Bazhanova E.D.,RAS Sechenov Institute of Evolutionary Physiology and Biochemistry |
Anisimov V.N.,Petrov Research Institute of Oncology
Doklady Biochemistry and Biophysics | Year: 2016
For the firsts time, the involvement of the STAT pathway in the regulation of neuronal apoptosis in physiological aging and in old mice overexpressing the HER-2/neu oncogene was studied. We showed that suppression of STAT3, STAT5, and STAT6 and overexpression of the proapoptotic factor STAT1, which provides p53-mediated apoptosis, are the causes for increasing the number of apoptotic neurons in physiological aging. HER-2 tyrosine kinase receptor overexpression promotes neuronal survival through activation of STAT-signaling pathway with simultaneous suppression of the proapoptotic factor STAT1. © 2016, Pleiades Publishing, Ltd.
Baselga J.,Harvard University |
Baselga J.,SOLTI Breast Cancer Research Group |
Bradbury I.,Frontier Science Scotland |
Bradbury I.,Queen's University of Belfast |
And 28 more authors.
The Lancet | Year: 2012
Background: The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. Methods: In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/m 2, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m 2) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. Findings: 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3; 95 CI 43·1-59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5; 22·4-37·5]; difference 21·1, 9·1-34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7, 18·1-32·3]) and the trastuzumab (difference -4·8, -17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4]) and lapatinib plus trastuzumab (32 [21·1]) than with trastuzumab (three [2·0]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5]) and lapatinib plus trastuzumab (15 [9·9]) than with trastuzumab (11 [7·4]). Interpretation: Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. Funding: GlaxoSmithKline. © 2012 Elsevier Ltd.
Long G.V.,University of Sydney |
Long G.V.,Materials Hospital |
Stroyakovskiy D.,Moscow City Oncology Hospital |
Gogas H.,National and Kapodistrian University of Athens |
And 32 more authors.
The Lancet | Year: 2015
Background Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. Funding GlaxoSmithKline. © 2015 Elsevier Ltd.
Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): Results of a phase 3, open-label, randomised trial
Grob J.J.,Aix - Marseille University |
Amonkar M.M.,Glaxosmithkline |
Karaszewska B.,Przychodnia Lekarska Komed |
Schachter J.,Sheba Medical Center |
And 21 more authors.
The Lancet Oncology | Year: 2015
Background: In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. Methods: COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. Findings: From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7.92, 7.62, 6.86, 7.47, 5.16, 7.56, and 7.57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0.001 for all assessments except p=0.005 at week 40), EORTC QLQ-C30 pain (-13.20, -8.05, -8.82, -12.69, -12.46, -11.41, and -10.57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0.001), EQ-5D thermometer scores (7.96, 8.05, 6.83, 11.53, 7.41, 9.08, and 10.51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0.001 for all assessments except p=0.006 at week 32), and FACT-M Melanoma Subscale score (3.62, 2.93, 2.45, 3.39, 2.85, 3.00, and 3.68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0.001). Interpretation: From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population. Funding: GlaxoSmithKline. © 2015 Elsevier Ltd.
Gianni L.,San Raffaele Institute |
Dafni U.,National and Kapodistrian University of Athens |
Gelber R.D.,Dana-Farber Cancer Institute |
Azambuja E.,Free University of Colombia |
And 20 more authors.
The Lancet Oncology | Year: 2011
Background: Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings: The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3% vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation: Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. Funding: F Hoffmann-La Roche, Michelangelo Foundation. © 2011 Elsevier Ltd.
Mikhaleva I.I.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry |
Prudchenko I.A.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry |
Ivanov V.T.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry |
Voitenkov V.B.,Petrov Research Institute of Oncology
Peptides | Year: 2011
Delta sleep inducing peptide (WAGGDASGE, DSIP) is a well known multifunctional regulatory peptide. Numerous studies have confirmed its stress-protective and adaptive activity which is independent of the origin or nature of the stress or other harmful factors. However, the biosynthetic origin of DSIP remains obscure, since nothing is known of its protein precursor(s) and their encoding gene(s). We have performed a comprehensive analysis of available gene and protein databases for homologous peptide sites within mammalian resources including man. A family of Jumonji C (JmjC)-domain-containing histone demethylases was shown to contain a sequence fragment closely homologous to DSIP. One type of these ubiquitous and phylogenetically ancient proteins encoded by JMJD1B gene includes the WKGGNASGE sequence that differs from DSIP by only 2 amino acid residues in positions 2 and 5. The respective peptide was synthesized and its biological effects were evaluated in a preliminary way in the forced swimming and antitoxic tests. We suggest that the histone demethylases of the JmjC-group containing DSIP-related region can be considered as possible protein precursors of endogenous peptides with DSIP-like activity. © 2011 Elsevier Inc.
Anisimov V.N.,Petrov Research Institute of Oncology |
Zharinov G.M.,The Surgical Center
Advances in Gerontology | Year: 2014
This article presents data on the average age of death (AAD) of 49064 representatives of different creative professions: visual artists (painters, sculptors, and architects, n = 8458), musicians (composers, conductors, singers, pianists, violinists, organists, etc., n = 7883), literary people (poets and writers, n = 11 488), and academics (n = 21 235). The AAD of literary people was significantly (p < 0.001) less than the age of death of artists, musicians, and scientists, while scientists lived longer than the other categories (p < 0.001). Females of any of the investigated professions lived significantly longer than males (p < 0.02). Analysis of the dynamics of the AAD from the 1st century before the Christian Era until the end of the 20th century showed that the AAD of representatives of various professions gradually but unevenly increased. Artists and males born after 1900 lived significantly longer (p < 0.001) than in previous historical periods. The AAD of scientists of both sexes who were born after 1900 was significantly higher (p < 0.002) in comparison with scientists who lived in the 19th century (p < 0.001). The first five places for life span among males are occupied by Nobel laureates (78.8 years), academics (72.7 years), corresponding members of the RAS (71.7 years), conductors (71.1 years), and scientists (71.0 years). Rock musicians have shorter lives than other people, 43.6 years, bards lived 53.6 years, and poets, 61.6 years. Among females, the first five places for AAD are occupied by conductors (83.2 years), harpists (80.9 years), RAS academics (80.3 years), harpsichordists (79.1 years) and violinists (78.2 years). Females who devote themselves to rock music (37.6 years), to author's songs (51.4 years), and to playing wind instruments (59.0 years) had shorter lives than other females. Females are far ahead of males in the relative number of oldest old persons (90+ years). The first five places are occupied by harpists (43.75%), conductors (33.33%), architects (29.17%), violinists and cellists (20%), and sculptors (18.99%). The top five positions among oldest old persons for males involve Nobel laureates (16.67%), conductors (12.12%), members of the RAS (7.51%), violinists (7.44%), and scientists (7.0%). The centenary line was crossed by 8.33% of the female academics and architects, 6.25% of the harpists, and 4.22% of the poets who wrote prose. Among men, the proportion of centenarians was smaller: pianists, 0.76%; scientists, 0.45%; and violinists, 0.42%. These data confirm the view that high intelligence and education directly correlate with long life span and longevity. © 2014 Pleiades Publishing, Ltd.
Parkhitko A.A.,Harvard University |
Favorova O.O.,Russian National Research Medical University |
Khabibullin D.I.,Harvard University |
Anisimov V.N.,Petrov Research Institute of Oncology |
Henske E.P.,Harvard University
Biochemistry (Moscow) | Year: 2014
Serine/threonine protein kinase mTOR regulates the maintenance of cellular homeostasis by coordinating transcription, translation, metabolism, and autophagy with availability of amino acids, growth factors, ATP, and oxygen. The mTOR kinase is a component of two protein complexes, mTORC1 and mTORC2, which are different in their composition and regulate different cellular processes. An uncontrolled activation of the mTOR kinase is observed in cells of the majority of tumors, as well as in diabetes and neurodegenerative and some other diseases. At present, inhibitors of the kinase complex mTORC1 are undergoing clinical trials. This review focuses on different aspects of the regulation of the mTORC1 and mTORC2 complexes, on their role in the regulation of protein synthesis, metabolism, and autophagy, as well as on using mTOR inhibitors for treatment of tumors and slowing of aging. © 2014 Pleiades Publishing, Ltd.
Berstein L.M.,Petrov Research Institute of Oncology
Advances in Gerontology | Year: 2011
When we speak of major noncommunicable diseases (NCDs), we mean, in the first place, cardiovascular (ischemic heart disease, hypertension) and cerebrovascular (stroke) pathologies, malignant tumors, and chronic nonspecific respiratory (pneumonic) diseases and diabetes mellitus, ascribing to them, respectively, 25-30, 13.7 and 2% of the mortality that world statistics recorded in the early 2010s . Guided by the core of the problem, but not by mortality rates , we should also class in the NCD group such diseases as osteoporosis, unipolar depression, and obesity . According to the domestic statistical data on oncology (15, 16, 21) and the cancer registries of the United States , summary morbidity due to neoplasms of hormone-dependent tissues make up nearly 35-45% of all cancer-related cases. The last few decades were characterized by pronounced demographic changes and more insistent projections of a growing share of major noncommunicable diseases, including cancer [65, 79]. Therefore, attempts to understand the place of hormone-dependent malignant tumors among other human NCDs and analyze the interrelations between the former and the latter in their age-specific aspect are regarded as a vital task for contemporary oncoendocrinology. Although major human chronic diseases are mainly diagnosed in the second half of life, their hormone-metabolic base begins to form many decades before the clinical manifestations of the related pathological processes and does not always demonstrate an obvious picture of associations with individual diseases in this group. The latter may serve as an explanation for the absence of parallelism in the frequency of these diseases, in particular, in the final stage of ontogenesis. © Pleiades Publishing, Ltd., 2011.
Long G.V.,University of Sydney |
Stroyakovskiy D.,Moscow City Oncology Hospital 62 |
Gogas H.,National and Kapodistrian University of Athens |
Levchenko E.,Petrov Research Institute of Oncology |
And 29 more authors.
New England Journal of Medicine | Year: 2014
Results The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib- trametinib group. Conclusions A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.Background Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.Methods In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. © 2014 Massachusetts Medical Society. All rights reserved.