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Kaye S.B.,Institute of Cancer Research | Poole C.J.,University of Warwick | Danska Bidzinska A.,Centrum Onkologii | Gianni L.,Istituto Nazionale dei Tumori | And 8 more authors.
Annals of Oncology | Year: 2013

Background: Pertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer. Patients and methods: Patients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms. Results: A total of 149 patients received either chemotherapy with pertuzumab (arm A, n = 74) or chemotherapy alone (arm B, n = 75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone. Conclusions: The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Gratchev A.,Blokhin Cancer Research Center | Gratchev A.,Tomsk State University
Immunobiology | Year: 2016

Tumour associated macrophages (TAM) represent an important component of tumour stroma. They develop under the influence of tumour microenvironment where transforming growth factor (TGF)β is frequently present. Activities of TAM regulated by TGFβ stimulate proliferation of tumour cells and lead to tumour immune escape. Despite high importance of TGFβ-induction of TAM activities till now our understanding of the mechanism of this induction is limited. We have previously developed a model of type 2 macrophages (M2) resembling certain properties of TAM. We established that in M2 TGFβRII is regulated on the level of subcellular sorting by glucocorticoids. Further studies revealed that in M2 with high levels of TGFβRII on the surface TGFβ activates not only its canonical Smad2/3-mediated signaling, but also Smad1/5-mediated signaling, what is rather typical for bone morphogenetic protein (BMP) stimulation. Complexity of macrophage populations, however, allows assumption that TGFβ signalling may function in different ways depending on the functional state of the cell. To understand the peculiarities of TGFβ signalling in human TAMs experimental systems using primary cells have to be developed and used together with the modern mathematical modelling approaches. © 2016 Elsevier GmbH.

Gilliam A.D.,University of Nottingham | Broome P.,Aphton Corporation | Topuzov E.G.,St. Petersburg State Medical Academy | Garin A.M.,Blokhin Cancer Research Center | And 6 more authors.
Pancreas | Year: 2012

OBJECTIVES: This study aimed to investigate G17DT, an immunogen producing neutralizing antibodies against the tumor growth factors amidated and glycine-extended forms of gastrin-17, in the treatment of pancreatic cancer. METHODS: A randomized, double-blind, placebo-controlled, group-sequential multicenter trial of G17DT in patients with advanced pancreatic cancer unsuitable for or unwilling to take chemotherapy. Inclusion criteria were a Karnofsky performance score of 60 or higher and a life expectancy of more than 2 months. Patients received G17DT or placebo emulsion at weeks 0, 1, 3, 24, and 52. The primary end point was survival, and secondary end points were tolerability, Karnofsky performance. RESULTS: A total of 154 patients were recruited: 79 G17DT and 75 placebo. A final analysis of the intention-to-treat population, using a proportional hazards model, stratifying by disease stage and adjusting for interim analysis, gave a hazard ratio for mortality of 0.75 (95% confidence interval, 0.51-1.10, P = 0.138; G17DT/placebo). A conventional analysis without adjustment for disease stage or interim analysis, censoring for chemotherapy and excluding protocol violators, gave median survival periods of 151 (G17DT) and 82 days (placebo) (log-rank test, P = 0.03).Patients developing anti-G17DT responses (73.8%) survived longer than nonresponders or those on placebo (median survival, 176 vs 63 vs 83; log-rank test, P = 0.003). G17DT was well tolerated. © 2012 Lippincott Williams & Wilkins, Inc.

Von Hoff D.D.,Translational Genomics Research Institute | Von Hoff D.D.,Virginia per Cancer Center | Ervin T.,Cancer Specialists | Arena F.P.,Arena Oncology Associates | And 20 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel- gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. Copyright © 2013 Massachusetts Medical Society.

Pandey S.,Stanford University | Ogloblina A.M.,Blokhin Cancer Research Center | Belotserkovskii B.P.,Stanford University | Dolinnaya N.G.,Moscow State University | And 3 more authors.
Nucleic acids research | Year: 2015

DNA sequences that can form unusual secondary structures are implicated in regulating gene expression and causing genomic instability. H-palindromes are an important class of such DNA sequences that can form an intramolecular triplex structure, H-DNA. Within an H-palindrome, the H-DNA and canonical B-DNA are in a dynamic equilibrium that shifts toward H-DNA with increased negative supercoiling. The interplay between H- and B-DNA and the fact that the process of transcription affects supercoiling makes it difficult to elucidate the effects of H-DNA upon transcription. We constructed a stable structural analog of H-DNA that cannot flip into B-DNA, and studied the effects of this structure on transcription by T7 RNA polymerase in vitro. We found multiple transcription blockage sites adjacent to and within sequences engaged in this triplex structure. Triplex-mediated transcription blockage varied significantly with changes in ambient conditions: it was exacerbated in the presence of Mn(2+) or by increased concentrations of K(+) and Li(+). Analysis of the detailed pattern of the blockage suggests that RNA polymerase is sterically hindered by H-DNA and has difficulties in unwinding triplex DNA. The implications of these findings for the biological roles of triple-stranded DNA structures are discussed. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

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