Precision medicine driven by cancer systems biology

Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Integrating structure to protein-protein interaction networks that drive metastasis to brain and lung in breast cancer

Blocking specific protein interactions can lead to human diseases. Accordingly, protein interactions and the structural knowledge on interacting surfaces of proteins (interfaces) have an important role in predicting the genotype-phenotype relationship. We have built the phenotype specific sub-networks of protein-protein interactions (PPIs) involving the relevant genes responsible for lung and brain metastasis from primary tumor in breast cancer. First, we selected the PPIs most relevant to metastasis causing genes (seed genes), by using the “guilt-by-association” principle. Then, we modeled structures of the interactions whose complex forms are not available in Protein Databank (PDB). Finally, we mapped mutations to interface structures (real and modeled), in order to spot the interactions that might be manipulated by these mutations. Functional analyses performed on these sub-networks revealed the potential relationship between immune system-infectious diseases and lung metastasis progression, but this connection was not observed significantly in the brain metastasis. Besides, structural analyses showed that some PPI interfaces in both metastasis sub-networks are originating from microbial proteins, which in turn were mostly related with cell adhesion. Cell adhesion is a key mechanism in metastasis, therefore these PPIs may be involved in similar molecular pathways that are shared by infectious disease and metastasis. Finally, by mapping the mutations and amino acid variations on the interface regions of the proteins in the metastasis sub-networks we found evidence for some mutations to be involved in the mechanisms differentiating the type of the metastasis.This work is supported by Spanish Government (MINECO) grant FEDER BIO2011-22568 and EUI2009-04018 (ERASysBio + SHIPREC) and The Scientific and Technological Research Council of Turkey (TUBITAK) grant 113E164

A hipericina aumenta a eficácia do laser de alta potência? Um estudo preliminar e experimental em ratos

CONTEXT AND OBJECTIVE: Lasers are widely used in treating symptomatic benign prostatic hyperplasia. In current practice, potassium titanyl phosphate (KTP) lasers are the most common type of laser systems used. The aim here was to evaluate the rapid effect of high-power laser systems after application of hypericin. DESIGN AND SETTING: Experimental animal study conducted in the Department of Urology, Gülhane Military Medical Academy, Ankara, Turkey, in 2012. METHODS: Sixteen rats were randomized into four groups: 120 W KTP laser + hypericin; 120 W KTP laser alone; 80 W KTP laser + hypericin; and 80 W KTP laser alone. Hypericin was given intraperitoneally two hours prior to laser applications. The laser incisions were made through the quadriceps muscle of the rats. The depth and the width of the laser incisions were evaluated histologically and recorded. RESULTS: To standardize the effects of the laser, we used the ratio of depth to width. These new values showed us the depth of the laser application per unit width. The new values acquired were evaluated statistically. Mean depth/width values were 231.6, 173.6, 214.1 and 178.9 in groups 1, 2, 3 and 4, respectively. The most notable result was that higher degrees of tissue penetration were achieved in the groups with hypericin (P < 0.05). CONCLUSIONS: The encouraging results from our preliminary study demonstrated that hypericin may improve the effects of KTP laser applications.CONTEXTO E OBJETIVO: Lasers são amplamente utilizados no tratamento de hiperplasia benigna de próstata sintomática. Na prática atual, lasers de fosfato de titanilo de potássio (KTP) são os tipos mais comuns usados dos sistemas. O objetivo foi avaliar o efeito rápido do sistema laser de alta potência após a aplicação de hipericina. TIPO DE ESTUDO E LOCAL: Estudo experimental animal, realizado no Departamento de Urologia, Academia de Medicina Militar de Gülhane, Ancara, Turquia, em 2012. MÉTODOS: 16 ratos foram divididos aleatoriamente em 4 grupos: 120W KTP laser + hipericina; 120W KTP laser somente; 80W KTP laser + hipericina; 80W KTP laser somente. Hipericina foi dada intraperitonealmente duas horas antes da aplicação do laser. As incisões a laser foram feitas através do músculo quadríceps dos ratos. A profundidade e a largura das incisões a laser foram avaliadas histologicamente e registradas. RESULTADOS: Para padronizar o efeito do laser foi utilizada a razão entre profundidade e largura. Estes novos valores nos mostraram a profundidade da aplicação do laser de largura por unidade. Os novos valores adquiridos foram avaliados estatisticamente. Os valores da média de profundidade/largura foram 231,6, 173,6, 214,1 e 178,9 nos grupos 1, 2, 3 e 4, respectivamente. O resultado mais notável foi atingir altos graus de penetração tecidual nos grupos com hipericina (P < 0,05). CONCLUSÕES: Os resultados promissores do nosso estudo preliminar mostraram que hipericina pode melhorar os efeitos das aplicações do laser KTP

Modeling of RAS complexes supports roles in cancer for less studied partners

Abstract Background RAS protein interactions have predominantly been studied in the context of the RAF and PI3kinase oncogenic pathways. Structural modeling and X-ray crystallography have demonstrated that RAS isoforms bind to canonical downstream effector proteins in these pathways using the highly conserved switch I and II regions. Other non-canonical RAS protein interactions have been experimentally identified, however it is not clear whether these proteins also interact with RAS via the switch regions. Results To address this question we constructed a RAS isoform-specific protein-protein interaction network and predicted 3D complexes involving RAS isoforms and interaction partners to identify the most probable interaction interfaces. The resulting models correctly captured the binding interfaces for well-studied effectors, and additionally implicated residues in the allosteric and hyper-variable regions of RAS proteins as the predominant binding site for non-canonical effectors. Several partners binding to this new interface (SRC, LGALS1, RABGEF1, CALM and RARRES3) have been implicated as important regulators of oncogenic RAS signaling. We further used these models to investigate competitive binding and multi-protein complexes compatible with RAS surface occupancy and the putative effects of somatic mutations on RAS protein interactions. Conclusions We discuss our findings in the context of RAS localization to the plasma membrane versus within the cytoplasm and provide a list of RAS protein interactions with possible cancer-related consequences, which could help guide future therapeutic strategies to target RAS proteins