bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B196: FGFR3 as a potential target for gastric cancer.
Authors: Lee Choong-kun , Lee Won Suk , Kim Jeong Min , Lee Myung Eun , Park Kyu Hyun , Kim Tae Soo , Kim Hyo Song , Jeung Hei-Cheul , Chung Hyun Cheol , Rha Sun Young 
Published: August 2014

Abstract
While trastuzumab against HER-2 over-expression is the only approved targeted therapy against gastric cancer, it is important to find the biologically significant genetic aberrations in most of gastric cancer without HER-2 overexpression. We performed phospho-RTK (receptor tyrosine kinase) array in 25 gastric cancer cell lines, and confirmed fibroblast growth factor receptor 2 and 3 (FGFR2, 3) as one of the highly phosphorylated RTKs. Knockdown of FGFR3 with transfecting small interfering RNA (siRNA) induced the decrement of phospho-FGFR (653/654) in a time-dependent manner in cell lines with highly activated FGFR3, Hs746T and SNU-5. While cell cycle analysis and apoptosis assay showed no significant changes, invasiveness and anchorage-independent growth was inhibited after FGFR3 siRNA transfection. Modulation of downstream signaling molecules was observed by western blot after transfecting FGFR3 siRNA in Hs746T and SNU-5 cell lines in comparing with FGFR2 activated cell lines (KATO III, SNU-16) transfected with FGFR2 siRNA, since previous reports showed that FGFR2 amplification is important in gastric cancer in influencing cell proliferation and survival. Phospho-AKT was down-regulated in both FGFR2 and FGFR3 activated cell lines after specific siRNA transfection, implying that gastric cancer cells with FGFR2 or FGFR3 activation might be both dependent on PI3K-AKT-mTOR pathway. When we treated mice bearing subcutaneous SNU-5 tumor xenografts with oral FGFR inhibitor TKI-258 (70mg/kg daily), TKI-258 treated group showed anti-tumor growth and anti-angiogenic effect compared with control group. Immunohistochemistry (IHC) against FGFR3 among 116 N3 gastric cancer patient tissues showed 3+ in 62.9%, while FGFR2 positivity was only 11.2%. In summary, we identified FGFR3 harbors significant biological role in subset of gastric cancer patients as FGFR2. Further studies for validating the efficacy of FGFR inhibition in preselected subset of patients would support the proper development of FGFR inhibitor in gastric cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B196.
Citation Format: Choong-kun Lee, Won Suk Lee, Jeong Min Kim, Myung Eun Lee, Kyu Hyun Park, Tae Soo Kim, Hyo Song Kim, Hei-Cheul Jeung, Hyun Cheol Chung, Sun Young Rha. FGFR3 as a potential target for gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B196.
Abstract B197: Proteomic based analysis of ovarian cancer pathways.
Authors: Rikova Klarisa , Hall Benjamin , Levy Tyler , Possemato Anthony , Wang Yi , Lee Kimberly , MacNeil Joan , Guo Ailan , Mulhern Daniel , Keroack Caroline , Ren Jian M. , Beausoleil Sean A. , Lonning Scott , Comb Michael J. 
Published: August 2014

Abstract
Recent genomic-based studies have suggested ovarian cancer is a disease of copy instability, with 63 regions of focal amplification, rather than a disease driven by mutation. However, this analysis has been unable to identify changes in protein expression, modification, and activity. In this study we developed a highly quantitative MS/MS approach to examine the ratio of protein levels, combining TMT labeling with a number of motif and site-specific antibodies to identify deregulated signaling pathways between tumor and normal specimens. We identified over 1400 uniquely upregulated proteins, and over 1600 upregulated post-translational modification sites across 79 tumors and 19 normal tissue samples. We were able to survey activity of over 400 kinases and over 100 other enzymes as well as the substrates associated with them. Our study was able to map these upregulated proteins based on abundance and activity level to their regions of focal amplifications. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels. This approach may reveal new connections among pathways and candidates for therapeutics and diagnostics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B197.
Citation Format: Klarisa Rikova, Benjamin Hall, Tyler Levy, Anthony Possemato, Yi Wang, Kimberly Lee, Joan MacNeil, Ailan Guo, Daniel Mulhern, Caroline Keroack, Jian M. Ren, Sean A. Beausoleil, Scott Lonning, Michael J. Comb. Proteomic based analysis of ovarian cancer pathways. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B197.
Abstract B199: Transcriptional regulation of KLF4 by Yin Yang 1 (YY1) in pediatric B-NHL and clinical significance.
Authors: Vega Mario I. , Valencia-Hipolito Alberto , Hernández-Atenógenes Miriam , Vega Gabriel G. , Mayani Hector , Huerta-Yepez Sara , Bonavida Benjamin 
Published: August 2014

Abstract
Krüppel-like factor 4 (KLF4) is a member of the KLF zinc-finger containing transcription factor family. Supporting evidence has established that KLF4 is either an oncogene or a tumor suppressor. Reported studies have indicated the involvement of KLF4 in the regulation of apoptosis, proliferation, and differentiation of B cells and B-cell malignancies. In contrast to adult lymphomas and solid tumors, recently, we have shown in a TMA the overexpression of KLF4 in pediatric NHL tumor tissues. The KLF4 overexpresion predicted unresponsiveness to CHOP treatment. In addition, we have also reported that the transcription factor Yin Yang 1 (YY1) is overexpressed in B-NHL and is a prognostic factor. We hypothesized that the coexpression of KLF4 and YY1 may result from the transcriptional regulation of KLF4 by YY1. This hypothesis was tested in various experimental designs both in cell lines and tumor tissues derived from patients. Analysis of the B-NHL cell line Ramos revealed that both KLF4 and YY1 are overexpressed compared to normal B cells. The transfection of Ramos with siRNA YY1 showed significant inhibition of KLF4. In silico analyses of the KLF4 promoter identified the presence of four putative binding sites for YY1. We confirmed that the -126 site as the binding site for YY1 by CHIP analysis. We also used a reporter system of the KLF4 promoter and mutated the putative binding site for YY1 (-126) and confirmed it as an important site for the regulation of KLF4. The coexpressions of KLF4 and YY1 were examined in TMA of pediatric lymphomas and showed by IHC that all of the tumor tissues exhibited a positive correlation between the expression of KLF4 and YY1 and the correlation was markedly significant in the Burkitt subtype. KLF4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. In addition, KLF4 suppresses the extrinsic apoptotic pathway by inhibiting the activation and cleavage of caspases (7, 9, and 3). Thus, the overexpression of KLF4 in lymphoma may be responsible, in part, in the pathogenesis, malignancy, and drug resistance. The present findings suggest that both KLF4 and YY1 are prognostic biomarkers in pediatric lymphoma. Further, inhibitors of KLF4 are being clinically tested and may be applicable in the treatment of lymphoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B199.
Citation Format: Mario I. Vega, Alberto Valencia-Hipolito, Miriam Hernández-Atenógenes, Gabriel G. Vega, Hector Mayani, Sara Huerta-Yepez, Benjamin Bonavida. Transcriptional regulation of KLF4 by Yin Yang 1 (YY1) in pediatric B-NHL and clinical significance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B199.
Abstract B202: Hand-foot syndrome, the main side effect of patients with metastatic renal cell carcinoma treated with sunitinib.
Authors: Bensalem Assia , Bouzid Kamel 
Published: August 2014

Abstract
Background: Hand-foot syndrome (HFS) and related skin toxicities are common side effects of tyrosine kinase inhibitors such as sunitinib (SU), a multitargeted inhibitor of VEGF and PDGF receptors plus other receptor tyrosine kinases. In the treatment of naïve metastatic renal cancer carcinoma (mRCC) patients (pts), sunitinib showed superior progression-free survival (PFS) and objective response rate (ORR) over interferon-alfa, with a median PFS of 11 mo and median overall survival (OS) of 26.4 mo, establishing SU as a reference standard of care (Motzer et al, 2009). In this analysis, correlations between SU-associated HFS and efficacy endpoints were investigated in mRCC pts from January 2009 to January 2011 in the first- and second-line treatment settings. Methods: A total of 23 patients who received single-agent SU as 50 mg/d on a 4-week-on/2-week-off schedule (n=17; 73.9%) or 37.5 mg (n=6; 26%). Median PFS and OS were estimated and compared between pts with vs without HFS. Adverse events were recorded regularly. Results: Of 23 pts, 9 (39%) developed any-grade HFS, compared with 14 (60.8%) who did not. Most HFS (58%) initially occurred during the first 3 treatment cycles. Pts who developed HFS had significantly better ORR (55% vs. 32%), PFS (12 vs. 8 mo), and OS (23 vs. 11 mo) than pts who did not develop HFS.Conclusions: In mRCC pts, SU-associated HFS was significantly and independently associated with improved clinical outcomes. Overall, pts who did not develop HFS still had substantial benefit from SU. However, the presence of HFS identified a subset of pts that manifested highly favorable efficacy results with SU. This is suggesting that development of HFS may serve as a predictive biomarker of SU efficacy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B202.
Citation Format: Assia Bensalem, Kamel Bouzid. Hand-foot syndrome, the main side effect of patients with metastatic renal cell carcinoma treated with sunitinib. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B202.
Abstract B212: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.
Authors: Ballard Peter , Ashton Susan , Cross Darren , Dimelow Richard , Yates James 
Published: August 2014

Abstract
Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need.
AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291.
A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B212.
Citation Format: Peter Ballard, Susan Ashton, Darren Cross, Richard Dimelow, James Yates. Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B212.
Abstract B224: HPV-stratified analysis of prognostic role of miR-21 in oropharyngeal squamous cell carcinoma.
Authors: Ko Yoon Ho , An Ho Jung , Sun Der Sheng , Won Hye Sung , Kang Jin Hyoung , Jung Chan-Kwon 
Published: August 2014

Abstract
Background: Both smoking and human papillomavirus (HPV) infection play an significant role in the development and progression of oropharyngeal squamous cell carcinoma (OSCC). MicroRNAs are short noncoding RNAs that regulate multiple mRNAs and are frequently dysregulated in cancer. The miR-21 microRNA is overexpressed in a wide variety of cancers and has been causally related to cellular proliferation and apoptosis. In this study, we investigated the association between the expression of miR-21 and the clinicopathologic features by stratified analysis based on HPV infection status.
Patients and Methods: The expression of miR-21 in the OSCC tissues of 137 patients was evaluated by in situ hybridization method. In addition, PDCD4 and PTEN were also examined by immunohistochemistry using tissue microarray. The clinicopathological implications of these molecules were analyzed statistically.
Results: The up-regulation of miR-21 expression was 22.7% for HPV negative group and 42.1% for HPV positive group (P = 0.081), and significantly correlated with advanced lymph node metastasis and extracapsular extension (P = 0.005 and P = 0.014, respectively). There was a significant association between miR-21 and cytoplasmic PDCD4 overexpression (P = 0.027). Kaplan-Meier analysis showed that up-regulation of miR-21 was significantly related with shorter overall survival (OS; 77.0 v 193.0 months; P =0.05) in HPV-negative OSCC, but not in HPV-positive OSCC (P =0.95). At HPV-stratified multivariate analysis, up-regulation of miR-21 was independent prognostic factor for both relapse-free survival (RFS; HR, 2.681; 95% CI, 1.090 to 6.591; P = 0.032) and OS (HR, 6.286; 95% CI, 2.047 to 19.302; P = 0.001).
Conclusion: Up-regulation of miR-21 expression is closely associated with poor prognosis in HPV-negative OSCC, but not in HPV-positive OSCC, suggesting that miR-21 may have a different role according to the HPV infection status.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B224.
Citation Format: Yoon Ho Ko, Ho Jung An, Der Sheng Sun, Hye Sung Won, Jin Hyoung Kang, Chan-Kwon Jung. HPV-stratified analysis of prognostic role of miR-21 in oropharyngeal squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B224.
Abstract B230: Targeting mitochondria for metastatic lung adenocarcinoma specific lethality.
Authors: Gruener Barbara M. , Chuang Chen-Hua , Linde Ian , Chiou Shin-Heng , Readhead Ben , Dudley Joel , Doench John , Root David , Winslow Monte M. 
Published: August 2014

Abstract
Introduction: Lung cancer is the leading cause of cancer deaths in the United States. Its ability to leave the primary tumor and establish inoperable metastasis impairs successful therapy and is a major contributor to its lethality. A genetically engineered mouse model recapitulates the human disease very well, incorporating conditional alleles of the Kras oncogene and p53 tumor suppressor. Recently, cell lines generated from non-metastatic primary lung tumors (TnonMet) and metastases (Met) in this model were shown to maintain their metastatic state and exhibit dramatic differences in gene expression programs. This unique set of cell lines from early stage non-metastatic tumors and late-stage metastases provides an opportunity to understand whether cancer progression also creates unique vulnerabilities.
Experimental design: A pooled lentiviral-shRNA library screen which targeted ∼20,000 genes with &gt;92,000 shRNA in two TnonMet and two Met cell lines was used to systematically uncover genes that are specifically required to sustain metastasis survival or growth. High-throughput sequencing of the shRNA in the cancer cell populations before and after 20 population doublings in culture identified shRNAs that disadvantaged each cell line. Gene-set enrichment algorithm was utilized to analyse the data. qRT-PCR, cell competition assays and mitochondria-specific dyes were used to verify the results and unravel the underlying mechanism.
Results and Conclusion: The analysis of our pooled shRNA screen revealed mitochondrial ribosomal protein (Mrp) complexes as the top two gene-sets; in fact individual shRNA targeting more than 15 Mrp genes selectively disadvantaging Met cells with minimal impact on TnonMet cells. These results were individually verified with qRT-PCR. Interestingly, Met cells showed increased expression of mitochondria encoded genes, pointing to a strong imbalance in mitochondrial homeostasis. Furthermore, mitochondria-targeted therapy blocking mitochondrial translation or replication significantly inhibited Met cell growth more than TnonMet cell growth. Taken together, these results point to mitochondria as a metastasis-specific therapeutic target in lung adenocarcinoma and need to be further investigated.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B230.
Citation Format: Barbara M. Gruener, Chen-Hua Chuang, Ian Linde, Shin-Heng Chiou, Ben Readhead, Joel Dudley, John Doench, David Root, Monte M. Winslow. Targeting mitochondria for metastatic lung adenocarcinoma specific lethality. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B230.
Abstract B232: PIM1 kinase is essential for the growth of MYC-overexpressing triple-negative breast tumors and is an efficacious therapeutic target.
Authors: Horiuchi Dai , Zhou Alicia Y. , Corella Alexandra N. , Yau Christina , Lawson Devon A. , Bazarov Alexey V. , Yaswen Paul , McManus Michael T. , Welm Alana L. , Werb Zena , Goga Andrei 
Published: August 2014

Abstract
While de-regulated MYC signaling has been identified in a wide variety of human malignancies, no targeted therapeutic strategies have been established to target tumors with elevated MYC expression. We have previously reported that receptor “triple negative” (TN) breast cancers, which lack predictive biomarkers of response (i.e., estrogen/progesterone receptors, human epidermal growth factor receptor 2), exhibit significantly elevated MYC expression as well as MYC pathway activation (Horiuchi, D., et al. 2012 JEM). In an effort to uncover the potential Achilles’ heels of TN tumors, we performed a kinome, synthetic-lethal shRNA screen in human mammary epithelial cells in which MYC activity can be controlled (i.e., HMEC-MycER cells). The screen yielded 13 potential synthetic lethal partners of MYC, including recently described AMPK-related kinase 5 (Liu, L., et al. 2012. Nature). One of our top hits is the proto-oncogene PIM1, previously shown by others to be a genetic enhancer of MYC in transgenic mouse models of lymphomas and prostate cancer. Our bioinformatics studies performed on four independent clinical cohorts (n: 146 ∼ 683 patients each) show that in all the cohorts both MYC and PIM1 are significantly enriched in the TN populations. MYC and PIM1 expression are correlated in three out of the four cohorts. Furthermore, we find that PIM1 overexpression is a poor prognostic factor associated with diminished recurrence-free survival. Our in vivo efficacy studies using conventional as well as novel “human-in-mouse” orthotopic xenograft models demonstrate that PIM1 is required for the growth of MYC-overexpressing human TN tumors. We are currently investigating the cellular mechanisms by which PIM kinase inhibition causes such growth defects.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B232.
Citation Format: Dai Horiuchi, Alicia Y. Zhou, Alexandra N. Corella, Christina Yau, Devon A. Lawson, Alexey V. Bazarov, Paul Yaswen, Michael T. McManus, Alana L. Welm, Zena Werb, Andrei Goga. PIM1 kinase is essential for the growth of MYC-overexpressing triple-negative breast tumors and is an efficacious therapeutic target. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B232.