bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Initial Gefitinib or Erlotinib versus Chemotherapy on Central Nervous System Progression in Advanced Non–Small Cell Lung Cancer with EGFR Mutations
Authors: Heon Stephanie , Yeap Beow Y. , Lindeman Neal I. , Joshi Victoria A. , Butaney Mohit , Britt Gregory J. , Costa Daniel B. , Rabin Michael S. , Jackman David M. , Johnson Bruce E. 
Published: June 2012

Abstract
Purpose: This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non–small cell lung cancer (NSCLC) with EGFR mutations.
Experimental Design: Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk.
Results: One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P = 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34–0.94].
Conclusions: Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC. Clin Cancer Res; 18(16); 4406–14. ©2012 AACR.
Role of Hedgehog Signaling in Malignant Pleural Mesothelioma
Authors: Shi Yandong , Moura Ubiratan , Opitz Isabelle , Soltermann Alex , Rehrauer Hubert , Thies Svenja , Weder Walter , Stahel Rolf A. , Felley-Bosco Emanuela 
Published: June 2012

Abstract
Purpose: The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM).
Experimental Design: The expression of hedgehog signaling components was assessed by quantitative PCR and in situ hybridization in 45 clinical samples. Primary MPM cultures were developed in serum-free condition in 3% oxygen and were used to investigate the effects of smoothened (SMO) inhibitors or GLI1 silencing on cell growth and hedgehog signaling. In vivo effects of SMO antagonists were determined in an MPM xenograft growing in nude mice.
Results: A significant increase in GLI1, sonic hedgehog, and human hedgehog interacting protein gene expression was observed in MPM tumors compared with nontumoral pleural tissue. SMO antagonists inhibited GLI1 expression and cell growth in sensitive primary cultures. This effect was mimicked by GLI1 silencing. Reduced survivin and YAP protein levels were also observed. Survivin protein levels were rescued by overexpression of GLI1 or constitutively active YAP1. Treatment of tumor-bearing mice with the SMO inhibitor HhAntag led to a significant inhibition of tumor growth in vivo accompanied by decreased Ki-67 and nuclear YAP immunostaining and a significant difference in selected gene expression profile in tumors.
Conclusions: An aberrant hedgehog signaling is present in MPM, and inhibition of hedgehog signaling decreases tumor growth indicating potential new therapeutic approach. Clin Cancer Res; 18(17); 4646–56. ©2012 AACR.
Vascular Endothelial Growth Factor Pathway Polymorphisms as Prognostic and Pharmacogenetic Factors in Cancer: A Systematic Review and Meta-analysis
Authors: Eng Lawson , Azad Abul Kalam , Habbous Steven , Pang Vincent , Xu Wei , Maitland-van der Zee Anke H. , Savas Sevtap , Mackay Helen J. , Amir Eitan , Liu Geoffrey 
Published: June 2012

AbstractAngiogenesis is an important host process that interacts with cancer cells to promote growth, invasion, and metastasis. Numerous therapeutic agents targeting the VEGF pathway have been developed. Host variability in VEGF pathway can influence angiogenesis-dependent signaling, altering sensitivity to antiangiogenic drugs and prognosis. A systematic review and meta-analysis was conducted (May 1990–July 2011). Eligible studies involved cancer patients and compared polymorphisms in the VEGF pathway [VEGF and molecules directly interacting with VEGF: KDR, FLT1, FGF, FGF2, FGFR, NRP1, endostatin (encoded by COL18A1)], and reported one of the following outcomes: overall survival, progression-free survival, time to recurrence, disease-free survival, response rate, or drug toxicity. We identified 48 cancer studies assessing prognosis and 12 cancer studies exploring pharmacogenetics of anti-VEGF therapy across various VEGF pathway polymorphisms. There was marked inter- and intradisease site heterogeneity in the effect of polymorphisms on both outcome and response to therapy. Meta-analyses of 5 VEGF polymorphisms (+936C&gt;T, −460T&gt;C, +405G&gt;C, −1154G&gt;A, and −2578C&gt;A) identified a significant prognostic relationship: VEGF +405G&gt;C variants showed a highly statistically significant improvement in overall survival [HR, 0.74; 95% confidence interval, 0.60–0.91; P = 0.004]. Variants (heterozygotes and/or homozygotes) of VEGF +405G&gt;C were significantly associated with improved survival in a meta-analysis of multiple cancer sites. Clin Cancer Res; 18(17); 4526–37. ©2012 AACR.
Abstract A1: Clinical and biological significance of GSK-3β inactivation in breast cancer: An immunohistochemical study
Authors: Armanious Hanan , Deschenes Jean , Gelebart Pascal , Ghosh Sunita , Mackey John , Lai Raymond 
Published: June 2012

Abstract
Glycogen synthase kinase 3β (GSK-3β), recently found to be functionally abnormal in various types of human disease, is negatively regulated by the PI3K/Akt signaling pathway. Since Akt is constitutively activated in a subset of breast cancer, we hypothesized that GSK-3β is inappropriately inactivated in these cases. In this study, we aimed to assess (1) the overall frequency of GSK-3β inactivation in breast cancer; (2) if there is an association between Akt activation and GSK-3β inactivation; and (3) whether there is correlation between GSK-3β inactivation and various pathologic and clinical parameters. The expression of the phosphorylated form of GSK-3β (pGSK-3β) and Akt (pAkt) were used as surrogate markers of GSK-3β inactivation and Akt activation, respectively. Immunohistochemistry applied to paraffin-embedded tissues was used to assess 72 consecutive invasive mammary carcinomas, of which 50 were estrogen receptor (ER)-positive. Overall, pGSK-3β and pAkt were positive in 34 (47.2%) and 35 (48.6%) cases, respectively. These two markers were significantly correlated with each other in the overall group and in the ER-positive subgroup (p=0.01 and 0.003, Spearman, respectively). Importantly, pGSK-3β, but not pAkt, significantly correlated a worse clinical outcome in this cohort (p=0.004, Log rank). In summary, evidence of GSK-3β inactivation was found in approximately half of the invasive mammary carcinomas. Our data suggest that this abnormality is likely attributed to Akt activation and that GSK-3β inactivation confers a worse clinical outcome.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A1.
Abstract A10: Off-target toxicity in white blood cells by AG-012986, a pan-CDK inhibitor, is mediated through inhibition of p38 MAPK signaling pathway
Authors: Lee Dong U. , Jessen Bart 
Published: June 2012

Abstract
Cyclin-dependent kinases (CDKs) have been an attractive target for cancer research because these kinases are predominantly active during cell division. AG-012986 is a small molecule pan-CDK inhibitor that has in vitro and in vivo antitumor properties. This compound was stopped during development due in part to rapid bone-marrow independent white blood cell toxicity in non-human primate and rodent species, and the potential for acute and delayed immunosuppression in humans. Because peripheral leukocytes are largely nonproliferating cells, it was hypothesized that the effects of AG-012986 was due to an off-target mechanism and not driven by the intended pharmacology. Using primary human peripheral blood mononuclear cells (PBMCs) and T-cells, we show that AG-012986 has a toxicity profile with greater specificity and more rapid cell death compared to the prototypical ATP-competitive kinase inhibitor, staurosporine. The cell toxicity mechanism was caspase-dependent and contained the hallmarks of apoptosis as indicated by cells staining double positive for propidium iodide and annexin-V. PBMCs or T-cells treated with AG-012986 and acutely stimulated either pharmacologically or through the T-cell receptor (TCR), exhibited decreased cellular toxicity compared to non-stimulated control cells. Interestingly under activating conditions with the pan-CDK compound, T-cells did not undergo significant cell division, as measured by BrdU incorporation, and were also rescued from apoptosis. This indicates that the pharmacology of AG-012986 was functioning as expected but that the toxicity due to its off-target effect had now been decoupled through cellular activation. Investigating the downstream signaling network showed that phosphorylation of p38 MAP kinase was impaired in the presence of AG-012986. Thus we hypothesize that AG-012986 may target the upstream kinase MKK3 and/or MKK6 for inhibition under basal conditions, leading to cell death in T cells and perhaps other white blood cells.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A10.
Abstract A11: Regulation of CD133 by the tubulin deacetylase HDAC6 can alter cancer cell state
Authors: Mak Anthony B. , Kittanakom Saranya , Chen Ginny I. , Mazitschek Ralph , Gingras Anne-Claude , Stagljar Igor , Moffat Jason 
Published: June 2012

Abstract
The CD133 antigen AC133/1 is a putative marker for enriching certain stem cells and cancer progenitor cells. Despite its wide application, the function and regulation of its expression remains unclear. Given the presence of its transcript in more differentiated cells, epigenetic regulation of CD133 transcripts alone cannot vouch for its utility as a marker. Therefore, understanding the regulation of CD133 protein expression is important for further defining the cellular state of tumor-initiating cells.
We used the MAPLE system (Mak et al, Mol Cell Proteomics, 2010) to identify bona fide protein interaction partners of CD133. We present the microtubule-associated histone deacetylase 6 (HDAC6) as a physical interaction partner of CD133. This interaction was validated by co-immunoprecipitation/Western Blot analyses and by a membrane yeast two-hybrid (MYTH) assay. In order to understand the functional consequence of the HDAC6 and CD133 interaction, we used lentiviral short-hairpin RNAs to knockdown HDAC6 in multiple cell types, including the human epithelial colorectal adenocarcinoma lines Caco- 2 and HT-29 and in the retinoblastoma cell line Weri-Rb-1. Interestingly, we observed a significant reduction of CD133 protein expression. This reduction was shown to be dependent on HDAC6 deacetylase activity using a deacetlyase deficient HDAC6 mutant as well as when using the small molecule inhibitor of HDAC6, tubacin.
HDAC6 promotes de-acetylation of alpha-tubulin to influence re-cycling of cell surface proteins. Furthermore, when we performed a CD133 MYTH screen against a cDNA library isolated from an adult human brain, we identified the late endosomal- and lysosomal-associated marker CD63 as an interaction partner of CD133. In fact, treatment of Caco-2 cells with tubacin resulted in trafficking of CD133 into endosomes for lysosomal degradation as determined by increased co-localization with CD63.
In an attempt to study the affect of HDAC6 knockdown on cell viability, we noticed that CD133 knockdown significantly impacted cell proliferation and clonogenicity of Caco-2 cells. We determined that the cause of this is likely due to increased differentiation as determined by the level of alkaline phosphatase activity and by quantitative realtime PCR for markers of differentiated colon cells. To assess the tumorigenic potential of Caco-2 cells with reduced CD133 expression in vitro we performed soft agar colony-forming assay, which resulted in the loss of anchorage independent growth, a well-known hallmark of cancer. Together, these results suggest that CD133 can exercise a function in establishing and maintaining a primitive cancer cell state and loss or reduction of its expression marks more differentiated cancer cells that may be nontumorigenic.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A11.
Abstract A12: Cardiac hormone receptor A, NPRA, as a prognostic marker and target for prostate cancer therapy
Authors: Wang Xiaoqin , Patel Ronil , Hellerman Gary , Coppola Domenico , Mohapatra Shyam S. , Mohapatra Subhra 
Published: June 2012

Abstract
Management of prostate cancer (PCa), the third leading cause of death among American men, is limited by lack of prognostic markers and therapies for targeting androgen-independent PCa. Herein we report that NPRA, the receptor for the cardiac hormone atrial natriuretic peptide, is a potential prognostic marker and therapeutic target for PCa. NPRA is abundantly expressed in the androgen-independent PCa cell lines, PC3 and DU145, but not in normal PrEC cells and only weakly in RWPE and benign prostate hyperplasia (BPH) cells. NPRA is more highly expressed by the tumorigenic TRAMP-C1 and -C2 and PTEN-CaP2 PCa cell lines than the nontumorigenic TRAMP-C3 and PTEN-P2 PCa cell lines. NPRA showed positive correlation with clinical staging in a human PCa tissue microarray (TMA). Prostate tumor cells implanted in mice deficient in atrial natriuretic peptide receptor A (NPRA-KO) failed to grow, and down-regulation of NPRA by siNPRA or NPRA inhibitor, iNPRA, induced apoptosis in PCa cells and reduced tumor burden in mice. The mechanism of iNPRA-induced anti-PCa effects was linked to NPRA-induced expression of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine overexpressed in prostate cancer and associated with tumor survival. SiNPRA significantly reduced MIF expression. Using the TRAMP spontaneous PCa model, we found that NPRA expression correlated with MIF expression during PCa progression and treatment of TRAMP-C1 xenografts with iNPRA reduced MIF expression. MIF was also seen in the human PCa TMA. This suggests that NPRA promotes PCa development by regulating MIF and may represent a prognostic marker and target for PCa therapy.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A12.
Abstract A13: Discovery of selective inhibitors of the kinase and metastatic activities of the activated Cdc42-associated kinase (ACK1)
Authors: Olabisi Oyenike , Kholodovych Vladyslav , Kamal Alam Nur-E- , Stewart-Singleton Safirah , Andayah Christina , Wood Richard , Welsh William 
Published: June 2012

Abstract
Activated Cdc42-associated kinase (ACK1) is a non-receptor tyrosine kinase and an effector protein of Cdc42. Previous reports have demonstrated that ACK1 is a critical factor in the cellular transformation of a number of cancer cell lines. ACK1 also contributes to cellular motility, and overexpression in certain cell lines results in enhanced motility. The significance of tyrosine kinase proteins such as ACK1 in cancer-related signaling pathways, and the implications of metastasis in the prognosis of cancer patients, point to the importance of the discovery of a potent yet selective inhibitor for this protein. As a result, we are engaged in a study focused on applying computational approaches to identify novel inhibitor molecules of ACK that will also hamper its ability to promote motility of cancer cells.
We employed customized in-house computational tools to retrieve approximately 50 small-molecule hits from our chemical databases that may bind with high affinity to the ACK1 ATP binding pocket. These hits were further screened for drug-like properties (Lipinski's Rule of 5) and rescored using GOLD docking to the ACK1 crystal structure (PDB3EQR). After rescoring, the top 25 hits were then tested for in vitro cytotoxicity in a variety of cancer cell lines. Compounds were specifically examined for their impact on the kinase activity of purified ACK1 and for their ability to modulate its metastatic properties in wound healing and transwell migration assays.
Our screening has revealed that several compounds have the ability to inhibit the in vitro kinase activity of ACK1 and also inhibit the in vitro growth of cancer cells. Ongoing immunofluorescence, cellular transformation, and cellular motility studies suggest that the selected compounds may modulate the effect of ACK1 on the motility of cancer cells. We are actively proceeding with specific structural modifications of our initial inhibitor compounds in order to find molecules which possess increased cytotoxicity to cancer cells and improved specificity for the inhibition of ACK.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A13.
Abstract A14: EGFR mutation status and the efficacy of gefitinib in combination with paclitaxel and carboplatin as neoadjuvant treatment in locally advanced cancer of the cervix: A study from eastern India
Authors: Pandey Ritwik , Mukhopadhyay Ashis 
Published: June 2012

Abstract
Purpose: To study the incidence of EGFR mutations (Exon 19-21) in locally advanced cervical cancer and to assess wether gefitinib, in combination with paclitaxel and carboplatin leads to better outcomes in patients who harbored EGFR mutations. Also, to study the response rates of paclitaxel and carboplatin as neoadjuvant treatment in locally advanced cervical cancer.
Materials and Methods: From January 2008 to April 2010, 108 patients of inoperable locally advanced carcinoma of the cervix (Stage Ib – II only) were prospectively evaluated for EGFR mutations (exon 19-21) and were randomized to receive paclitaxel (175 mg/m2) and carboplatin (AUC 5) with gefitinib (For mutation +ve patients) or without gefitinib (for mutation -ve patients). Patients were assessed for incidence of EGFR mutation, response rates to treatment and conversion to operable disease after receiving neoadjuvant chemotherapy. The patients who were still inoperable after this treatment were offered chemoradiation.
Results: 30 of 108 patients (30.5%) were positive for EGFR mutations. 50 of 78 patients who received paclitaxel and carboplatin had a more than partial response to treatment giving a response rate of 64.1 %. 20 of 78 (25.6%) patients had a stable disease while 8 of 70 (11.4%) patients had a progressive disease. 25 of 30 patients who were EGFR mutation +ve had a response to paclitaxel + carboplatin + gefitinib giving this combination a response rate of 83.3%. This response rate was significantly higher (p=0.001) as compared to mutation negative patients. Only 1 of 30 (0.03%) patients in this subgroup had a progressive disease. 20 of 25 (80%) patients in the mutation +ve group had an R0 resection as compared to 35 of 78 (44.8%) patients in the mutation -ve group (p=0.02).
Inference: Approximately one-third of the cervical cancer patients were positive for EGFR mutations. These patients when given gefitinib in combination with chemotherapy had a significantly higher response rate and conversion to operability. Also that paclitaxel + carboplatin is an effective neoadjuvant regimen for locally advanced cancer of cervix giving a response rate of about 65% and high conversion to operability.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A14.
Abstract A16: Thrombin promotes hepatocellular carcinoma metastasis via mediating osteopontin-dependent tumor growth and adhesion activity
Authors: Xue Yu-Hua , Zhang Xiao-Fei , Dong Qiong-Zhu , Ye Qing-Hai , Qin Lun-Xiu 
Published: June 2012

Abstract
In our previous study, osteopontin (OPN) was identified as one of the leading genes that promote the metastasis of hepatocellular carcinoma (HCC), and a potential therapeutic target for HCC metastasis. The serine protease thrombin can interact with OPN and modify its biologic activity. To explore the role of thrombin alone or collaborating with OPN in HCC, we investigated the thrombin level and its correlation to the prognosis of 72 HCCs with different OPN backgrounds using real-time PCR and Western blot, and evaluated the effects of OPN fragments formed by thrombin cleavage on in vitro proliferation and adhesion of HCC cells. We found that the expression level of thrombin was positively related to the metastatic potentials of HCC cell lines, and was remarkably overexpressed in HCCs compared with the adjacent nontumor tissues. In addition, HCC tissues from patients with recurrent disease displayed much higher thrombin levels, particularly in those with OPN overexpressed. In the immunohistochemical study of 230 HCCs, only in those with a higher OPN level, a significant association was found between the higher thrombin level and the overall survival (OS; P &lt; 0.01) and time to recurrence (TTR; P &lt; 0.0001) of patients. Assays in vitro demonstrated that thrombin could promote the proliferation and adhesion of OPN+ HCC cells. And N-terminal of OPN showed better effects on the proliferation and adhesion abilities of HCC cells than the intact protein. Thrombin treatment could activate FAK pathway of OPN+ HCC cells, and this activation was blocked by the inhibition of integrin β1. Conclusions: Thrombin plays an important role in OPN-mediated aggressive phenotype and poor prognosis of HCC, which may be through the activation of the integrin β1 -FAK signaling. So, thrombin might be a potential therapeutic target to combat HCC progression in thrombin+/OPN+ patients.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A16.