer research ,biology.protein ,CDK4/6 Inhibition ,E2F ,Cyclin A2 ,medicine.drug - Abstract
Estrogen receptor positive breast cancers show frequent deregulation of Cyclin D-CDK4/6 signaling. Combining CDK4/6 inhibitors with hormonal therapies produces clinical benefit, supporting drug approval of the first CDK4/6 inhibitor, Palbociclib, in combination with Letrozole or Fulvestrant. Due to the adaptive nature of cancers, development of drug resistance is common and resistance to CDK4/6 inhibitors can be expected. To understand potential mechanisms of resistance to palbociclib, ER+ breast cancer cells were made resistant to Palbociclib in vitro. Characterization of resistance models derived from T47D and MCF7 cell lines revealed different mechanisms of resistance to Palbociclib. Resistant T47D revealed loss of functional Rb through a large 3 prime genomic deletion of RB1. Palbociclib failed to inhibit proliferation of these cells confirming Rb inactivation as the primary mechanism of Palbociclib activity. Palbociclib-resistant MCF7 cells retained Rb mRNA and protein expression suggesting direct loss of Rb function was not the mechanism of resistance. RNAseq and CNV analysis of several resistant MCF7 lines revealed distinguishing features of the resistant lines including up-regulation of E2F, TGFβ, WNT and NF-κB transcriptional networks. Also, proteomic analysis showed that prominent features of all the resistant MCF7 cells included elevated Myc expression as well as increased abundance of Rb, phosphorylated Rb, E2F1 and its downstream targets Cyclin E1, Cyclin A2 among others. Palbociclib treatment of resistant MCF7 lines showed that CDK4/6 inhibition still modulated phosphorylated Rb and E2F1 levels, but repressed levels were higher than compared to basal levels of vehicle treated parental MCF7 cells. Given the precedence for Cyclin E/CDK2 activity to redundantly regulate Rb function at the G1 checkpoint, Cyclin E1 expression was inhibited using shRNA. Results show that knockdown of Cyclin E1 protein in Palbociclib-resistant cells restores sensitivity to Palbociclib. Palbociclib-resistant MCF7 transcriptomes also exhibited significantly decreased expression of Estrogen Receptor target genes. Resistant cells proved unresponsive to the ER antagonist Fulvestrant, suggesting a loss of dependence on ER signaling. Cyclin E1 dysregulation is also implicated in resistance to hormonal therapy and Cyclin E1 knockdown resensitized Palbociclib-resistant MCF7 cells to Fulvestrant treatment. The observations of cross resistance to CDK4/6 inhibitors and hormonal therapy highlight the co-dependence of Cyclin D-CDK4/6 and ER signaling in ER+ breast cancer. Continued studies are focused on describing the alterations driving increased Cyclin E1 expression in response to CDK4/6 inhibition and strategies to circumvent development of resistance via Cyclin E/CDK2 signaling. Citation Format: Lee NV, Eisele KJ, Chionis J, Yuan J, Zhu Z, Liu C, Li D, Olson PA, Fantin V, Arndt KT, Shields DJ, VanArsdale TL. Mechanisms of resistance to CDK4/6 inhibition in ER+ breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-06-01.
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- 2016
14. IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma
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Chong, Phyllis S.Y., primary, Zhou, Jianbiao, additional, Lim, Julia S.L., additional, Hee, Yan Ting, additional, Chooi, Jing-Yuan, additional, Chung, Tae-Hoon, additional, Tan, Zea Tuan, additional, Zeng, Qi, additional, Waller, Daniel D., additional, Sebag, Michael, additional, and Chng, Wee-Joo, additional
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- 2019
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15. TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling
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Gou, Hongyan, primary, Liang, Jessie Qiaoyi, additional, Zhang, Lijing, additional, Chen, Huarong, additional, Zhang, Yanquan, additional, Li, Rui, additional, Wang, Xiaohong, additional, Ji, Jiafu, additional, Tong, Joanna H., additional, To, Ka-Fai, additional, Sung, Joseph J.Y., additional, Chan, Francis K.L., additional, Fang, Jing-Yuan, additional, and Yu, Jun, additional
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- 2019
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16. Correction: Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors
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Qi, Jing, primary, Dong, Zizheng, additional, Liu, Jianguo, additional, Peery, Robert C., additional, Zhang, Shaobo, additional, Liu, Jing-Yuan, additional, and Zhang, Jian-Ting, additional
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- 2018
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17. Long Noncoding RNA GAPLINC Regulates CD44-Dependent Cell Invasiveness and Associates with Poor Prognosis of Gastric Cancer
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Jing-Yuan Fang, Xuan Kong, Weiping Zou, Haoyan Chen, Jie-Ting Tang, Ying-Xuan Chen, Jie Hong, Ye Hu, Jie Xu, Jin Qian, Ji-Lin Wang, and Ying-Chao Wang
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Cancer Research ,medicine.disease_cause ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,microRNA ,medicine ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,RNA, Neoplasm ,Cell Proliferation ,Oncogene ,biology ,Gene Expression Profiling ,CD44 ,Cancer ,HCT116 Cells ,Prognosis ,medicine.disease ,Molecular biology ,Long non-coding RNA ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,MicroRNAs ,Hyaluronan Receptors ,Oncology ,Cancer cell ,Cancer research ,biology.protein ,RNA, Long Noncoding ,Carcinogenesis - Abstract
It is increasingly evident that long noncoding RNAs (lncRNA) have causative roles in carcinogenesis. In this study, we report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization (ISH) analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue ISH analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival. Taken together, our results identify a noncoding regulatory pathway for the CD44 oncogene, shedding new light on the basis for gastric cancer cell invasiveness. Cancer Res; 74(23); 6890–902. ©2014 AACR.
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- 2014
18. miR-508 Defines the Stem-like/Mesenchymal Subtype in Colorectal Cancer
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Jiayin Tang, Lin-Lin Ren, Ilona Kryczek, Jie Hong, Haoyan Chen, Weiping Zou, Danfeng Sun, Ming Zhong, Tingting Yan, Qian Liang, Witold Zgodziński, Zhenhua Wang, Jinxian Chen, Chaoqin Shen, Qiang Liu, Marek Majewski, Jing-Yuan Fang, Piotr Radwan, Ying-Xuan Chen, and Ya-Nan Yu
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0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,Colorectal cancer ,Transplantation, Heterologous ,Mice, Nude ,Mice, SCID ,CDH1 ,03 medical and health sciences ,Mice ,SALL4 ,Antigens, CD ,Cell Movement ,Mice, Inbred NOD ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Polycomb Repressive Complex 1 ,Mice, Inbred BALB C ,biology ,Cancer ,Zinc Finger E-box-Binding Homeobox 1 ,Mesenchymal Stem Cells ,medicine.disease ,Cadherins ,HCT116 Cells ,Transplantation ,MicroRNAs ,030104 developmental biology ,Oncology ,BMI1 ,Cancer research ,biology.protein ,Ectopic expression ,RNA, Long Noncoding ,Caco-2 Cells ,Colorectal Neoplasms ,HT29 Cells ,Neoplasm Transplantation ,Transcription Factors - Abstract
Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment. Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751–65. ©2018 AACR.
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- 2017
19. Abstract 2499: Identification of functional proteins interacting with NSD2 in multiple myeloma
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Chooi, Jing Yuan, primary, Xie, Zhigang, additional, Swa, Hannah Lee-Foon, additional, Gunaratne, Jayantha, additional, Kappei, Dennis, additional, and Chng, Wee Joo, additional
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- 2018
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20. miR-508 Defines the Stem-like/Mesenchymal Subtype in Colorectal Cancer
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Yan, Ting-Ting, primary, Ren, Lin-Lin, additional, Shen, Chao-Qin, additional, Wang, Zhen-Hua, additional, Yu, Ya-Nan, additional, Liang, Qian, additional, Tang, Jia-Yin, additional, Chen, Ying-Xuan, additional, Sun, Dan-Feng, additional, Zgodzinski, Witold, additional, Majewski, Marek, additional, Radwan, Piotr, additional, Kryczek, Ilona, additional, Zhong, Ming, additional, Chen, Jinxian, additional, Liu, Qiang, additional, Zou, Weiping, additional, Chen, Hao-Yan, additional, Hong, Jie, additional, and Fang, Jing-Yuan, additional
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- 2018
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21. Abstract 4374: Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia
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Qi Zeng, Jianbiao Zhou, Jayantha Gunaratne, Phyllis S.Y. Chong, Wee Joo Chng, and Jing Yuan Chooi
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Cancer Research ,Phosphatase ,Wnt signaling pathway ,Myeloid leukemia ,Cancer ,Biology ,medicine.disease ,Transactivation ,Cyclin D1 ,Oncology ,Catenin ,Cancer research ,medicine ,Signal transduction - Abstract
Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for the dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients subset who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation. Citation Format: Phyllis SY Chong, Jianbiao Zhou, Jing Yuan Chooi, Wee Joo Chng, Jayantha Gunaratne, Qi Zeng. Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia [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 4374.
- Published
- 2018
22. Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors
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Jianguo Liu, Jing Qi, Zizheng Dong, Shaobo Zhang, Jian Ting Zhang, Robert C. Peery, and Jing-Yuan Liu
- Subjects
0301 basic medicine ,Models, Molecular ,Cancer Research ,In silico ,Survivin ,Apoptosis ,Biology ,Pharmacology ,Inhibitor of Apoptosis Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Cell Line, Tumor ,Animals ,Humans ,chemistry.chemical_classification ,Small molecule ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Enzyme ,Oncology ,chemistry ,Cell culture ,Cancer cell ,Cancer research ,Lead compound ,Dimerization - Abstract
Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule–based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. Cancer Res; 76(2); 453–62. ©2016 AACR.
- Published
- 2015
23. Targeting the AIB1 Oncogene through Mammalian Target of Rapamycin Inhibition in the Mammary Gland
- Author
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Jamie L. DellaGatta, Maria I. Torres-Arzayus, Andrew L. Kung, Heidi Lane, Myles Brown, and Jing Yuan
- Subjects
Cancer Research ,Cell Survival ,Blotting, Western ,Mammary gland ,Estrogen receptor ,Mice, Transgenic ,Biology ,Nuclear Receptor Coactivator 3 ,Mice ,Tumor Cells, Cultured ,medicine ,Animals ,Everolimus ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Histone Acetyltransferases ,Sirolimus ,Dose-Response Relationship, Drug ,Oncogene ,TOR Serine-Threonine Kinases ,Estrogen Receptor alpha ,G1 Phase ,Mammary Neoplasms, Experimental ,Cancer ,Oncogenes ,medicine.disease ,Antiestrogen ,Immunohistochemistry ,Tamoxifen ,medicine.anatomical_structure ,Receptors, Estrogen ,Oncology ,Endometrial Hyperplasia ,Nuclear receptor coactivator 3 ,Trans-Activators ,Cancer research ,Female ,Precancerous Conditions ,Protein Kinases ,Immunosuppressive Agents - Abstract
Amplified in breast cancer 1 (AIB1), an estrogen receptor (ER) coactivator, is frequently amplified or overexpressed in human breast cancer. We previously developed a transgenic mouse model in which AIB1 can act as an oncogene, giving rise to a premalignant hyperplastic mammary phenotype as well as to a high incidence of mammary tumors that are primarily ER+. In this model, the AIB1 transgene is responsible for continued activation of the insulin-like growth factor-I receptor, suggesting a role for the activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway in the premalignant phenotype and tumor development. Here we show that treatment of AIB1 transgenic mice with the mTOR inhibitor RAD001 reverts the premalignant phenotype. Furthermore, treatment of cell lines derived from AIB1-dependent mammary tumors with RAD001 in culture leads to a G1 cell cycle arrest. Lastly, tumor growth after injection of ER+ AIB1 tumor cell lines into wild-type animals is inhibited by RAD001 treatment. In this ER+ model, inhibition of tumor growth by RAD001 was significantly better than inhibition by the antiestrogen 4-hydroxytamoxifen alone, whereas a combination of both RAD001 and 4-hydroxytamoxifen was most effective. Based on these results, we propose that the combination of mTOR inhibition and ER-targeted endocrine therapy may improve the outcome of the subset of ER+ breast cancers overexpressing AIB1. These studies provide preclinical support for the clinical development of RAD001 and suggest that AIB1 may be a predictive factor of RAD001 response. (Cancer Res 2006; 66(23): 11381-8)
- Published
- 2006
24. Abstract 2084: Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers
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Kavitha Venkatesan, Jaison Jacob, Shumei Liu, Fei Feng, Brandon Antonakos, Zhao B. Kang, Jonathan R. LaRochelle, Jason R. Dobson, Hui Gao, Laura R. La Bonte, Huaixiang Hao, Rajesh Karki, Samuel B. Ho, Guizhi Yang, Markus Warmuth, Ping Zhu, Matthew J. LaMarche, Brant Firestone, Matthew J. Meyer, Stephen C. Blacklow, Edmund Price, Kathy Hsiao, Jorge Garcia-Fortanet, Zhuoliang Chen, Chen Christine Hiu-Tung, Palermo Mark G, Vesselina G. Cooke, Cary Fridrich, Jay Larrow, Ping Wang, Sarah Williams, Ying-Nan P. Chen, Subarna Shakya, William R. Sellers, Nicholas Keen, Jing Yuan, Michael Shultz, Gang Liu, Michelle Fodor, Michael G. Acker, Pascal D. Fortin, Ho Man Chan, Timothy Michael Ramsey, Zhan Deng, Ji-Hu Zhang, Mitsunori Kato, Dyuti Majumdar, Peter Fekkes, Minying Pu, and Travis Stams
- Subjects
Cancer Research ,biology ,Philosophy ,Allosteric regulation ,Cancer therapy ,Protein tyrosine phosphatase ,medicine.disease ,Mapk signaling ,Oncology ,Allosteric enzyme ,Neuroblastoma ,Cancer research ,medicine ,biology.protein ,Tumor growth ,Majumdar - Abstract
The non-receptor protein tyrosine phosphatase (PTP) SHP2 is an important component of RTK signaling in response to growth factor stimulus and sits just upstream of the RAS-MAPK signaling cascade. The first oncogenic phosphatase to be identified, SHP2 is dysregulated in multiple human diseases including the developmental disorders Noonan and Leopard syndromes, as well as leukemia, lung cancer and neuroblastoma where aberrant activity of SHP2 leads to uncontrolled MAPK signaling. Cancer-associated activating mutations in SHP2 impart an “auto-on” state of the enzyme, boosting basal activity by shifting the equilibrium away from the auto-inhibited state. Reduction of SHP2 activity through genetic knockdown suppresses tumor growth, validating SHP2 as a target for cancer therapy. SHP099, a recently reported potent and selective allosteric inhibitor of SHP2, stabilizes the auto-inhibited form of SHP2 through interactions with the N-terminal SH2 and C-terminal PTP domains of the protein. SHP099 suppresses MAPK signaling in RTK amplified cancers resulting in suppressed proliferation in vitro and inhibition of tumor growth in mouse tumor xenograft models. Together, these data demonstrate the therapeutic potential of SHP2 inhibition in the treatment of cancer and other RAS/MAPK-linked diseases. Citation Format: Michael G. Acker, Ying-Nan P. Chen, Matthew J. LaMarche, Ho Man Chan, Peter Fekkes, Jorge Garcia-Fortanet, Jonathan R. LaRochelle, Brandon Antonakos, Christine Hiu-Tung Chen, Zhuoliang Chen, Vesselina G. Cooke, Jason R. Dobson, Zhan Deng, Fei Feng, Brant Firestone, Michelle Fodor, Cary Fridrich, Hui Gao, Huai-Xiang Hao, Jaison Jacob, Samuel Ho, Kathy Hsiao, Zhao B. Kang, Rajesh Karki, Mitsunori Kato, Jay Larrow, Laura R. La Bonte, Gang Liu, Shumei Liu, Dyuti Majumdar, Matthew J. Meyer, Mark Palermo, Minying Pu, Edmund Price, Subarna Shakya, Michael D. Shultz, Kavitha Venkatesan, Ping Wang, Markus Warmuth, Sarah Williams, Guizhi Yang, Jing Yuan, Ji-Hu Zhang, Ping Zhu, Stephen C. Blacklow, Timothy Ramsey, Nicholas J. Keen, William R. Sellers, Travis Stams, Pascal D. Fortin. Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2084. doi:10.1158/1538-7445.AM2017-2084
- Published
- 2017
25. Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors
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Qi, Jing, primary, Dong, Zizheng, additional, Liu, Jianguo, additional, Peery, Robert C., additional, Zhang, Shaobo, additional, Liu, Jing-Yuan, additional, and Zhang, Jian-Ting, additional
- Published
- 2016
- Full Text
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26. Abstract 2740: Mechanistic basis of Palbociclib combinatorial activity in ER+ breast cancer and non-breast indications
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Todd VanArsdale, Chaoting Liu, Tao Xie, Nathan V. Lee, David J. Shields, John Chionis, Ping Wei, Paul A. Rejto, Jing Yuan, Enhong Chen, and Stephen Dann
- Subjects
Gynecology ,Senescence ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,medicine.drug_class ,Kinase ,Letrozole ,Retinoblastoma protein ,Cancer ,Palbociclib ,medicine.disease ,Breast cancer ,Oncology ,Estrogen ,medicine ,Cancer research ,biology.protein ,business ,medicine.drug - Abstract
Phosphorylation of the retinoblastoma protein (Rb) by cyclin-dependent kinases 4 and 6 (CDK4/6) is a critical checkpoint for G1/S cell cycle progression and commitment to cellular proliferation. Human malignancies often subvert these control mechanisms through a range of genetic and biochemical adaptations. Accordingly, tumors that depend on CDK4/6 activity for proliferation and survival are particularly sensitive to inhibition of this pathway by palbociclib (IbranceTM), a highly selective inhibitor of CDK4/6 kinase activities. Treatment regimen of palbociclib with letrozole significantly improved progression-free survival in a randomized phase 2 study of women with advanced estrogen receptor-positive (ER+), HER2-negative breast cancer. Likewise, in ER+ breast cancer models palbociclib and estrogen antagonists combine for greater anti-proliferative activity, increased hallmarks of cellular senescence and prolonged durability of response following drug removal. Dual inhibition of CDK4/6 and ER signaling demonstrated robust anti-tumor activity in xenograft studies. The addition of Palbociclib to other targeted therapeutics elicits improved activity in pre-clinical models of several non-breast indications and these effects also manifest through modulation of cellular proliferation, senescence and growth arrest. Data will be presented on the molecular basis of combination benefit with Palbociclib in ER+ breast and other oncology indications. Citation Format: Stephen Dann, Jing Yuan, John Chionis, Chaoting Liu, Tao Xie, Nathan V. Lee, Enhong Chen, Ping Wei, Paul A. Rejto, David J. Shields, Todd VanArsdale. Mechanistic basis of Palbociclib combinatorial activity in ER+ breast cancer and non-breast indications. [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 2740.
- Published
- 2016
27. Long Noncoding RNA GAPLINC Regulates CD44-Dependent Cell Invasiveness and Associates with Poor Prognosis of Gastric Cancer
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Hu, Ye, primary, Wang, Jilin, additional, Qian, Jin, additional, Kong, Xuan, additional, Tang, Jieting, additional, Wang, Yingchao, additional, Chen, Haoyan, additional, Hong, Jie, additional, Zou, Weiping, additional, Chen, Yingxuan, additional, Xu, Jie, additional, and Fang, Jing-Yuan, additional
- Published
- 2014
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28. Abstract 4: WISP-1 increases angiogenesis and VEGF-A expression in human oral squamous cell carcinomas
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Tsao, Ching-Wen, primary, Tang, Chih-Hsin, additional, and Chuang, Jing-Yuan, additional
- Published
- 2014
- Full Text
- View/download PDF
29. Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells
- Author
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Sudhir Rao, Jennifer O'Neil, Lex H.T. Van der Ploeg, Nancy E. Kohl, Peter Strack, Cole Liberator, Pamela Carroll, Theresa Zhang, Victoria M. Richon, Jing Yuan, Xudong Dai, A. Thomas Look, James S. Hardwick, Edyta Tyminski, Christopher Winter, and Giulio Draetta
- Subjects
Cancer Research ,Cell signaling ,Tumor suppressor gene ,Transcription, Genetic ,Notch signaling pathway ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Transfection ,Retinoblastoma Protein ,S Phase ,Cell Line, Tumor ,Thiadiazoles ,Humans ,Protease Inhibitors ,CDKN2D ,Cyclin-Dependent Kinase Inhibitor p19 ,Phosphorylation ,Receptor, Notch1 ,Gamma secretase ,Gene Expression Profiling ,G1 Phase ,Intracellular Signaling Peptides and Proteins ,Cyclin-Dependent Kinase 4 ,Cell cycle ,Cyclic S-Oxides ,Oncology ,Cancer research ,CDKN1B ,Signal transduction ,Amyloid Precursor Protein Secretases ,Cyclin-Dependent Kinase Inhibitor p27 ,Signal Transduction - Abstract
NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19INK4d) and CDKN1B (p27Kip1), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL. [Cancer Res 2009;69(7):3060–8]
- Published
- 2009
30. Abstract 5062: Ovarian cancer cells induce the microenvironment changes and subsequently promote disease propagation and dissemination through epithelial-mesenchymal transition and enrichment of tumorigenic cells
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Nanni Huser, Jing Yuan, Zhengming Yan, and Cathy Zhang
- Subjects
Oncology ,Cancer Research ,education.field_of_study ,medicine.medical_specialty ,Stromal cell ,biology ,business.industry ,medicine.medical_treatment ,CD44 ,Population ,Cancer ,medicine.disease ,Minimal residual disease ,Targeted therapy ,Internal medicine ,biology.protein ,Medicine ,Epithelial–mesenchymal transition ,business ,education ,Ovarian cancer - Abstract
Ovarian cancer has the highest mortality rate of all gynecological cancers primarily due to the high incidence of metastatic spread prior to diagnosis. Understanding the biology of this malignancy and developing models that reflect the patient disease phenotype will create opportunities for testing targeted therapy. We used the Ovcar 3 cell line to establish a metastasis model through serial in vivo passage. After the treatment of docetaxel and carboplatin, the characteristics of minimal residual disease were assessed. Notably, the stromal environment and tumor initiating subpopulation play critical roles on the Ovcar 3MET disease invasiveness and progression. Compared to the molecular profile of the parental cells, these invasive Ovcar 3MET cells exhibited higher expressions of β-catenin, slug, N-cadherin and ZEB1, suggesting the epithelial-mesenchymal transition in these Ovcar 3MET cells. In addition, a higher fraction of the CD44+/CD24- subpopulation was found in the Ovcar 3MET cells, suggesting enrichment of the tumorigenic population. With the treatment of chemotherapeutic agents, we observed an enrichment of CD44+/CD24- subpopulation in the minimal residual disease. The self-renewal functional analysis demonstrated a higher tumorigenic potential of the MRD cells compared to the cells from vehicle treated mice. In contrast, treatment of the dual PI3K/mTOR inhibitor PF-04691502 resulted in significant anti-tumor and anti-metastatic activities without increasing the MRD self-renewal potential. These results warrant the combination assessment of chemotherapy with targeted agents to reduce or eradicate MRD, therefore to mitigate the risk of disease relapse. Citation Format: Nanni Huser, Zhengming Yan, Jing Yuan, Cathy C. Zhang. Ovarian cancer cells induce the microenvironment changes and subsequently promote disease propagation and dissemination through epithelial-mesenchymal transition and enrichment of tumorigenic cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5062. doi:10.1158/1538-7445.AM2015-5062
- Published
- 2015
31. Abstract LB-136: Mechanistic exploration of combined CDK4/6 and ER inhibition in ER-positive breast cancer
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Nathan V. Lee, David J. Shields, Jing Yuan, Cory L. Painter, Koleen Eisele, Kim Arndt, Julie L.C. Kan, Joan Q. Cao, John Chionis, Todd VanArsdale, and Chaoting Liu
- Subjects
Cancer Research ,medicine.medical_specialty ,biology ,Fulvestrant ,business.industry ,Letrozole ,Estrogen receptor ,Cancer ,Palbociclib ,medicine.disease ,Endocrinology ,Breast cancer ,Oncology ,Internal medicine ,medicine ,biology.protein ,Cancer research ,Cyclin-dependent kinase 6 ,business ,Tamoxifen ,medicine.drug - Abstract
The de-regulation of the Retinoblastoma tumor suppressor is widespread in cancers occurring through the direct mutation or loss of RB1, or enhanced signaling through the Cyclin dependent kinases CDK4 and CDK6 via amplification and/or over expression of D-type cyclins, or loss of p16 (CDKN2A) function. Tumors retaining intact RB1 functions therefore rely on the activity of CyclinD-CDK4/6 complexes to inactivate RB1 and promote progression through the G1 restriction point into S phase. Hormone receptor positive breast cancers are one tumor type where RB1 remains intact in most tumors and deregulation of CDK4/6-Cyclin D signaling is common. As such, dependence on CDK4/6 signaling in ER positive breast cancers has been demonstrated using the specific CDK4/6 inhibitor, PD-0332991 (palbociclib), and the combination of palbociclib and letrozole has been shown to provide significant clinical activity in ER+ breast cancer patients. To determine the mechanism of action for this combination, we investigated the effects of palbociclib with anti-estrogen therapeutics such as letrozole, fulvestrant and tamoxifen on ER+ breast cancer cell lines (MCF7, CAMA1, and T47D). Mechanistic analyses reveal that the combination of palbociclib with fulvestrant or letrozole enhanced inhibition of Rb phosphorylation leading to significantly greater loss of E2F1, FoxM1 and downstream target genes such as PLK1, SKP2 and CCNE2, leading to greater inhibition of cell proliferation. The enhanced growth arrest of the ER+ breast cell lines treated with palbociclib and ER antagonists is accompanied by increased hallmarks of cell senescence, cell enlargement and SA-β-Galactosidase staining, significantly greater than either single agent inhibitor treatment. Also, the arrest of cells following drug removal is maintained significantly longer for cells treated with the combination. To explore these activities in vivo, an ER+ breast patient derived xenograft (PDX) model was studied using the combination of palbociclib and letrozole (aromatase inhibitor). These studies recapitulate in vitro model systems, showing greater tumor growth inhibition with combination therapy, enhanced dephosphorylation of RB1 and accompanied inhibition of downstream signaling. PDX tumors treated with the combination of palbociclib and letrozole displayed reduced KI67 staining compared to single agent treatments and β-galactosidase staining revealed that cell senescence is also a component of the functional response of ER+ breast tumors to the combined inhibition of CDK4/6 and ER signaling in vivo. As apoptotic cell death was not clearly evident in any of these model systems, the mechanism of combined CDK4/6 inhibition and ER antagonism is likely driven by cellular senescence and accompanying long term arrest of tumor cells to prevent disease progression. Citation Format: Nathan V. Lee, Jing Yuan, Koleen Eisele, Joan Q. Cao, Cory L. Painter, John Chionis, Chaoting Liu, David J. Shields, Julie L.C. Kan, Kim Arndt, Todd VanArsdale. Mechanistic exploration of combined CDK4/6 and ER inhibition in ER-positive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-136. doi:10.1158/1538-7445.AM2014-LB-136
- Published
- 2014
32. The RhoGAP protein DLC-1 functions as a metastasis suppressor in breast cancer cells
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Virginia Urquidi, Derek D. Sloan, Cheng Li, Ryung S. Kim, Jing Yuan, Steve Goodison, and Nicholas C. Popescu
- Subjects
Cancer Research ,DNA, Complementary ,Cell ,Transplantation, Heterologous ,Mice, Nude ,Breast Neoplasms ,Biology ,Article ,Mice ,Cell Movement ,Transduction, Genetic ,medicine ,Animals ,Humans ,Metastasis suppressor ,Neoplasm Metastasis ,Oligonucleotide Array Sequence Analysis ,Mice, Inbred BALB C ,Tumor Suppressor Proteins ,GTPase-Activating Proteins ,Up-Regulation ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,Metastasis Suppressor Gene ,medicine.anatomical_structure ,Oncology ,Cell culture ,Tumor progression ,Monoclonal ,Cancer research ,Female ,DLC1 ,Neoplasm Transplantation - Abstract
The identification of molecular signatures characteristic of tumor cells that are capable of metastatic spread is required for the development of therapeutic interventions to abrogate this lethal process. To facilitate this, we have previously characterized an experimental system in which the role of candidate metastasis-related genes can be screened and tested. Monoclonal cell lines M4A4 and NM2C5 are spontaneously occurring sublines of the MDA-MB-435 cell breast tumor cell line that exhibit phenotypic differences in growth, invasion, and metastatic efficiency in athymic mice. In this study, transcriptional profiles of these cell lines were created using oligonucleotide microarrays representing over 12,000 genes. Intensity modeling and hierarchical clustering analysis identified a 171-gene expression signature that correlated with metastatic phenotype and highlighted several GTPase signaling components. Restoration of one of these GTPases, deleted in liver cancer-1 (DLC-1), in metastatic M4A4 cells to levels observed in the nonmetastatic NM2C5 cell line resulted in the inhibition of migration and invasion in vitro and a significant reduction in the ability of these cells to form pulmonary metastases in athymic mice. These studies show the utility of expression profiling, in an appropriate experimental system, to identify genetic determinants of metastatic sufficiency. The finding that DLC-1 can act as a metastasis-suppressor gene supports an influential role for GTPase signaling in tumor progression.
- Published
- 2005
33. Abstract 322: Dual targeting of the PI3K/mTOR pathways by PF-04691502 or PF-05212384 exhibits therapeutic effects against the metastatic disease progression in the Ovcar 3 disseminated model
- Author
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Jing Yuan, Douglas D. Fang, Julie Kan, Cathy Zhang, Zhengming Yan, and Brett H. Simmons
- Subjects
Cancer Research ,Stromal cell ,business.industry ,medicine.medical_treatment ,Cancer ,Malignancy ,medicine.disease ,Targeted therapy ,Oncology ,In vivo ,Immunology ,medicine ,Cancer research ,Ovarian cancer ,business ,PI3K/AKT/mTOR pathway ,Ex vivo - Abstract
Ovarian cancer has the highest mortality rate of all gynecological cancers primarily due to the high incidence of metastatic spread prior to diagnosis. Understanding the biology of this malignancy and developing models that reflect the patient disease phenotype will create better pre-clinical opportunities for testing targeted therapy. We used the Ovcar 3 cell line to establish a metastasis model through serial in vivo passage. The dual PI3K/mTOR inhibitors PF-04691502 and PF-05212384 were then investigated in this model for their therapeutic effect against metastatic disease progression. Notably, the stromal environment and tumor initiating subpopulation play critical roles on the Ovcar 3MET disease invasiveness and progression. Based on the molecular profile, these invasive Ovcar 3MET cells exhibited a more EMT phenotype when compared to parental cells. Impairing PI3K/mTOR pathway with the dual PI3K/mTOR inhibitors resulted in significant anti-metastatic activity and increased survival in the Ovcar 3MET model. Serum CA125 level, which is a validated clinical marker, correlated with anatomic measurement of tumor burdens via BLI and mouse survival time in these studies, providing means for longitudinal monitoring of disease progression and response to therapy. In addition, using ex vivo tumorsphere analysis under serum-free condition, both PF-04691502 and PF-05212384 demonstrated robust activity against the self-renewal ability of Ovcar 3 tumor cells. In summary, this translational tumor model may serve as a valuable tool for testing targeted therapies such as PI3K/mTOR inhibitors for their ability to impact progression of metastatic ovarian disease. Citation Format: Zhengming Yan, Douglas Fang, Brett Simmons, Jing Yuan, Julie Kan, Cathy C. Zhang. Dual targeting of the PI3K/mTOR pathways by PF-04691502 or PF-05212384 exhibits therapeutic effects against the metastatic disease progression in the Ovcar 3 disseminated model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 322. doi:10.1158/1538-7445.AM2013-322
- Published
- 2013
34. Abstract 4464: Elucidation of crizotinib resistance in NCI-H3122 and strategies to circumvent bypass resistance
- Author
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Lars D. Engstrom, Scott J. Garza, Joan Cao, Timothy Scheffelin, Stephen Huang, Maruja E. Lira, James G. Christensen, Nathan V. Lee, Blake Enyart, Julie Kan, and Jing Yuan
- Subjects
Cancer Research ,biology ,Crizotinib ,Combination therapy ,medicine.drug_class ,business.industry ,Cancer ,medicine.disease ,Receptor tyrosine kinase ,ALK inhibitor ,Oncology ,medicine ,biology.protein ,Cancer research ,Anaplastic lymphoma kinase ,business ,Tyrosine kinase ,Insulin-like growth factor 1 receptor ,medicine.drug - Abstract
The Anaplastic Lymphoma Kinase (ALK) fusion proteins such as EML4-ALK act as oncogenic drivers in approximately 5-7% of non-small cell lung carcinomas (NSCLC). The rationale for targeting this kinase as a means of treatment has been validated by the clinical efficacy and subsequent approval of the ALK inhibitor, crizotinib (Xalkori ®). The overall response rate of 61% suggests potential intrinsic resistance to crizotinib. In addition, like many tyrosine kinase inhibitors, acquired resistance inevitably leads to treatment refractory cancers. To better understand resistance mechanisms (both intrinsic and acquired), and circumvent resistance to crizotinib, we developed in vitro resistance models through prolonged crizotinib exposure. We isolated resistance clones and characterization identified different resistance mechanisms, including pathway bypass as well as an ALK kinase mutation (G1269A), similar to those that have been reported from refractory patient samples. The majority of the resistance clones escaped crizotinib suppression via pathway bypass. In several resistance clones, simultaneous activation of EGFR and IGF1R receptors limited the efficacy of double combination strategies and required triple combinations. In addition, phospho-proteomic analysis revealed simultaneous activation of different receptor tyrosine kinases, suggesting that combination treatment with inhibitors of downstream mediators such as PI3K and MEK may be effective strategies. Our resistance models demonstrate the heterogeneity of cancers and reveal the multiplicity of escape mechanisms. Our results provide support for the evaluation of combination therapy with downstream mediator inhibitors as a way to restore as well as enhance sensitivity to crizotinib. Citation Format: Nathan V. Lee, Joan Cao, Timothy Scheffelin, Lars Engstrom, Stephen Huang, Maruja Lira, Scott Garza, Jing Yuan, Blake Enyart, James Christensen, Julie Kan. Elucidation of crizotinib resistance in NCI-H3122 and strategies to circumvent bypass resistance. [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 4464. doi:10.1158/1538-7445.AM2013-4464
- Published
- 2013
35. Abstract 1392: CTGF inhibits cell motility in oral cancer cells through reducing COX-2 expression
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Yang, Wan-Yu, primary, Tang, Chih-Hsin, additional, and Chuang, Jing-Yuan, additional
- Published
- 2011
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36. Abstract 1389: Cyr61 increases cell migration in human oral cancer cells through FAK, ERK and NF-κB pathways
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Yu, Nuo-Yi, primary, Chuang, Jing-Yuan, additional, Hsieh, Chin Hsuan, additional, and Tang, Chih-Hsin, additional
- Published
- 2011
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37. Abstract 3010: IL-6 enhances migration and ICAM-1 expression of human oral squamous cell carcinoma involves IL-6 receptor signaling pathway
- Author
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Jing-Yuan Chuang, Wei-Lin Yen, and Chih-Hsin Tang
- Subjects
Cancer Research ,biology ,Cancer ,Syk ,medicine.disease ,Cell biology ,Oncology ,Interleukin-6 receptor ,Cancer cell ,medicine ,biology.protein ,Cancer research ,Antibody ,Signal transduction ,Interleukin 6 ,Receptor - Abstract
Oral squamous cell carcinoma(SCC) has a striking tendency to migration and metastasize. Interleukin-6(IL-6) has been implicated in the promotion of many cancers proliferation and migration. Intercellular adhesion molecule-1(ICAM-1), a member of the immunoglobulin supergene family, is an inducible surface glycoprotein that mediates adhesion-dependent cell-to-cell interactions. However, the effects of IL-6 in migration and ICAM-1 expression in human oral cancer cells are largely unknown. We found that IL-6 increased migration and ICAM-1 expression in human oral cancer cells. Using a specific inhibitor and genetic inhibition of IL-6 receptor, we discovered that the IL-6 receptor is involved in migration and ICAM-1 expression of human oral cancer cells. IL-6-mediated migration and ICAM-1 up-regulation were attenuated by inhibitor of Syk, JNK and AP-1. Activation of the Syk, JNK and AP-1 signaling pathway occurred after IL-6 stimulation. IL-6 induced AP-1 activity was inhibited by Syk and JNK inhibitor. Our results indicated that IL-6 enhances the migration of human oral cancer cells by increasing ICAM-1 expression through the IL-6 receptor, Syk, JNK and AP-1 signal transduction pathway. 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 3010. doi:1538-7445.AM2012-3010
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- 2012
38. Abstract 2817: Preclinical studies of the PI3K/mTOR dual inhibitors in endometrial cancer cell lines
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Koleen Eisele, Nathan V. Lee, Scott J. Garza, Julie L. Kan, Angela Pasis, James G. Christensen, Timothy Scott Fisher, Kenneth E. Hook, Jing Yuan, and Joan Cao
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Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Angiogenesis ,Cell growth ,Endometrial cancer ,Cancer ,medicine.disease ,Loss of heterozygosity ,Endocrinology ,Oncology ,In vivo ,Internal medicine ,medicine ,Cancer research ,biology.protein ,PTEN ,business ,PI3K/AKT/mTOR pathway - Abstract
The PI3K pathway plays a pivotal role in many cellular functions that include regulation of cell proliferation, survival, growth, angiogenesis, and motility. Dysregulation of the PI3K/AKT pathway is a common occurrence in cancer and could be a result of mutations in PIK3CA and PTEN, as well as loss of heterozygosity of PTEN. In endometrial cancer patients, the most frequent aberration is the activation of the PI3K/mAKT pathway with; (1) 80% loss of PTEN function and 30% PIK3CA mutations in type I endometrial cancer and (2) 20% PIK3CA mutation and 46% PIK3CA amplification in type II endometrial cancer. In this study, we investigated the functional consequences of the dual PI3K/mTOR inhibitors PF-04691502 and PF-05212384 in endometrial cancer cell lines for antiproliferative effects, pathway signaling inhibition and tumor growth inhibition. Both compounds had antiproliferative activity in vitro that translated to tumor growth inhibition in vivo. Moreover, in the MFE-280 xenograft model that harbors a PIK3CA mutation (P1047R), the dual PI3K/mTOR inhibitors showed tumor regression. These studies support the use of the dual PI3K/mTOR inhibitors for endometrial cancer. 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 2817. doi:1538-7445.AM2012-2817
- Published
- 2012
39. Abstract 3978: Mechanism of orlistat hydrolysis by fatty acid synthase thioesterase
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Jing-Yuan Liu, Jian Ting Zhang, and Valerie E. Fako
- Subjects
chemistry.chemical_classification ,Cancer Research ,biology ,Fatty acid ,Active site ,Serine hydrolase ,chemistry.chemical_compound ,Acyl carrier protein ,Orlistat ,Fatty acid synthase ,Oncology ,Biochemistry ,chemistry ,Catalytic triad ,biology.protein ,medicine ,Fatty acid synthesis ,medicine.drug - Abstract
Fatty acid synthase (FASN), a seven domain enzyme, is the sole protein capable of de novo synthesis of free fatty acids, most commonly 16-carbon palmitate. The fatty acid synthesis cycle begins with the condensation of acetyl-CoA and malonyl-CoA, and continues with the elongation of the fatty acid chain, which is tethered to an acyl carrier protein domain (ACP), via a repeating cycle. At the end of elongation, the thioesterase (TE) domain of FASN, a member of the serine hydrolase family with an Asp-His-Ser catalytic triad, cleaves the bond between palmitate and ACP, and releases free palmitate. FASN has been found to be over-expressed in a wide variety of human cancers, and this over-expression is correlated to a higher metastatic potential and poorer prognosis in cancer patients. FASN over-expression is also associated with increased resistance toward cancer chemotherapeutics. Orlistat, an FDA approved drug for obesity treatment that prevents uptake of dietary fats by inhibiting pancreatic lipases in the gastrointestinal tract, is a compound found to act as a reversible inhibitor of FASN TE. A previous study using the co-crystal structure of the TE domain with orlistat found that orlistat was covalently bound to the active site Ser within the TE domain, indicating that inhibition of FASN by orlistat halts the fatty acid synthesis cycle by blocking the release of free palmitate from the ACP. A hydrolyzed form of orlistat was also observed in the active site of TE, demonstrating that orlistat is not a stable inhibitor of FASN. In this study, we examined the mechanism of orlistat hydrolysis within the TE domain of FASN using molecular dynamics simulations. We found that the hexanoyl tail of orlistat is capable of shifting while covalently bound to the active site Ser, and that this shift is accompanied by the destabilization of a hydrogen bond that exists between a hydroxyl moiety of orlistat and the active site His. Once this hydrogen bond is destabilized, a catalytic water molecule can enter the active site of TE with the proper orientation for catalysis of the covalent bond between orlistat and Ser. These findings suggest that the hexanoyl tail of orlistat plays an important role in its hydrolysis and may guide the future design of new inhibitors that target the TE domain of FASN with greater endurance for potential use in the treatment of cancer. 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 3978. doi:1538-7445.AM2012-3978
- Published
- 2012
40. Abstract 1392: CTGF inhibits cell motility in oral cancer cells through reducing COX-2 expression
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Wan-Yu Yang, Jing-Yuan Chuang, and Chih-Hsin Tang
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CTGF ,Cancer Research ,Oncology ,Chemistry ,Cancer cell ,Cancer research ,Motility - Abstract
Oral squamous cell carcinoma (SCC) has a striking tendency to migrate and metastasize. Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin synthase, has been implicated in tumor metastasis. Connective tissue growth factor (CTGF), a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells. However, the effect of CTGF on migration activity and COX-2 expression in human oral cells is mostly unknown. Here we found that CTGF reduced the migration and expression of COX-2 in human oral cancer cells. αvβ5 monoclonal antibody (mAb), phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002 and wortmannin) and Akt inhibitor reversed the CTGF-inhibited the migration and COX-2 down-regulation of oral cancer cells. CTGF stimulation decreased the phosphorylation of focal adhesion kinase (FAK), PI3K and Akt. In addition, c-Jun siRNA also antagonized the CTGF-inhibited migration and COX-2 expression. Moreover, CTGF decreased the binding of c-Jun to the AP-1 element on the COX-2 promoter. Taken together, our results indicated that CTGF inhibits the migration of oral cancer cells by decreasing COX-2 expression through the αvβ5 integrin receptor, FAK, PI3K, Akt, c-Jun and AP-1 signal transduction pathway. 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 1392. doi:10.1158/1538-7445.AM2011-1392
- Published
- 2011
41. Abstract 1389: Cyr61 increases cell migration in human oral cancer cells through FAK, ERK and NF-κB pathways
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Nuo-Yi Yu, Jing-Yuan Chuang, Chih-Hsin Tang, and Chin Hsuan Hsieh
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MAPK/ERK pathway ,Cancer Research ,Kinase ,business.industry ,Cell migration ,Transfection ,Squamous carcinoma ,Cell biology ,Focal adhesion ,Oncology ,CYR61 ,Cancer cell ,Cancer research ,Medicine ,business - Abstract
Cysteine-rich 61 (Cyr61), from the CCN gene family, is a secreted and matrix-associated protein, which is involved in many cellular activities such as growth and differentiation. Most of CCN family can regulate the cell motility, division and adhesion. However, the effect of Cyr61 on migration activity in human oral squamous carcinoma cells is mostly unknown. Here, we found that Cyr61 increased the migration in human oral squamous carcinoma cells (SCC-4 cells). Activations of focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK) and NF-κB pathways after Cyr61 treatment was demonstrated, and Cyr61-induced migration activity was inhibited by specific inhibitor of ERK and NF-κB cascades. Transfection of cells with FAK, ERK, IKKα(IkappaB kinase alpha) and IKKβ mutant also reduced Cyr61-mediated cancer migration. Taken together, our results suggest that Cyr61 acts through FAK/ERK, which in turn activates NF-κB, contributing to the migration of human oral squamous carcinoma cells. 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 1389. doi:10.1158/1538-7445.AM2011-1389
- Published
- 2011
42. Abstract 1976: The discovery of mechanisms of resistance to SMO antagonists and the therapeutic implications
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Anlai Wang, Kathy Hsiao, Stefan Peukert, Anthony Vattay, Paul Fordjour, Jing Yuan, Dustin L. Anderson, Ribo Guo, Joseph Kelleher, Christoph Lengauer, William R. Sellers, Kimberly Briggs, Michael Morrissey, Markus Warmuth, Sauver-Michel Maira, John Monahan, Yung-mae Yao, Xu Wu, Carlos Garcia-Echeverria, Marion Dorsch, Silvia Buonamici, Juliet Williams, D. Neil Watkins, Shifeng Pan, and Lance Ostrom
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Patched ,Cancer Research ,Biology ,Bioinformatics ,medicine.disease_cause ,Oncology ,GLI2 ,Cancer research ,medicine ,Signal transduction ,Smoothened ,Carcinogenesis ,Transcription factor ,Hedgehog ,PI3K/AKT/mTOR pathway - Abstract
Smoothened (Smo) is a G-protein coupled receptor (GPCR)-like molecule that activates the Hedgehog (Hh) signal transduction pathway. In the resting state, the 12-pass transmembrane protein Patched (Ptch) inhibits Smo activity. When Ptch inhibition is attenuated, Smo signals via a cytosolic complex of proteins leading to activation of the Gli family of transcription factors. Genetic activation of the Hh pathway at or upstream of Smo is linked to tumorigenesis in several cancers. In particular, somatic mutations in Ptch and Smo leading to constitutive pathway activation are found in sporadic medulloblastoma (MB) and basal cell carcinoma (BCC). Evidence suggests that antagonists of Smo may abrogate the tumorigenic phenotype engendered by Ptch inactivation. NVP-LDE225 is a potent and selective orally available Smo antagonist that robustly inhibits Smo-dependent signaling in vitro and in vivo. NVP-LDE225 exerted dose-related anti-tumor activity in vivo in several genetically defined MB models that are driven by mutations in Ptch leading to near complete tumor regression and Hh pathway inhibition. However, following long-term continuous dosing of NVP-LDE225 in medulloblastoma allograft models, evidence of resistance to NVP-LDE225 was observed. Here, we describe our efforts to proactively identify mechanisms of resistance to targeted therapy of Smo. Genome-wide DNA- and RNA-profiling of resistant tumors revealed distinct resistance mechanisms allowing tumors to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, was identified as one mechanism leading to restoration of pathway signaling despite adequate drug exposure. Additional mining of the gene expression data for pathway signatures that are selectively deregulated in resistant tumors identified increased phosphatidylinositol-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTor inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma. 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 1976.
- Published
- 2010
43. Abstract 387: Development of a model of acquired resistance to a multi targeted VEGFR TKI and strategies to target resistance mechanisms through combination
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Scott J. Garza, Maruja E. Lira, Dana D. Hu-Lowe, Julie Kan, James G. Christensen, Keith A. Ching, Kenneth E. Hook, and Jing Yuan
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Sorafenib ,Cancer Research ,Chemotherapy ,Bevacizumab ,biology ,business.industry ,Sunitinib ,MEK inhibitor ,medicine.medical_treatment ,Pharmacology ,Phenotype ,Receptor tyrosine kinase ,Oncology ,medicine ,biology.protein ,Cancer research ,business ,PI3K/AKT/mTOR pathway ,medicine.drug - Abstract
Anti angiogenic agents that target the VEGF pathway (bevacizumab, sorafenib and sunitinib (SU)) have demonstrated improved clinical benefit as single agents or in combination with chemotherapy in a variety of solid tumor types. Although this class of agents has provided an improved treatment option to certain tumor types, it is evident that some patients do not respond to therapy or will relapse despite an initial response to treatment due to an acquired resistance. To better understand this mode of acquired resistance to this class of agents, a model of Renal Cell Carcinoma (RCC) which has shown regression, eventually developed evasive resistance during long term administration of the single agent sunitinib (a small-molecule inhibitor of the VEGF-1, 2, 3, PDGF-α,β, KIT, CSF-1R and FLT-3 receptor tyrosine kinases). Despite the observation that resistant tumors under continuous treatment with sunitinib (60 mg/kg PO, QD) demonstrated a gross phenotypic reduction of micro-vascular density (MVD), they continued to show a progressive increase in size. Because the observed low MVD phenotype was suggestive of an ability of resistant tumor cells to survive in an increasingly hypoxic environment with a reduced functional vasculature, emphasis was placed on identifying tumor cell derived resistance factors. Gene expression and/or proteomic profiling studies accompanied by confirmatory immunoblotting indicated a subset of differentially expressed genes and/or proteins in resistant vs. sensitive treated tumors. Although profiling studies did not clearly elucidate definitive resistance mechanisms, the dysregulation of EGFR, FGFR1, & TGFB1 pathways and downstream signaling through PI3K and MEK were potentially implicated. Comparative genomic hybridization studies did not identify any resistance mechanisms at the cytogenetic level. Sunitinib combination studies designed to target pathways potentially involved in resistance (SU + a PI3K/mTOR inhibitor; SU + a MEK inhibitor) demonstrated the ability to restore sensitivity in the sunitinib resistance model. The ability to identify and characterize resistance mechanisms and circumvent resistance through combination approaches may have utility in developing future combination regimens for anti angiogenic therapies. 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 387.
- Published
- 2010
44. Abstract 4479: PF-04691502, a potent and selective PI3K/mTOR dual inhibitor with antitumor activity
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Jeff Wang, Shubha Bagrodia, Nathan V. Lee, Peter K. Vogt, Cheng Hengmiao, Tom Carlson, Lynn Ueno, Julie Kan, Eric Zhang, Adam Pavlicek, Kristina Rafidi, Jing Yuan, Matthew A. Marx, Minghao Sun, Kenneth T. Luu, Chun Luo, Jon Almaden, Jeffrey H. Chen, Jon Engebretsen, Aileen McHarg, and Michelle Hemkens
- Subjects
Cancer Research ,Oncology ,Kinase ,Cell growth ,biology.protein ,Phosphorylation ,PTEN ,Biology ,Pharmacology ,Protein kinase B ,IC50 ,Receptor tyrosine kinase ,PI3K/AKT/mTOR pathway - Abstract
The PI3K pathway, which regulates cell growth, proliferation and survival, is activated in many types of human tumors by mutational activation of PI3Kα, loss of function of PTEN or activation of receptor tyrosine kinases. Inhibition of key signaling proteins in the pathway, such as PI3K, AKT and mTOR, therefore represents a high value targeting strategy for diverse cancers. PF-04691502 is a dual-specificity inhibitor of PI3K and mTOR which shows potent and selective activity in in vitro biochemical, cell and xenograft models. In in vitro biochemical assays PF-04691502 inhibited recombinant PI3Kα, β, γ and δ isoforms with Ki's of 1.2-2.2 nM and recombinant mTOR with a Ki of 9.1 nM. PF-04691502 demonstrated a high degree of selectivity for inhibition of PI3K family kinases as shown by lack of activity against a panel of >75 protein kinases, including the Class III PI3K hVps34. PF-04691502 also inhibited transformation of avian fibroblasts mediated by PI3K γ, δ, mutant PI3Kα E545K or membrane-localized AKT with IC50's of ∼100nM. In cell assays PF-04691502 inhibited PI3K/mTOR signaling in SKOV3 ovarian cancer cells with PI3Kα mutations and in U87MG glioblastoma cells with PTEN alteration, as indicated by reduced levels of phosphorylation of AKT(T308), AKT(S473) and S6 ribosomal proteins. Functional studies for anti-proliferative effects suggest PF-04691502 has broad efficacy across tumor types. In SKOV3 and U87MG xenograft models PF-04691502 treatment resulted in dose-dependent tumor growth inhibition (TGI) with maximum TGI of ∼70% at the maximum tolerated dose of 10 mg/kg, by once daily oral dosing. Inhibition of AKT(S473) phosphorylation and S6RP(S235/236)/PRAS40(T246)/4EBP1(T37/46) phosphorylation were used as quantitative and qualitative pharmacodynamic (PD) endpoints, respectively; a clear pharmacokinetic (PK)/PD relationship was established in both models after multiple dose oral administration. In the U87MG xenograft model AKT(S473) phosphorylation was inhibited with an estimated EC50 of 5.7 nM (free plasma concentration) based on PK/PD modeling. The free plasma Area Under Curve was estimated to be 850 nM*hr for 70% TGI at 10mg/kg and was found to be similar in the SKOV3 model. The projected human efficacious dose of 10 mg once daily oral dosing provides Caverage steady state exposure of 22.4 nM (free plasma concentration) which is sufficient for 50-80% inhibition of pAKT S473, and corresponds to 74% TGI. Phase 1 clinical trials of PF-04691502 as a single agent are planned. 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 4479.
- Published
- 2010
45. Abstract 3492: A novel PI3K/mTOR dual inhibitor provides correlations of pharmacokinetic pharmacodynamic and tumor growth inhibition in a prostate PC3 xenograft model for application in clinical trials
- Author
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William Carley, Shaoxian Sun, Shubha Bagrodia, Carleen Cullnane, Grant A. McArthur, Jing Yuan, Jingjing Ye, and Cheng Hengmiao
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,Cancer ,medicine.disease ,In vitro ,medicine.anatomical_structure ,Oncology ,In vivo ,Prostate ,Phosphoprotein ,Cancer research ,biology.protein ,Medicine ,PTEN ,business ,IC50 ,PI3K/AKT/mTOR pathway - Abstract
PF-04691502 is a dual inhibitor of both PI3K and mTOR, inhibits PI3K signaling in cancer cell lines, and exhibits in vitro and in vivo anti-proliferative activity in PI3K-pathway driven cell lines. It is a nanomolar inhibitor of all 4 isoforms of the catalytic subunit of PI3K and of both TORC1 and TORC2. Anti-cancer activity of the inhibitor is hypothesized to be through inhibition of survival, proliferative, and anti-apoptotic processes. Its predicted human bioavalibility is roughly 60% and it will soon be entering phase 1 studies. To provide an improved predictability of this compound and its PD markers in the clinic we correlated PK, PD (phosphoproteins and FDG-PET imaging) and tumor growth inhibition in a single model. Since this inhibitor exhibits an IC50 of 37 nM in the PC3 prostate cell line (PTEN null) in vitro we chose this cell line for a xenograft model. Three groups (Vehicle, 5 and 7.5 mg/kg.) were dosed p.o. daily and subsequently evaluated. Tissues were harvested on day 7 and 13 at 4.5 hr post-dose. FDG-PET imaging was completed on days 1, 3, 7 and 13 at 3 hr post-dose. First, negative correlations were established between blood levels of PF-04691502 and the following tumor phosphoprotein epitopes: pS6, pAKTS473 and pAKTT308. The R2 values for these proteins were −0.3, −0.4 and −0.4, respectively. P-values of the correlations are all significant for all three proteins. Second, all PD markers were positively correlated with TGI. When correlating FDG-PET and TGI, day 7 has the best correlation and an R2 of 0.3 while days 3 and 13 have poorer correlations (R2 of 0.04 and 0.13, respectively). Although the R2 isn't high for day 7, the positive trend between image and TGI is statistically significant. When correlating PD markers and TGI, R2 values for pS6, pAKTS473 and pAKTT308 were 0.6, 0.8 and 0.6, respectively. In conclusion, the data from this single model indicates PD phosphoprotein markers are more reflective of TGI than FDG-PET imaging. These results will be applied to estimating the size of the cohort recruited for mechanistic evaluation in phase 1 trials of PF-04691502. 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 3492.
- Published
- 2010
46. Abstract LB-302: Activity of PF-04691502, A dual PI3K/mTOR inhibitor in breast cancer cell lines and models discriminates between ER, PR and HER2 positive and negative segments
- Author
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Scott J. Garza, Nathan V. Lee, James G. Christensen, Kenneth E. Hook, Mark Ozeck, Adam Pavlicek, Joan Cao, Julie L.C. Kan, Matthew A. Marx, Keith A. Ching, and Jing Yuan
- Subjects
Cancer Research ,medicine.medical_specialty ,biology ,Cell growth ,business.industry ,Angiogenesis ,medicine.disease ,Breast cancer ,Endocrinology ,Oncology ,Docetaxel ,Hormone receptor ,Internal medicine ,Cancer cell ,biology.protein ,medicine ,Cancer research ,PTEN ,business ,PI3K/AKT/mTOR pathway ,medicine.drug - Abstract
The PI3K pathway plays a role in key cellular functions that include regulation of cell growth, proliferation, survival, angiogenesis, and motility. PI3K/AKT pathway aberrations are common in cancer comprising PTEN loss of function through mutations, deletion, and methylation events and gain of function at the PIK3CA locus including mutations and amplification events resulting in deregulation of this pathway. Thus, pharmacological intervention of this pathway should impact cellular functions central to survival of cancer cells. PIK3CA mutations/amplification and PTEN loss of heterozygosity have been reported to occur in approximately 35-40% and 20% of breast cancer, respectively and suggest this patient population could benefit from treatment using a small molecule inhibitor that targets the PI3K pathway. PF-04691502 which is a potent inhibitor of all PI3K isoforms and mTOR (TORC1 and TORC2) presently in Phase 1 trials was evaluated for its growth inhibitory or cytoreductive activity over a panel of 30 breast cancer cell lines. PF-04691502 had robust 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 LB-302.
- Published
- 2010
47. Abstract 5043: Effects of a novel PI3 kinase/mTOR inhibitor on proliferation and pAKT signaling in canine lymphoma
- Author
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Jon Engebretse, Pamela Jo Berlinski, Jeffrey H. Chen, Shaoxian Sun, Eric Zhang, Bernadette Pascual, John Barker, Nancy Forester, Aileen McHarg, Leslie Nguyen, Michael R. Gehring, Aihua Zou, Henry Cheng, Steven Glenn Kamerling, Heather Colhoun, Shubha Bagrodia, Tom Carlson, Michelle Hemkens, Keith R. Marotti, Kristina Rafidi, Chau Almaden, Jing Yuan, Sophie Wang, Andrea Shen, and William Carley
- Subjects
Cancer Research ,Canine Lymphoma ,medicine.medical_specialty ,business.industry ,Kinase ,Follicular lymphoma ,medicine.disease ,Lymphoma ,Endocrinology ,Oncology ,Apoptosis ,Internal medicine ,Cancer research ,Medicine ,business ,Protein kinase B ,Anaplastic large-cell lymphoma ,PI3K/AKT/mTOR pathway - Abstract
PF-04691503 is a dual inhibitor of both PI3K and mTOR, inhibits PI3K signaling in cancer cell lines, and exhibits in vitro and in vivo anti-proliferative activity in PI3K-pathway driven cell lines. It is a nanomolar inhibitor of all 4 isoforms of the catalytic subunit of PI3K and of both TORC1 and TORC2. Anti-cancer activity of the inhibitor is hypothesized to be through inhibition of survival, proliferative, and anti-apoptotic processes. Phosphorylation of the protein kinase, Akt, is associated with activation of the phosphatidyl 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) signaling pathway, which plays a role in cell proliferation (Witzig and Kaufmann 2006). Recent studies by Gulmann et al (2005) showed increased pAKT in human lymphoma samples, and those of Rassidakis et al (2005) suggested that inhibition of Akt phosphorylation (pAKT) may be of value in the treatment of lymphoma. Using flow cytometry we report that cells obtained from 10 of 11 lymph node biopsies of dogs with lymphoma exhibit detectable pAKT using a phospho-Akt (Ser473) antibody, compared to an IgG isotype control or a competative phospho-Akt (Ser473) blocking peptide. Cells from normal canine lymph nodes do not exhibit detectable pAKT. The majority of the pAKT signal was generated from lymphoblasts present in the malignant, but not in the normal, lymph nodes. In separate studies, lymph node cells obtained from healthy dogs and dogs with lymphoma were stimulated in vitro with the mitogen, Con A. The novel PI3K/mTOR dual inhibitor, PF-04691503, produced dose dependent inhibition of proliferation as exemplified in a dog with T-cell lymphoma (EC50 = 18 nM)) and in a normal dog (EC50 = 53 nM)). No pAKT signal could be detected in peripheral blood mononuclear cells, from normal or lymphoma patients stimulated with hu-IGF-1 (the endogenous ligand for PI3), Con-A or LPS. These data suggest that PI-3 kinase and pAKT (1) are activated in canine lymphoma, (2) play a role in the lymphoproliferation associated with this disease, (3) represent legitimate targets for therapeutic intervention in lymphoma, and (4) can be studied ‘translationally’ in dogs as a model for humans. Gulmann C, Espina V, Petricoin E, et al. Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. Clin Cancer Res 11:5847-5855, 2005. Rassidakis GZ, Feretzaki M, Atwell C, et al. Inhibition of Akt increases p27 Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 105:827-829, 2005. Witzig TE and Kaufmann SH. Inhibition of phosphatidyl 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway in hematologic malignancies. Current Treatment Options in Oncology 7:285-294, 2006. 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 5043.
- Published
- 2010
48. Abstract 4290: The smoothened antagonist NVP-LDE225 targets stroma and cancer stem cells in primary human pancreatic tumor xenografts
- Author
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Stefan Peukert, Markus Warmuth, Beatriz Ospina, Xu Wu, Kathy Hsiao, William R. Sellers, Shifeng Pan, John Monahan, Silvia Buonamici, Jing Yuan, Juliet Williams, Yung-mae Yao, Lance Ostrom, Anthony Vattay, Marion Dorsch, Julia Xing Zhu, Joseph Kelleher, Fang Li, James Deeds, and Rebecca Mosher
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,Cancer ,Biology ,medicine.disease ,Oncology ,Stroma ,In vivo ,Cancer stem cell ,Pancreatic tumor ,medicine ,Cancer research ,Stem cell ,Smoothened - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality. Despite surgical intervention and treatment with Gemcitabine, the standard of care, the 5-year survival rate remains less than 5%. Because the aberrant activation of the Hedgehog (Hh) pathway in stroma cells and cancer stem cells in PDAC has become evident during the last few years, therapeutic agents able to inhibit Smoothened (Smo), the positive regulator of the pathway, are under vigorous investigation. We have developed a selective Smo antagonist, NVP-LDE225, which is orally bioavailable and potently inhibits Hh signaling in vitro and in vivo. Using a combination of in vitro and in vivo assays, we evaluated the effects of NVP-LDE225 alone or in combination with Gemcitabine in primary human tumor xenograft models. In these models, NVP-LDE225 dosed together with Gemcitibine resulted in a trend towards combination activity. Tumor samples collected at the end of the studies showed that the Hh pathway was completely inhibited in the stroma of the NVP-LDE225 treated animals. Moreover, analysis of the ratio of tumor to stroma area demonstrated no differences between the drug treated as compared to vehicle treated tumors. After subcutaneous implantation of the human tumors in mice, the mouse stroma replaces the human stroma. Using mouse and human Affymetrix analysis of tumors following in vivo treatment, we were able to differentiate the changes occurring in murine stromal cells versus human epithelial cells. This analysis revealed changes in the regulation of several key developmental and growth factor pathways in the mouse stroma. To study cancer stem cells, we isolated Aldehyde Dehydrogenase (ALDH) positive cells from untreated xenograft tumors and confirmed up regulation of the Hh pathway genes, and that ALDH positive cells were more tumorigenic than ALDH negative cells when implanted in animals. Furthermore, we used 2 different stem cell functional assays, in vitro sphere formation and in vivo serial transplantation to evaluate the effect of NVP-LDE225 on cancer stem cells. We observed that upon NVP-LDE225 treatment the cells had impaired ability to form spheres in vitro and similarly, tumor growth was delayed following in vivo serial transplantation. These experiments suggest that Smo inhibitors can have a high impact on the treatment of this very aggressive cancer. 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 4290.
- Published
- 2010
49. Abstract LB-220: Molecular predictors of sensitivity to an IGF1R inhibitor in pre-clinical models of lung and colon cancers
- Author
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Scott J. Garza, Xianxian Zheng, Joan Cao, Nathan V. Lee, Stephanie T. Shi, Julie Kan, Maruja E. Lira, Jing Yuan, Jingjing Ye, Paul A. Rejto, Adam Pavlicek, Keith O. Ching, Antonio Gualberto, James G. Christensen, Kenneth E. Hook, and Mark Ozeck
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Cancer Research ,Colorectal cancer ,business.industry ,Cell ,IGFBP3 ,Cancer ,Bioinformatics ,medicine.disease ,Figitumumab ,chemistry.chemical_compound ,medicine.anatomical_structure ,Oncology ,chemistry ,Cancer research ,medicine ,ERBB3 ,Growth inhibition ,business ,Insulin-like growth factor 1 receptor - Abstract
Targeting the insulin like growth factor receptor (IGF1R) signaling pathway is a promising approach against a variety of cancers and several clinical trials are now underway designed to evaluate the efficacy of IGF1R inhibitors singly or in combination with chemotherapeutic agents. Identification of the optimal patient population likely to respond is critical to the success of this class of targeted agents. To identify potentially predictive biomarkers, we sought to correlate response to figitumumab (CP-751,871), a fully human monoclonal antibody against IGF1R with molecular characteristics across a panel of cell lines. Growth inhibition to CP-751,871 was assessed in a panel of non-small cell lung carcinoma (NSCLC) (n=27) and colon cancer cell lines (n=21) cultured in anchorage and anchorage-independent conditions. Mutation status, whole-genome mRNA expression and DNA copy number were correlated to drug sensitivity. In addition, RNA expression of key genes in relevant signaling pathways was also interrogated via real time PCR. In the present studies, the frequency of response was greater in colon cancer cell lines than in NSCLC. Tissue or cell origin-specific expression levels of insulin-like growth factor binding proteins (IGFBPs) were associated with sensitivity. Low IGFBP3 expression [p=0.0035] correlated with response in NSCLC cell lines whereas low IGFBP6 [p=0.013] and IGF2BP3 [p=0.038] expression correlated with response in colon cancer lines. Increased IGF1R mRNA [p=0.045] levels, microsatellite stability, and PIK3CA wild-type status were also correlated with sensitivity in colon cancer lines. In addition, high expression of erbB2 [p=0.04] and erbB3 [p=0.04] were also associated with sensitivity of colon cancer lines. Collectively, findings from these studies are of potential value to identify patient populations with increased probability of benefit from IGF1R targeted agents. Our results further indicate that molecular predictors associated with the IGF1R pathway are potentially distinct between lung and colon cancer lines and additional studies to extend to other tumor types are warranted. 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 LB-220.
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- 2010
50. Abstract 3224: Preclinical PKPD modeling and human dose projection of PF-04691502, a PI3K/mTOR dual inhibitor
- Author
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Eric Zhang, Kenneth T. Luu, Shubha Bagrodia, and Jing Yuan
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Volume of distribution ,Cancer Research ,business.industry ,Cell growth ,Pharmacology ,Oncology ,Elimination rate constant ,Medicine ,Distribution (pharmacology) ,Potency ,business ,Protein kinase B ,IC50 ,PI3K/AKT/mTOR pathway - Abstract
PF-04691502 is a potent dual inhibitor of PI3K and mTOR, which are involved in regulating cell growth, proliferation and survival. The main objective of this work was to develop a preclinical pharmacokinetic-pharmacodynamic (PKPD) model for the compound and project the human efficacious dose. The PK of PF-04691502 in mouse obtained following oral dosing was described by a linear 2-compartment model which was used to drive two separate PD models: 1) an exponential growth model describing the tumor growth inhibition (TGI) and 2) an indirect-response model describing changes in intratumoral pAKT-S473/AKT in the U87MG xenograft mouse model. Based on the PK model, the half-life calculated from the linear elimination constant (k = 0.306 hr−1) was 2.3 hr and the plasma-compartment volume of distribution was 8.72 L/kg. The inter-compartmental distribution rate constants were 0.282 hr−1 and 0.212 hr−1 for k12 and k21, respectively. The model estimated in-vivo potency (IC50) for pAKT-S473/AKT suppression was 38.3 nM which was within the range of the IC50 (23 nM) for TGI (as parameterized by the model). The Imax estimated from the model was 0.975 (or 97.5%), which indicated nearly complete suppression of pAKT-S473/AKT production rate by PF-04691502. Based on the PKPD model and the scaled human PK, a clinical dose of 10 mg QD was determined to be adequate for maintaining the level of pAKT-S473/AKT below 50% of baseline. At steady-state PK this dose yielded a range of 50-80% human pAKT-S473/AKT suppression over the 24 hr dosing interval. In conclusion, PF-04691502 was determined to have a robust PKPD relationship in the preclinical animal model and was projected to have a clinically achievable efficacious dose of approximately 10 mg QD. 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 3224.
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- 2010
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