Here are 10 of our most important research papers published in peer-reviewed scientific journals.
Synergistic suppression of t(8;21)-positive leukemia cell growth by combining oridonin and MAPK1/ERK2 inhibitors. Spirin P, Lebedev T, Orlova N, Morozov A, Poymenova N, Dmitriev SE, Buzdin A, Stocking C, Olga K, Vladimir P. Oncotarget. 2017 Jun 16. doi: 10.18632/oncotarget.18503. IF: 5.168
Full text: http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=18503
In previous research we predicted that targeted therapy against AML2-ETO fused oncogene can be synergistically enhanced by using the MAP1/ERK2 inhibition. Here we showed that simultaneous inhibition of MAP1/ERK2 and AML2-ETO indeed works synergistically by strongly inhibiting the survival of the t(8;21) mutated leukemia cell. This article is the first published proof-of-concept that the algorithm (the foundation for Oncobox:Integral Test) may be used to design new efficient cancer target drugs and combination drug therapies.
VEGF blockade enhances the antitumor effect of BRAFV600E inhibition. Comunanza V, Corà D, Orso F, Consonni FM, Middonti E, Di Nicolantonio F, Buzdin A, Sica A, Medico E, Sangiolo D, Taverna D, Bussolino F. EMBO Molecular Medicine. 2016 Dec 14. pii: e201505774. IF: 8.7
Full text: http://embomolmed.embopress.org/content/early/2016/12/14/emmm.201505774.long
In this paper, we explore a combinatorial anti-VEGF and anti-V600E mutant BRAF treatment therapy on a mouse model. We show it provides substantial advantages compared to its single components taken individually. We applied our original algorithm to explain these synergistic effects and to identify molecular bases of the effects observed.
In silico Pathway Activation Network Decomposition Analysis (iPANDA) as a method for biomarker development. Ozerov IV, Lezhnina KV, Izumchenko E, Artemov AV, Medintsev S, Vanhaelen Q, Aliper A, Vijg J, Osipov AN, Labat I, West MD, Buzdin A, Cantor CR, Nikolsky Y, Borisov N, Irincheeva I, Khokhlovich E, Sidransky D, Camargo ML, Zhavoronkov A. Nature Communications. 2016 Nov 16;7:13427. doi: 10.1038/ncomms13427. IF: 11.3
Full text: http://www.nature.com/articles/ncomms13427
We publish here a variant of the OncoFinder pathway analysis utility tailored for the analysis of Affymetrix microarray gene expression data. The method termed “in silico Pathway Activation Network Decomposition Analysis” (iPANDA) combines precalculated gene coexpression data with gene importance factors based on the degree of differential gene expression and pathway topology decomposition for obtaining pathway activation scores.
A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation. Artem Artemov, Alexander Aliper, Michael Korzinkin, Ksenia Lezhnina, Leslie Jellen, Nicolay Zhukov, Sergey Roumiantsev, Nurshat Gaifullin, Alex Zhavoronkov, Nicolas Borisov, Anton Buzdin. Oncotarget. 2015 IF: 6.6
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745731/
Choosing the most effective personalized treatment remains a major challenge in oncology and is still largely trial and error. Here we published a novel approach for predicting target drug efficacy based on the gene expression signature of the individual tumor samples. To validate the method, we compared the distribution of predicted drug efficacy scores for five drugs and seven cancer types with the available clinical trials data for the respective cancer types and drugs. The percent of responders to a drug treatment correlated significantly with the percent of tumors showing high drug scores calculated with the current algorithm (Pearson's correlation 0.77, p = 0.02).
Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs. Larisa Venkova, Alexander Aliper, Maria Suntsova, Roman Kholodenko, Denis Shepelin, Nicolas Borisov, Galina Malakhova, Raif Vasilov, Sergey Roumiantsev, Alex Zhavoronkov, Anton Buzdin. Oncotarget. 2015 IF: 6.6
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694985/
Here, we compared the experimental data obtained by us and in the Genomics of Drug Sensitivity in Cancer (GDS) project for comparing responses to anticancer drugs, and transcriptomes of various cell lines. We assayed four blockbuster anticancer target drugs: sorafenib, pazopanib, sunitinib and temsirolimus, and 238 human cell lines. Using the OncoFinder-processed data on ~600 molecular pathways, we identified pathways showing significant correlation between pathway activation strength and response scores for these drugs. For most of these pathways, we generated molecular models of their interaction with known molecular target(s) of the respective drugs. For the first time, our study uncovered mechanisms underlying cancer cell response to drugs at the high-throughput molecular interatomic level.
Pathway Activation Strength (PAS) is a Novel Independent Prognostic Biomarker for Cetuximab Sensitivity in Colorectal Cancer Patients. Qingsong Zhu, Evgeny Izumchenko, Alexander Aliper, Evgeny Makarev, Keren Paz, Anton Buzdin, Alex Zhavoronkov, and David Sidransky. Human Genome Variation. (Nature Publishing Group) 2015.
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785572/
Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been shown to be active against colorectal cancer. However, there is no universal marker or method of clinical utility that could guide its treatment. Here, we demonstrate a method based on the OncoFinder algorithm to predict response to cetuximab in patients with colorectal cancer. The approach and models were validated using a clinical trial data set. Our approach could efficiently predict patients' response to cetuximab and thus holds promise as a selection criterion for cetuximab treatment in metastatic colorectal cancer.
Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways. K. Lezhnina, O. Kovalchuk, A.A. Zhavoronkov, M.B. Korzinkin, A.A. Zabolotneva, P.V. Shegay, D.G. Sokov, N.M. Gaifullin, I.G. Rusakov, A.M. Aliper, S.A., Roumiantsev, B.Y. Alekseev, N.M. Borisov, and A.A. Buzdin. Oncotarget, 2014, Oct 15;5(19):9022-32. IF: 6.6
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253415/
Here, for the first time, we applied OncoFinder for normal and malignant tissues to identify biomarkers of human bladder cancer. We calculated pathway activation strength values and identified signaling pathways that were regulated differently in bladder cancer tissues and in normal controls. We found 44 signaling pathways that serve as excellent new biomarkers of BC, supported by very good statistical characteristics. We conclude that the OncoFinder approach is highly efficient in finding new biomarkers for cancer. These markers are mathematical functions involving multiple gene products, which distinguishes them from "traditional" expression biomarkers that only assess concentrations of single genes.
Signaling pathway activation profiles make better markers of cancer than expression of individual genes. N.M. Borisov, N.V. Terekhanova, A.M. Aliper, L.S. Venkova, P.Yu. Smirnov, S.Roumiantsev, M.B. Korzinkin, A.A. Zhavoronkov, A.A. Buzdin. Oncotarget, 2014 Oct 30;5(20):10198-205 IF: 6.6
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259415/
Identification of reliable and accurate molecular markers of cancer remains a major challenge. Here, we showed that the pathway activation value itself may serve as the biomarker for cancer, and compared it with the "traditional" molecular markers based on the expression of individual genes. We applied OncoFinder to profile gene expression datasets for the nine human cancer types, totally for 292 cancer and 128 normal tissue samples. We profiled activation of 82 signaling pathways featuring ~2700 gene products. For all of the cancer types tested, the PAS values showed better area-under-the-curve (AUC) scores compared to the individual genes enclosing each of the pathways. These results evidence that the PAS values can be used as a new type of cancer biomarkers, superior to the traditional gene expression biomarkers.
Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling. Spirin PV, Lebedev TD, Orlova NN, Gornostaeva AS, Prokofjeva MM, Nikitenko NA, Dmitriev SE,Buzdin AA, Borisov NM, Aliper AM, Garazha AV, Rubtsov PM, Stocking C, Prassolov VS. Leukemia (Nature Publishing Group). 2014 Apr 14. doi: 10.1038/leu.2014.130. IF: 9.4
Link to the paper: http://www.nature.com/leu/journal/v28/n11/full/leu2014130a.html
The t(8;21) rearrangement represents the most common chromosomal translocation in acute myeloid leukemia (AML). It results in transcript encoding for the fusion protein AML1-ETO (AE). AE is considered to be an attractive target for treating t(8;21) leukemia. However, AE expression alone is insufficient to cause transformation, and thus the potential of such therapy remains unclear. Several genes are deregulated in AML cells, including KIT that encodes a key tyrosine kinase receptor. Here, we show that AML cells transduced with short hairpin RNA vector targeting AE mRNAs have a dramatic decrease in growth rate that is caused by induction of apoptosis and deregulation of the cell cycle. A reduction in KIT mRNA levels was also observed in AE-silenced cells and while silencing KIT expression reduced cell growth, it did not induce apoptosis. OncoFinder-based profiling of cells that escape cell death revealed activation of a number of signaling pathways involved in survival and proliferation. In particular, we find that the MAPK1 protein could mediate activation of 23 out of 29 (79%) of these upregulated pathways and thus may be regarded as the key player in establishing the t(8;21)-positive leukemic cells resistant to AE suppression.
OncoFinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data. Buzdin AA, Zhavoronkov AA, Korzinkin MB, Venkova LS, Zenin AA, Smirnov PY, Borisov NM. Frontiers in Genetics. 2014 Mar 25;5:55. doi: 10.3389/fgene.2014.00055.
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971199/
In this paper, we propose a biomathematical algorithm OncoFinder for both quantitative and qualitative analysis of the intracellular signaling pathway activation. This method may be used for the analysis of any physiological, stress, malignancy or other perturbed conditions at the molecular level. In contrast with other existing techniques for aggregation and generalization of gene expression data for individual samples, we suggest distinguishing the positive/activator and negative/repressor role of every gene product in each pathway.
Show all relevant publications of our team
Here for the first time we provide a triple-validated gene expression signature of MYCN-amplified neuroblastomas. We built the first molecular pathway crosslinking the top featured genes and validated it on the two biggest published datasets of neuroblastoma gene expression profiles and on the clinical material profiled by microarrays.
Gene expression and molecular pathway activation signatures of MYCN-amplified neuroblastomas. Petrov I., Suntsova M., Ilnitskaya E., Roumiantsev S., Sorokin M., Garazha A., Spirin P., Lebedev T., Gaifullin N., Larin S., Kovalchuk O., Konovalov D., Prassolov V., Roumiantsev A., Buzdin A. Oncotarget. 2017 (In press) IF: 5.168
Friends-Enemies: Endogenous Retroviruses Are Major Transcriptional Regulators of Human DNA. Buzdin AA, Prassolov V, Garazha AV. Front Chem. 2017 Jun 8;5:35. doi: 10.3389/fchem.2017.00035. IF: 3.994
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462908/
We review here current knowledge on human gene expression regulation by endogenous retroviruses and their role in human pathology, including cancer.
In this paper, we applied the OncoFinder algorithm to uncover a previously unknown mechanism of STING activation in T-cells. STING is an intracellular molecular sensor of foreign DNA. We found that unlike its mechanisms of action in the other cell types, in T-cells, internal STING activation results in interferon responses and cell death.
Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death. Larkin B, Ilyukha V, Sorokin M, Buzdin A, Vannier E, Poltorak A. J Immunol. 2017 Jun 14. doi: 10.4049/jimmunol.1601999. IF: 4.922
Differentially expressed proteins in glioblastoma multiforme identified with a nanobody-based anti-proteome approach and confirmed by OncoFinder as possible tumor-class predictive biomarker candidates. Jovčevska I, Zupanec N, Urlep Ž, Vranič A, Matos B, Stokin CL, Muyldermans S, Myers MP, Buzdin AA, Petrov I, Komel R. Oncotarget. 2017 Apr 24. doi: 10.18632/oncotarget.17390. IF: 5.168
Full text: https://www.ncbi.nlm.nih.gov/pubmed/28498803
Based on the differential proteomics techniques and bioinformatic analysis, we identified novel gene product network as a potential biomarker of glioblastoma progression.
Here we applied the OncoFinder algorithm to investigate for the first time the effects of surgical portal vein embolization at the molecular level. The molecular pathway activation profiles evidenced that at least in mice, the temporary portal vein embolization was as active as the permanent vein embolization in terms of intracellular signaling.
Temporary portal vein embolization is as efficient as permanent portal vein embolization in mice. Wirsching A, Melloul E, Lezhnina K, Buzdin AA, Ogunshola OO, Borger P, Clavien PA, Lesurtel M. Surgery. 2017 Apr 13 IF: 3.904
Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells. Petrov I, Suntsova M, Mutorova O, Sorokin M, Garazha A, Ilnitskaya E, Spirin P, Larin S, Kovalchuk O, Prassolov V, Zhavoronkov A, Roumiantsev A, Buzdin A. Aging (Albany NY). 2016 Nov 19;8(11):2936-2947. IF: 3.98
Full text: http://www.aging-us.com/full/8/2936
We show here that there are more differences than similarities between adult and pediatric forms of acute myeloid leukemia (AML). These findings suggest that adult and pediatric AML may require very different treatment strategies, which is not the standard of care now. The OncoFinder analysis also predicts that a target drug Bortezomib currently in use for various AML subtypes may be especially efficient against drug-resistant pediatric acute lymphoblast leukemia (ALL).
Early stage of cytomegalovirus infection suppresses host microRNA expression regulation in human fibroblasts. Anton A. Buzdin, Alina V. Artcibasova, Natalya F. Fedorova, Maria V. Suntsova, Andrew V. Garazha, Maxim I. Sorokin, Daria Allina, Mikhail Shalatonin, Nikolay M. Borisov, Alex A. Zhavoronkov, Igor Kovalchuk, Olga Kovalchuk & Alla A. Kushch. Cell Cycle. 2016 Dec 16;15(24):3378-3389. doi: 10.1080/15384101.2016.1241928. IF: 4.0
Link to the article: https://www.ncbi.nlm.nih.gov/pubmed/28051642
Using the OncoFinder-based approach MIRImpact, we demonstrate that human cytomegaloviral (HCMV) infection at the earliest stages results in a paralysis of cellular microRNA expression. These data suggest new functions for HCMV gene products.
In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aliper A, Belikov AV, Garazha A, Jellen L, Artemov A, Suntsova M, Ivanova A, Venkova L, Borisov N, Buzdin A, Mamoshina P, Putin E, Swick AG, Moskalev A, Zhavoronkov A. Aging (Albany NY). 2016 Sep 24;8(9):2127-2152. , doi: 10.18632/aging.101047 IF: 3.98
Full text: http://www.aging-us.com/full/8/2127
Here we apply OncoFinder and its variant GeroScope to identify geroprotector molecules preventing human pluripotent fibroblast cultures from senescence. Among the predicted hits, six top molecules were tested on human cell cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties. This work serves as a proof-of-concept for the OncoFinder method in streamlining drug prediction, repurposing and personalized medicine.
Common pathway signature in lung and liver fibrosis. Makarev E, Izumchenko E, Aihara F, Wysocki PT, Zhu Q, Buzdin A, Sidransky D, Zhavoronkov A, Atala A. Cell Cycle. 2016 Jul 2;15(13):1667-73. PMID: 27267766. IF: 4.0
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957589/
Here we applied OncoFinder to elucidate molecular mechanisms governing the development of lung and liver fibrosis. In both tissues, our analysis detected major conserved signaling pathways strongly associated with fibrosis, suggesting that some of the pathways identified may be attractive targets for future therapeutic interventions.
MiRImpact, a new bioinformatic method using complete microRNA expression profiles to assess their overall influence on the activity of intracellular molecular pathways. Artcibasova AV, Korzinkin MB, Sorokin MI et al. Cell Cycle. 2016. 15:689-698. doi: 10.1080/15384101.2016.1147633. IF: 5.0
Full text: http://www.tandfonline.com/doi/full/10.1080/15384101.2016.1147633
MicroRNAs (miRs) are short noncoding RNA molecules that regulate expression of target mRNAs. Here we propose a new technique, MiRImpact, which enables the linking of miR expression data with its estimated outcome on the regulation of molecular pathways, including signaling, metabolic, cytoskeleton rearrangement, and DNA repair. MiRImpact uses OncoFinder rationale for pathway activity calculations. MiRImpact operates with 2 types of databases: for molecular targets of miRs and for gene products that play a role in molecular pathways. We applied MiRImpact to compare regulation of bladder cancer-specific signaling pathways at the levels of mRNA and miR expression. This method has unparalleled robustness and feasibility.
Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells. Alexandrova E, Nassa G, Corleone G, Buzdin A, Aliper AM, Terekhanova N, Shepelin D, Zhavoronkov A, Tamm M, Milanesi L, Miglino N, Weisz A, Borger P. Oncotarget. 2016 Feb 5. doi: 10.18632/oncotarget.7209. IF: 6.6
Full text: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path=7209&pubmed-linkout=1
Bronchial smooth muscle (BSM) cells from asthmatic patients maintain in vitro a distinct hyper-reactive ("primed") phenotype, characterized by increased release of pro-inflammatory factors and mediators, as well as hyperplasia and/or hypertrophy. In this paper, we applied OncoFinder to identify signalling pathways in cultured primary BSMs of asthma patients and non-asthmatic subjects. Comprehensive pathway activation analysis revealed that at least 103 pathways clearly characterize BSM cells of asthmatic individuals (p<0.01). We identified 7 clusters of coherently acting pathways functionally related to the disease, with pathways down-regulated in asthma mostly covering cell death-promoting processes and up-regulated ones affecting cell growth and proliferation, inflammatory response, control of smooth muscle contraction and hypoxia-related signalization. These first-time results can be exploited in the development of novel therapeutic strategies targeting pathway signatures linked to asthma pathophysiology.
Balance between short and long isoforms of cFLIP regulates Fas-mediated apoptosis in vivo. Ram DR, Ilyukha V, Volkova T, Buzdin A, Tai A, Smirnova I, Poltorak A. Proc Natl Acad Sci U S A (PNAS). 2016 Jan 21. pii: 201517562. PMID: 26798068 IF: 9.8
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760830/
Here, using the OncoFinder molecular pathway analysis tool, we discovered a model of resistance to Fas receptor-mediated liver failure in a mouse model. cFLIP, an inhibitor of apoptosis, is a crucial regulator of cellular death by apoptosis and necroptosis; its importance in development is exemplified by the embryonic lethality in cFLIP-deficient animals. A homolog of caspase 8 (CASP8), cFLIP exists in two main isoforms: cFLIPL (long) and cFLIPR (short). Although both regulate death receptor (DR)-induced apoptosis by CASP8, the specific role of each isoform was poorly understood. We identified a 21-bp insertion in the 3' UTR that influences differential splicing of cFLIP mRNA. Intriguingly, we observed that MSM liver cells predominantly express the FLIPL variant, in contrast to B6 liver cells, which have higher levels of cFLIPR. Genome-wide RNA sequencing revealed a relative abundance of FLIPL transcripts in MSM hepatocytes whereas B6 liver cells had significantly more FLIPR mRNA. Importantly, we show that, in the liver, CASP8 is present exclusively as its cleaved p43 product, bound to cFLIPL. Because of partial enzymatic activity of the heterodimer, it might prevent necroptosis. On the other hand, it prevents cleavage of CASP8 to p10/20 necessary for cleavage of caspase 3 and, thus, apoptosis induction. Therefore, hepatocytes are predisposed for protection from DR-mediated cell death.
Receptor tyrosine kinase KIT can regulate the expression of genes involved in spontaneous regression of neuroblastoma. T. D. Lebedev, P. V. Spirin, M. V. Suntsova, A. V. Ivanova, A. A. Buzdin, M. M. Prokofjeva, P. M. Rubtsov, V. S. Prassolov. Molecular Biology. November 2015, Volume 49, Issue 6, pp 943-945 IF 0.6
Link to the article: https://www.ncbi.nlm.nih.gov/pubmed/26710790
In this paper, using the OncoFinder database of pathways and protein interactions, we propose models of a receptor tyrosine kinase receptor KIT –based control of the fate of human neuroblastoma cells and of the spontaneous regression of this tumor.
Molecular functions of human endogenous retroviruses in health and disease. Suntsova M, Garazha A, Ivanova A, Kaminsky D, Zhavoronkov A, Buzdin A. Cellular and Molecular Life Sciences. 2015 Jun 18. IF 5.8
Link to the article: http://link.springer.com/article/10.1007%2Fs00018-015-1947-6
Human endogenous retroviruses (HERVs) form 504 distinct families and occupy ~8% of the human genome. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Our recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs and on their implications in human evolution, normal physiology and disease.
New bioinformatic tool for quick identification of functionally relevant endogenous retroviral inserts in human genome. A.Garazha, A.Ivanova, M.Suntsova, G.Malakhova, S.Roumiantsev, A.Zhavoronkov, A. Buzdin. Cell Cycle. 2015 Apr 8:0. IF: 5.0
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612461/
Here, we performed a genome-wide identification of human Endogenous retroviruses (ERVs) containing transcription factor binding sites (TFBS) according to the ENCODE project. We created the first interactive ERV database that groups the individual inserts according to their familial nomenclature, number of mapped TFBS and divergence from their consensus sequence. Information on any particular element can be easily extracted by the user. We also created a genome browser tool, which enables quick mapping of any ERV insert according to genomic coordinates, known human genes and TFBS. These tools can be used to easily explore functionally relevant individual ERVs and for studying their impact on the regulation of human genes.
Screening and personalizing nootropic drugs and cognitive modulator regimens in silico. Jellen LC, Aliper A, Buzdin A, Zhavoronkov A. Front Syst Neurosci. 2015 Feb 6;9:4. doi: 10.3389/fnsys.2015.00004. eCollection 2015.
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319391/
We propose here an OncoFinder platform-based method for in silico screening of novel putative cognitive enhancers followed by high-throughput in vivo and in vitro validation. The method uses gene expression data to evaluate activated and suppressed signaling pathways in tissues or neurons of the cognitively enhanced brain. An algorithm maps expression data onto molecular pathways and quantifies their individual activation strength. The collective pathways and their activation form (the signaling pathway cloud) are a biological fingerprint of cognitive enhancement. Drugs can then be screened and ranked based on their ability to minimize, mimic, or exaggerate pathway activation or suppression within that cloud. Using this approach, one may predict the efficacy of drugs that may enhance various aspects of cognition to increase effectiveness of costly preclinical studies and clinical trials.
Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells. Alexander Aliper, Antonei Benjamin Csoka, Anton Buzdin, Tomasz Jetka, Sergey Roumiantsev, Alexey Moskalev, Alex Zhavoronkov. Aging (Albany NY). 2015, IF: 5.1
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350323/
In this paper, we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using a variant of the OncoFinder pathway analysis platform, we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also point to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.
Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Moskalev A, Chernyagina E, de Magalhães JP, Barardo D, Thoppil H, Shaposhnikov M, Budovsky A, Fraifeld VE, Garazha A, Tsvetkov V, Bronovitsky E, Bogomolov V, Scerbacov A, Kuryan O, Gurinovich R, Jellen LC, Kennedy B, Mamoshina P, Dobrovolskaya E, Aliper A, Kaminsky D, Zhavoronkov A. Aging (Albany NY). 2015 Sep;7(9):616-28.
Full text: http://www.aging-us.com/full/7/616
Here, we introduce the first public, rapidly searchable database that catalogues over 250 experiments involving over 200 known or candidate geroprotectors that extend lifespan in model organisms (http://geroprotectors.org). Each compound has a comprehensive profile complete with biochemistry, mechanisms, and lifespan effects in various model organisms, along with information ranging from chemical structure, side effects, and toxicity to FDA drug status. These are presented in a visually intuitive, efficient framework fit for casual browsing or in-depth research alike. Links are provided to the source studies or databases, providing quick and convenient access to original data. The Geroprotectors database facilitates
Pathway activation profiling reveals new insights into Age-related Macular Degeneration and provides avenues for therapeutic interventions. Makarev E, Cantor C, Zhavoronkov A, Buzdin A, Aliper A, Csoka AB. Aging (Albany NY). 2014 Dec 27. [Epub ahead of print] IF: 5.1
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298366/
Age-related macular degeneration (AMD) is a major cause of blindness in older people and is caused by loss of the central region of the retinal pigment epithelium (RPE). We developed a new OncoFinder algorithm-based software program, "AMD Medicine", and discovered differential pathway activation profiles in samples of human RPE/choroid from AMD patients and controls. We found 29 differential pathways in RPE-choroid AMD phenotypes. In AMD, we identified a graded activation of pathways related to wound response, complement cascade, and cell survival. Also, there was downregulation of two pathways responsible for apoptosis. Furthermore, significant activation of pro-mitotic pathways is consistent with dedifferentiation and cell proliferation events, which occur early in the pathogenesis of AMD. Significantly, we discovered new global pathway activation signatures of AMD involved in the cell-based inflammatory response: IL-2, STAT3, and ERK.
Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer. Aliper AM, Frieden-Korovkina VP, Buzdin A, Roumiantsev SA, Zhavoronkov A. Oncotarget 2014, Sep 16. IF: 6.6
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294358/
In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)-tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. The mechanisms that facilitate such infiltration or a subsequent immune suppression are so far poorly understood. In this study, we aimed to delineate disparate molecular pathways, which MDSC utilize in murine models of colon or breast cancer. Using OncoFinder-based pathways enrichment analysis, we completed interactome maps of multiple signaling pathways in MDSC from spleens and tumor infiltrates of mice with c26GM colon cancer and tumor infiltrates of MDSC in 4T1 breast cancer. In both models, infiltrating MDSC, but not CD11b+ splenic cells, have been found to be enriched in multiple signaling molecules suggestive of their enhanced proliferative and invasive phenotypes. The interactome data has been subsequently used to reconstruct a previously unexplored regulation of MDSC cell cycle by the c-myc transcription factor which was predicted by the analysis. Thus, this study represented a first interactome mapping of distinct multiple molecular pathways whereby MDSC sustain cancer progression.
The OncoFinder algorithm for minimizing the errors introduced by the high-throughput methods of transcriptome analysis. Anton A. Buzdin, Alex A. Zhavoronkov, Mikhail B. Korzinkin, Sergey A. Roumiantsev, Alexander M. Aliper, Larisa S. Venkova, Philip Y. Smirnov and Nikolay M. Borisov. Frontiers in Molecular Biosciences, 26 August 2014 | doi: 10.3389
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428387/
The diversity of the experimental platforms used for high-throughput profiling of gene expression make it a virtually impossible obstacle to compare the gene expression datasets obtained using the different methods. Recently, we proposed a new concept of signalome-wide analysis, termed OncoFinder. In this study, we show that the OncoFinder method significantly reduces the errors introduced by transcriptome-wide experimental techniques. We compared the gene expression data for the same biological samples obtained by both the next generation sequencing (NGS) and microarray methods. We demonstrate that there is virtually no correlation between the initial gene expression values for all datasets analyzed. In contrast, when the OncoFinder algorithm is applied to the data, we detected clear-cut correlations between the NGS and microarray gene expression datasets, thus allowing for the platform-agnostic analytical applications. We conclude that this feature of the OncoFinder enables characterization of the functional states of the transcriptomes and interactomes more accurately than before, which makes OncoFinder a method of choice for many applications including genetics, physiology, biomedicine, and molecular diagnostics.
Stimulation of Cell Proliferation by Carnosine: Cell and Transcriptome Approaches. K. S. Vishnyakova, M. A. Babizhayev, A. M. Aliper, A. A. Buzdin, A. V. Kudryavzeva, and Y. E. Yegorov. Molecular Biology, 2014, Vol.48, No5, 718-726 IF: 0.7
Link to the paper: https://www.ncbi.nlm.nih.gov/pubmed/25842868
Concentration of endogenous dipeptide carnosine in human muscle tissue reaches tens of millimoles. For over 100 years, a lot of data concerning carnosine functions has accumulated, among which anti-aging effects are regarded most important. Here, the effect of carnosine in cell cultures was studied. This study finds that apart from the known action-an increase of the Hayflick limit and morphological rejuvenation, carnosine stimulates cell division in colony-forming assays and during transition of cells to the quiescent state. The analysis of the gene expression performed using the OncoFinder tool, showed that carnosine-induced changes are mainly related to positive regulation of the cell cycle at all levels, from the onset of the DNA synthesis to chromosome condensation.
A role for G-CSF and GM-CSF in nonmyeloid cancers Aliper AM, Frieden-Korovkina VP, Buzdin A, Roumiantsev SA, Zhavoronkov A. Cancer Medicine. 2014 Aug;3(4):737-46. doi: 10.1002/cam4.239. Epub 2014 Apr 2.
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303143/
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) modulate progression of solid tumors. Rapid diagnostic tools to differentiate G-CSF- or GM-CSF-secreting cancers are not well developed, which hinders efforts to individualize treatments for these patients. Given an increasing utilization of adjuvant G-/GM-CSF in cancer therapy, we summarized recent studies exploring their roles in pathophysiology of solid tumors and provided insights into some complexities of their therapeutic applications.
Signaling pathway cloud regulation for in silico screening and ranking of the potential geroprotective drugs. Zhavoronkov A, Buzdin AA, Garazha AV, Borisov NM, Moskalev AA. Frontiers in Genetics. 2014 Mar 3;5:49. doi: 10.3389/fgene.2014.00049.
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940060/
We propose the OncoFinder algorithm-based in silico method for screening and ranking the possible geroprotector molecules followed by the high-throughput in vivo and in vitro validation. The proposed method evaluates the changes in the collection of activated or suppressed signaling pathways involved in aging and longevity, termed signaling pathway cloud, constructed using the gene expression data and epigenetic profiles of young and old patients' tissues. The possible interventions are selected and rated according to their ability to regulate age-related changes and minimize differences in the signaling pathway cloud.
Genetics and epigenetics of aging and longevity. Moskalev AA, Aliper AM, Smit-McBride Z, Buzdin A, Zhavoronkov A. Cell Cycle. 2014 Apr 1;13(7):1063-77. doi: 10.4161/cc.28433. Epub 2014 Mar 6. IF: 4.99
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013158/
Evolutionary theories of aging predict the existence of certain genes that provide selective advantage early in life with adverse effect on lifespan later in life or longevity insurance genes. Indeed, the study of human and animal genetics is gradually identifying new genes that increase lifespan when overexpressed or mutated: gerontogenes. Furthermore, genetic and epigenetic mechanisms are being identified that have a positive effect on longevity. The gerontogenes are classified as lifespan regulators, mediators, effectors, housekeeping genes, genes involved in mitochondrial function, and genes regulating cellular senescence and apoptosis. In this review we demonstrate that the majority of the genes as well as genetic and epigenetic mechanisms that are involved in regulation of longevity are highly interconnected and related to stress response.
A systematic experimental evaluation of microRNA markers of human bladder cancer. Zabolotneva AA, Zhavoronkov AA, Shegay PV, Gaifullin NM, Alekseev BY, Roumiantsev SA, Garazha AV, Kovalchuk O, Aravin A, Buzdin AA. Frontiers in Genetics. 2013 Nov 15;4:247. doi: 10.3389/fgene.2013.00247.
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828615/
In this study, we reported the first comprehensive database of miRNA markers of human bladder cancer. For the first time, we validated the reported data on the entire set of published differential microRNAs (miRs), 102 in total, through a series of transcriptome-wide experiments. We have conducted genome-wide miR profiling in urothelial carcinoma tissues and in nine normal bladder samples using three experimental methods: (1) An Illumina HT-12 microarray hybridization (MA) analysis (2) a suppression-subtractive hybridization (SSH) assay followed by deep sequencing (DS) and (3) DS alone. We show that DS data correlate with previously published information in 87% of cases, whereas MA and SSH data have far smaller correlations with the published information (6 and 9% of cases, respectively). qRT-PCR tests confirmed reliability of the DS data. Based on our data, MA and SSH data appear to be inadequate for studying differential miRNA expression in the bladder.
Characteristic patterns of microRNA expression in human bladder cancer. Zabolotneva AA, Zhavoronkov A, Garazha AV, Roumiantsev SA, Buzdin AA. Frontiers in Genetics. 2013 Jan 4;3:310. doi: 10.3389/fgene.2012.00310. eCollection 2012.
Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539722/
MicroRNAs (miRNAs) represent promising diagnostic and prognostic molecular biomarkers and also serve as novel therapeutic targets. We performed a systematic analysis of scientific reports that link differences in miRNA expression with the pathogenesis of bladder cancer (BC). This literature review is the first comprehensive database of miRNA molecules with biased expression profiles in BC. In addition, we discuss the possible roles of differentially expressed miRNAs in the regulation of intracellular signaling pathways in BC.
Metastatic tumor case studies
OncoBox team report on ASCO 2017: http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.e23142
Activation of intracellular signaling pathways is the new type of biomarkers for selection of target anticancer drugs
Anticancer target drugs (ATDs) specifically bind and inhibit molecular targets that play important roles in tumorigenesis. More than 150 different ATDs have been approved for clinical use worldwide, and the clinicians are faced with the problem of choosing the best therapeutic solution for each patient. The problem of efficient ATD selection remains largely unsolved and personalized approaches are needed to select the best ATD candidates for individual patients.
We propose a new approach termed OncoFinder. It is based on digesting gene expression profiles for the analysis of activation of intracellular signalling pathways as a marker for the selection of target therapies. The original bioinformatic algorithms were integrated with the databases featuring molecular drug targets, compositions of signalling pathways, including the functional role of each gene product, for more than 1700 pathways (Buzdin, Front.Genet 2014; Ozerov, Nature Communications 2016).
We showed that pathway activation strengths are more stable and reliable biomarkers of cancer than the expressions of individual genes. OncoFinder allows to detect changes at the level of pathway activation and to predict the effectiveness of drugs based on the knowledge of their molecular targets. We applied it to find new biomarkers of clinical response to the ATD cetuximab; for modelling the combined chemotherapy of acute myeloid leukemia and combined anti-VEGF/BRAF therapy of melanoma. For two unrelated datasets obtained for colon cancer patients before treatment with the ATD bevacizumab, we were able to distinguish between those who responded to treatment and not (p<0.01). We next assayed biopsies for kidney cancer patients with known responses to the ATD sorafenib. The responders and non-responders showed a significant difference (p=0.02). Finally, the OncoFinder platform was prospectively used for decision making support to patients with advanced metastatic solid tumors (n=23). The efficiency of the ATD treatment was 61% (complete + partial response, RECIST).
Conclusions: OncoFinder method may be effective for predicting response to ATD based on gene expression profiles.