bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Phase III Trial of Gefitinib versus Docetaxel in Non–Small Cell Lung Cancer Patients Who Have Previously Received Platinum-Based Chemotherapy
Authors: Lee Dae Ho , Park Keunchil , Kim Joo Hang , Lee Jong-Seok , Shin Sang Won , Kang Jin-Hyoung , Ahn Myung-Ju , Ahn Jin Seok , Suh Cheolwon , Kim Sang-We 
Published: February 2010

Abstract
Purpose: The ISTANA (IRESSA as Second-line Therapy in Advanced NSCLC—KoreA) study compared gefitinib with docetaxel in patients with advanced or metastatic non–small cell lung carcinoma (NSCLC) pretreated with platinum-based chemotherapy.
Experimental Design: We conducted a multicenter, randomized, open-label phase III trial of gefitinib (250 mg/d) versus docetaxel (75 mg/m2 day 1 every 3 weeks) in patients with advanced or metastatic NSCLC treated with one previous platinum-based chemotherapy. The primary endpoint was progression-free survival.
Results: A total of 161 patients (male, 62%; never smoker, 41%; adenocarcinoma, 68%) were enrolled. Progression-free survival was longer for gefitinib compared with docetaxel (hazard ratio, 0.729; 90% confidence interval, 0.533-0.998; one-sided P = 0.0441). Gefitinib significantly improved objective response rate (28.1% versus 7.6%; two-sided P = 0.0007). In the final analysis of overall survival, the hazard ratio was 0.870 (95% confidence interval, 0.613-1.236; two-sided P = 0.4370). No significant differences were seen in the quality of life or symptom improvement rates between the two treatment groups. Gefitinib was well tolerated, was consistent with previous data and disease, and had fewer serious adverse events and fewer Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events than docetaxel. The incidence of interstitial lung disease–type events was 3.7% (n = 3) with gefitinib and 3.9% (n = 3) with docetaxel.
Conclusions: The primary endpoint of progression-free survival was longer with gefitinib than docetaxel, and the secondary endpoints showed superior objective response rate, good tolerability, and similar quality of life improvement rates for gefitinib than docetaxel. Therefore, gefitinib is an important valid treatment option for second-line therapy for Korean NSCLC patients. Clin Cancer Res; 16(4); 1307–14
AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer
Authors: Hickinson D. Mark , Klinowska Teresa , Speake Georgina , Vincent John , Trigwell Cath , Anderton Judith , Beck Sarah , Marshall Gayle , Davenport Sara , Callis Rowena , Mills Elizabeth , Grosios Konstantina , Smith Paul , Barlaam Bernard , Wilkinson Robert W. , Ogilvie Donald 
Published: February 2010

Abstract
Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo.
Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors.
Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC50, 4 nmol/L), erbB2 (IC50, 3 nmol/L), and erbB3 (IC50, 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non–small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.
Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159–69
Phase I Trial of Pelvic Radiation, Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC #663249) for Locally Advanced Cervical Cancer
Authors: Kunos Charles A. , Waggoner Steven , von Gruenigen Vivian , Eldermire Elisa , Pink John , Dowlati Afshin , Kinsella Timothy J. 
Published: February 2010

Abstract
Purpose: This study assessed the safety/tolerability, pharmacokinetics, and clinical activity of three times weekly i.v. 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in combination with once-weekly i.v. cisplatin and daily pelvic radiation in patients with gynecologic malignancies. 3-AP is a novel small-molecule inhibitor of ribonucleotide reductase (RNR) and is being tested as a potential radiosensitizer and chemosensitizer.
Experimental Design: Patients with stage IB2 to IVB cervical cancer (n = 10) or recurrent uterine sarcoma (n = 1) were assigned to dose-finding cohorts of 2-hour 3-AP infusions during 5 weeks of cisplatin chemoradiation. Pharmacokinetic and methemoglobin samples and tumor biopsy for RNR activity were obtained on day 1 and day 10. Clinical response was assessed.
Results: The maximum tolerated 3-AP dose was 25 mg/m2 given three times weekly during cisplatin and pelvic radiation. Two patients experienced manageable 3-AP–related grade 3 or 4 electrolyte abnormalities. 3-AP pharmacokinetics showed a 2-hour half-life, with median peak plasma concentrations of 277 ng/mL (25 mg/m2) and 467 ng/mL (50 mg/m2). Median methemoglobin levels peaked at 1% (25 mg/m2) and 6% (50 mg/m2) at 4 hours after initiating 3-AP infusions. No change in RNR activity was found on day 1 versus day 10 in six early complete responders, whereas elevated RNR activity was seen on day 10 as compared with day 1 in four late complete responders (P = 0.02). Ten (100%) patients with stage IB2 to IVB cervical cancer achieved complete clinical response and remained without disease relapse with a median 18 months of follow-up (6-32 months).
Conclusions: 3-AP was well tolerated at a three times weekly i.v. 25 mg/m2 dose during cisplatin and pelvic radiation. Clin Cancer Res; 16(4); 1298–306
Blockade of the Extracellular Signal-Regulated Kinase Pathway Enhances the Therapeutic Efficacy of Microtubule-Destabilizing Agents in Human Tumor Xenograft Models
Authors: Watanabe Kazushi , Tanimura Susumu , Uchiyama Aya , Sakamoto Toshiaki , Kawabata Takumi , Ozaki Kei-ichi , Kohno Michiaki 
Published: February 2010

Abstract
Purpose: The extracellular signal-regulated kinase (ERK) pathway is upregulated in human cancers and represents a target for mechanism-based approaches to cancer treatment. However, specific blockade of the ERK pathway alone induces mostly cytostatic rather than proapoptotic effects, resulting in a limited therapeutic efficacy of inhibitors that target the mitogen-activated protein kinase/ERK kinase (MEK). Given the cytoprotective role of the ERK pathway, we examined whether its blockade by the MEK inhibitor PD184352 might enhance the therapeutic efficacy of anticancer drugs in human tumor xenograft models.
Experimental Design: We recently showed that blockade of the ERK pathway by MEK inhibitors enhances the induction of apoptosis by microtubule-destabilizing agents, including TZT-1027 and vinorelbine, in various tumor cells with aberrant activation of the ERK pathway in vitro. We here examined the therapeutic efficacy of the combination of PD184352 with TZT-1027 or vinorelbine in nude mice harboring HT-29 or HT1080 tumor xenografts, in which the ERK pathway is activated as a result of mutations of BRAF and NRAS, respectively.
Results: Coadministration of PD184352 markedly sensitized HT-29 or HT1080 tumor xenografts to TZT-1027–induced or vinorelbine-induced cytotoxicity. Low doses of TZT-1027 or vinorelbine that by themselves showed little or moderate cytotoxicity thus suppressed the growth of HT-29 xenografts almost completely and induced essentially complete regression of HT1080 xenografts when administered with PD184352. The enhanced therapeutic efficacy of the drug combinations was achieved by a relatively transient blockade of the ERK pathway.
Conclusions: Administration of both a MEK inhibitor and a microtubule-destabilizing agent represents a promising chemotherapeutic strategy with improved safety for cancer patients. Clin Cancer Res; 16(4); 1170–8
Potential Clinical Significance of a Plasma-Based KRAS Mutation Analysis in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Wang Shuhang , An Tongtong , Wang Jie , Zhao Jun , Wang Zhijie , Zhuo Minglei , Bai Hua , Yang Lu , Zhang Yan , Wang Xin , Duan Jianchun , Wang Yuyan , Guo Qingzhi , Wu Meina 
Published: February 2010

Abstract
Purpose: Non–small cell lung cancer (NSCLC) with KRAS mutation may be resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). This study aims to evaluate a plasma-based KRAS mutation analysis and the clinical significance of plasma KRAS mutation as a predictive marker for tumor resistance to EGFR-TKIs in patients with NSCLC.
Experimental Design: DNA extracted from plasma and matched tumor tissues were obtained from 273 patients with advanced stage NSCLC. Patients were followed up prospectively for treatment outcomes. KRAS mutations in codon 12 and 13 were detected using PCR-restriction fragment length polymorphism. Mutations in plasma and matched tumors were compared. Associations between KRAS mutation status and patients' clinical outcomes were analyzed.
Results: KRAS mutation was found in 35 (12.8%) plasma samples and 30 (11.0%) matched tumor tissues. The consistency of KRAS mutations between plasma and tumors is 76.7% (23 of 30; κ = 0.668; P &lt; 0.001). Among 120 patients who received EGFR-TKI treatment, the response rate was only 5.3% (1 of 19) for patients with plasma KRAS mutation compared with 29.7% for patients with no KRAS mutation in plasma DNA (P = 0.024). The median progression-free survival time of patients with plasma KRAS mutation was 2.5 months compared with 8.8 months for patients with wild-type KRAS (P &lt; 0.001).
Conclusions: KRAS mutation in plasma DNA correlates with the mutation status in the matched tumor tissues of patients with NSCLC. Plasma KRAS mutation status is associated with a poor tumor response to EGFR-TKIs in NSCLC patients and may be used as a predictive marker in selecting patients for such treatment. Clin Cancer Res; 16(4); 1324–30
Phase I Oncology Studies: Evidence That in the Era of Targeted Therapies Patients on Lower Doses Do Not Fare Worse
Authors: Jain Rajul K. , Lee J. Jack , Hong David , Markman Maurie , Gong Jing , Naing Aung , Wheler Jennifer , Kurzrock Razelle 
Published: February 2010

Abstract
Purpose: To safely assess new drugs, cancer patients in initial cohorts of phase I oncology studies receive low drug doses. Doses are successively increased until the maximum tolerated dose (MTD) is determined. Because traditional chemotherapy is often more effective near the MTD, ethical concerns have been raised about administration of low drug doses to phase I patients. However, a substantial portion of oncology trials now investigate targeted agents, which may have different dose-response relationships than cytotoxic chemotherapies.
Experimental Design: Twenty-four consecutive trials treating 683 patients between October 1, 2004, and June 30, 2008, at MD Anderson Cancer Center were analyzed. Patients were assigned to a low-dose (≤25% MTD), medium-dose (25-75% MTD), or high-dose (≥75% MTD) group, and groups were compared for response rate, time-to-treatment failure, progression-free survival, overall survival, and toxicity. To remove negatively biasing data from the high-dose group, in a second analysis, patients treated above the MTD were excluded (high-dose group, 75-100% MTD). Of the 683 patients, 97.7% received targeted agents.
Results: Even when excluding patients above the MTD, there was an early trend favoring the low- versus high-dose group in time-to-treatment failure, with 32.9% versus 25.2% of patients on therapy at 3 months (P = 0.08). In addition, the low-dose group fared at least as well as the other groups in all other outcomes, including response rate, progression-free survival, overall survival, and toxicity.
Conclusions: These data may help alleviate concerns that patients who receive low drug doses on contemporary phase I oncology trials fare worse and suggest targeted agents may have different dose-response relationships than cytotoxic chemotherapies. Clin Cancer Res; 16(4); 1289–97
Targeting the Cytoprotective Chaperone, Clusterin, for Treatment of Advanced Cancer
Authors: Zoubeidi Amina , Chi Kim , Gleave Martin 
Published: February 2010

Abstract
Many strategies used to kill cancer cells induce stress-responses that activate survival pathways to promote emergence of a treatment resistant phenotype. Secretory clusterin (sCLU) is a stress-activated cytoprotective chaperone up-regulated by many varied anticancer therapies to confer treatment resistance when overexpressed. sCLU levels are increased in several treatment recurrent cancers including castrate resistant prostate cancer, and therefore sCLU has become an attractive target in cancer therapy. sCLU is not druggable with small molecule inhibitors, therefore nucleotide-based strategies to inhibit sCLU at the RNA level are appealing. Preclinical studies have shown that antisense oligonucleotide (ASO) or siRNA knockdown of sCLU have preclinical activity in combination with hormone- and chemotherapy. Phase I and II clinical trial data indicate that the second generation ASO, custirsen (OGX-011), has biologic and clinical activity, suppressing sCLU expression in prostate cancer tissues by more than 90%. A randomized study comparing docetaxel-custirsen to docetaxel alone in men with castrate resistant prostate cancer reported improved survival by 7 months from 16.9 to 23.8 months. Strong preclinical and clinical proof-of-principle data provide rationale for further study of sCLU inhibitors in randomized phase III trials, which are planned to begin in 2010. Clin Cancer Res; 16(4); 1088–93
Proanthocyanidins Inhibit In vitro and In vivo Growth of Human Non–Small Cell Lung Cancer Cells by Inhibiting the Prostaglandin E2 and Prostaglandin E2 Receptors
Authors: Sharma Som D. , Meeran Syed M. , Katiyar Santosh K. 
Published: February 2010

Abstract
Overexpression of cyclooxygenase-2 (COX-2) and prostaglandins (PG) is linked to a wide variety of human cancers. Here, we assessed whether the chemotherapeutic effect of grape seed proanthocyanidins (GSP) on non–small cell lung cancer (NSCLC) cells is mediated through the inhibition of COX-2 and PGE2/PGE2 receptor expression. The effects of GSPs on human NSCLC cell lines in terms of proliferation, apoptosis, and expression of COX-2, PGE2, and PGE2 receptors were determined using Western blotting, fluorescence-activated cell sorting analysis, and reverse transcription-PCR. In vitro treatment of NSCLC cells (A549, H1299, H460, H226, and H157) with GSPs resulted in significant growth inhibition and induction of apoptosis, which were associated with the inhibitory effects of GSPs on the overexpression of COX-2, PGE2, and PGE2 receptors (EP1 and EP4) in these cells. Treatment of cells with indomethacin, a pan-COX inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell growth and induced cell death. The effects of a GSP-supplemented AIN76A control diet fed to nude mice bearing tumor xenografts on the expression of COX-2, PGE2, and PGE2 receptors in the xenografts were also evaluated. The growth-inhibitory effect of dietary GSPs (0.5%, w/w) on the NSCLC xenograft tumors was associated with the inhibition of COX-2, PGE2, and PGE2 receptors (EP1, EP3, and EP4) in tumors. This preclinical study provides evidence that the chemotherapeutic effect of GSPs on lung cancer cells in vitro and in vivo is mediated, at least in part, through the inhibition of COX-2 expression and subsequently the inhibition of PGE2 and PGE2 receptors. Mol Cancer Ther; 9(3); 569–80
Repression of Human Telomerase Reverse Transcriptase Using Artificial Zinc Finger Transcription Factors
Authors: Sohn Joon Hyung , Yeh Byung-Il , Choi Jong-Whan , Yoon Joonho , Namkung Jun , Park Kwang-Kyun , Kim Hyun-Won 
Published: February 2010

Abstract
Telomerase activation is a key step in the development of human cancers. Expression of the catalytic subunit, human telomerase reverse transcriptase (hTERT), represents the limiting factor for telomerase activity. In this study, we have used artificial zinc finger protein (ZFP) transcription factors (TF) to repress the expression of hTERT in human cancer cell lines at the transcriptional level. We have constructed four-fingered ZFPs derived from the human genome which binds 12-bp recognition sequences within the promoter of the hTERT gene and fused them with a KRAB repressor domain to create a potent transcriptional repressor. Luciferase activity was decreased by &gt;80% in all of the transcriptional repressors with luciferase reporter assay. When they were transfected into the telomerase-positive HEK293 cell line, a decrease of mRNA level and telomerase activity together with shortening of telomere length was observed. Actual growth of HEK293 cells was also inhibited by transfection of artificial ZFP-TFs. The repression was maintained for 100 days of culture. The repression of telomerase expression by artificial ZFP-TFs targeting the promoter region of the hTERT presents a new promising strategy for inhibiting the growth of human cancer cells. Mol Cancer Res; 8(2); 246–53
Sec5 and Exo84 Foster Oncogenic Ras-Mediated Tumorigenesis
Authors: Issaq Sameer H. , Lim Kian-Huat , Counter Christopher M. 
Published: February 2010

Abstract
The genes encoding the Ras family of small GTPases are mutated to yield constitutively active GTP-bound oncogenic proteins in one third of all human cancers. Oncogenic Ras binds to and activates a number of proteins that promote tumorigenic phenotypes, including the family of Ral guanine nucleotide exchange factors (RalGEF). Activated RalGEFs convert the Ral family of small GTPases, composed of RalA and RalB, from an inactive GDP-bound state to an active GTP-bound state. As both RalA and RalB have been implicated in a variety of tumorigenic phenotypes, we sought to determine which proteins downstream of Rals promote transformation and tumorigenesis. Here, we report that shRNA-mediated knockdown of the Ral effector proteins Sec5 and Exo84, but less so in the case of RalBP1, reduced oncogenic RalGEF-mediated transformation and oncogenic Ras-driven tumorigenic growth of human cells. These results suggest that Rals promote oncogenic Ras-mediated tumorigenesis through, at least in part, Sec5 and Exo84. Mol Cancer Res; 8(2); 223–31
Sustained c-Jun-NH2-Kinase Activity Promotes Epithelial-Mesenchymal Transition, Invasion, and Survival of Breast Cancer Cells by Regulating Extracellular Signal-Regulated Kinase Activation
Authors: Wang Jinhua , Kuiatse Isere , Lee Adrian V. , Pan Jingxuan , Giuliano Armando , Cui Xiaojiang 
Published: February 2010

Abstract
The c-Jun NH2-terminus kinase (JNK) mediates stress-induced apoptosis and the cytotoxic effect of anticancer therapies. Paradoxically, recent clinical studies indicate that elevated JNK activity in human breast cancer is associated with poor prognosis. Here, we show that overexpression of a constitutively active JNK in human breast cancer cells did not cause apoptosis, but actually induced cell migration and invasion, a morphologic change associated with epithelial-mesenchymal transition (EMT), expression of mesenchymal-specific markers vimentin and fibronectin, and activity of activator protein transcription factors. Supporting this observation, mouse mammary tumor cells that have undergone EMT showed upregulated JNK activity, and the EMT was reversed by JNK inhibition. Sustained JNK activity enhanced insulin receptor substrate-2–mediated ERK activation, which in turn increased c-Fos expression and activator protein activity. In addition, hyperactive JNK attenuated the apoptosis of breast cancer cells treated by the chemotherapy drug paclitaxel, which is in contrast to the requirement for inducible JNK activity in response to cytotoxic chemotherapy. Blockade of extracellular signal-regulated kinase activity diminished hyperactive JNK-induced cell invasion and survival. Our data suggest that the role of JNK changes when its activity is elevated persistently above the basal levels associated with cell apoptosis, and that JNK activation may serve as a marker of breast cancer progression and resistance to cytotoxic drugs. Mol Cancer Res; 8(2); 266–77
Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer
Authors: Mudduluru Giridhar , Vajkoczy Peter , Allgayer Heike 
Published: February 2010

Abstract
Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P &lt; 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression. Mol Cancer Res; 8(2); 159–69.