Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease.

Antioxid Redox Signal. 2016 Jul 10;25(2):61-77

Authors: Lastres-Becker I, García-Yagüe AJ, Scannevin RH, Casarejos MJ, Kügler S, Rábano A, Cuadrado A

Abstract
AIMS: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation.
RESULTS: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature.
INNOVATION: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy.
CONCLUSION: DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61-77.

PMID: 27009601 [PubMed - indexed for MEDLINE]

Repurposing Drugs in Oncology: Next Steps.

Trends Cancer. 2017 Aug;3(8):543-546

Authors: Verbaanderd C, Meheus L, Huys I, Pantziarka P

Abstract
The repurposing of existing non-cancer drugs is a potential source of new treatment options for cancer patients with high unmet medical needs. While scientific research is progressing rapidly in the field of drug repurposing, the implementation of drug repurposing still faces important financial and regulatory hurdles that should be addressed to optimise clinical adoption.

PMID: 28780930 [PubMed - in process]

Myotonic dystrophy: candidate small molecule therapeutics.

Drug Discov Today. 2017 Aug 02;:

Authors: Konieczny P, Selma-Soriano E, Rapisarda AS, Fernandez-Costa JM, Perez-Alonso M, Artero R

Abstract
Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing and therapeutic gene modulation.

PMID: 28780071 [PubMed - as supplied by publisher]

Pharmacology and drug development in rare diseases: the attractiveness and expertise of the French medical pharmacology.

Fundam Clin Pharmacol. 2017 Aug 05;:

Authors: Micallef J, Boutouyrie P, Blin O

Abstract
Developing drugs for rare disease can be challenging due to specific rare disease characteristics. The French Medical Pharmacology is structured and positioned to play a major role in Orphan Drug Research and Development due to the required expertise concentrated into pharmacology departments, exclusively implemented within the French University Hospitals, public hospitals that are linked to a medical school (and often a pharmacy school) with numerous INSERM or CNRS labelled research units. In addition, these structures allow a close collaboration between researchers, academic institutions and biotech start-up (most of them being spin-off of the academic structures). Also, within University Hospitals are located the Clinical investigation Centres, linking to the FCRIN network and also to Inserm and hospitals, that enable care staff and researchers to be associated and clinical research protocols to be carried out on site, in full respect with ethic and regulatory aspects. As a consequence, this intra and multidisciplinary expertise offers all resource to elaborate a tailored approach for orphan drug development, in new entities as well as in repositioning. For preclinical development: drug screening, candidate selection (taking into account PK, metabolism, variability, potential toxicity), preclinical models (iPS, animal models) that could allow a better translation to human research. For clinical development, we will mention here dose determination, safety evaluation, Orphan Drug Designation and Protocol Assistance preparation and submission. For post marketing evaluation and surveys, the pharmacovigilance, addictovigilance and pharmacoepidemiology expertise, combined with access to large databases allow a better approach to orphan drug use and safety. As outlined through two success stories (Charcot Marie Tooth, vascular Ehlers-Danlos syndrome), the added value of French Medical Pharmacology structures and expertise has been evidenced in the know-how, multidimensional and multidisciplinary approaches, allowing the development of numerous drugs that have been granted with Orphan Drug Designation and later Market Approval. Even if specific and possibly even more, the field of Orphan Drugs requires the respect of highest standards of safety and quality. French Medical Pharmacology intends to continue on this way and constantly improve his involvement in this field, committed to a single objective: answer the unmet medical need of patients with rare diseases. This article is protected by copyright. All rights reserved.

PMID: 28779530 [PubMed - as supplied by publisher]

In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening.

Sci Rep. 2017 Aug 03;7(1):7249

Authors: Louet M, Bitam S, Bakouh N, Bignon Y, Planelles G, Lagorce D, Miteva MA, Eladari D, Teulon J, Villoutreix BO

Abstract
The human ClC-Kb channel plays a key role in exporting chloride ions from the cytosol and is known to be involved in Bartter syndrome type 3 when its permeation capacity is decreased. The ClC-Kb channel has been recently proposed as a potential therapeutic target to treat hypertension. In order to gain new insights into the sequence-structure-function relationships of this channel, to investigate possible impacts of amino-acid substitutions, and to design novel inhibitors, we first built a structural model of the human ClC-Kb channel using comparative modeling strategies. We combined in silico and in vitro techniques to analyze amino acids involved in the chloride ion pathway as well as to rationalize the possible role of several clinically observed mutations leading to the Bartter syndrome type 3. Virtual screening and drug repositioning computations were then carried out. We identified six novel molecules, including 2 approved drugs, diflusinal and loperamide, with Kd values in the low micromolar range, that block the human ClC-Kb channel and that could be used as starting point to design novel chemical probes for this potential therapeutic target.

PMID: 28775266 [PubMed - in process]

Drug combination approach to overcome resistance to EGFR tyrosine kinase inhibitors in lung cancer.

Cancer Lett. 2017 Jul 31;:

Authors: Tong CWS, Wu WKK, Loong HHF, Cho WCS, To KKW

Abstract
The discovery of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) has led to unprecedented clinical response in a subset of lung cancer patients carrying the sensitizing EGFR mutations (L858R or exon 19 deletion). However, disease progression invariably occurs within a year after the initial TKI treatment, predominantly due to the development of acquired resistance caused by the secondary EGFR T790M mutation. Numerous second generation irreversible and third generation EGFR T790M selective EGFR TKIs have been developed to overcome resistance. Besides developing new EGFR TKIs, combination therapy represents another promising strategy to combat resistance. This approach aims at circumventing drug resistance through a so-called bypass signaling mechanism by targeting horizontal pathways or vertical pathways or both. The logical combinations of different molecular targeted drugs inhibiting various oncogenic signaling have been studied. On the other hand, the repurposing of drugs with indications other than oncology has also emerged as a promising approach. In this review, we focus on the effectiveness of combination therapy of EGFR-TKIs with different agents in advanced lung cancer.

PMID: 28774798 [PubMed - as supplied by publisher]

Discovery of novel therapeutic properties of drugs from transcriptional responses based on multi-label classification.

Sci Rep. 2017 Aug 02;7(1):7136

Authors: Xie L, He S, Wen Y, Bo X, Zhang Z

Abstract
Drug repositioning strategies have improved substantially in recent years. At present, two advances are poised to facilitate new strategies. First, the LINCS project can provide rich transcriptome data that reflect the responses of cells upon exposure to various drugs. Second, machine learning algorithms have been applied successfully in biomedical research. In this paper, we developed a systematic method to discover novel indications for existing drugs by approaching drug repositioning as a multi-label classification task and used a Softmax regression model to predict previously unrecognized therapeutic properties of drugs based on LINCS transcriptome data. This approach to complete the said task has not been achieved in previous studies. By performing in silico comparison, we demonstrated that the proposed Softmax method showed markedly superior performance over those of other methods. Once fully trained, the method showed a training accuracy exceeding 80% and a validation accuracy of approximately 70%. We generated a highly credible set of 98 drugs with high potential to be repositioned for novel therapeutic purposes. Our case studies included zonisamide and brinzolamide, which were originally developed to treat indications of the nervous system and sensory organs, respectively. Both drugs were repurposed to the cardiovascular category.

PMID: 28769090 [PubMed - in process]

Improved anticancer drug response prediction in cell lines using matrix factorization with similarity regularization.

BMC Cancer. 2017 Aug 02;17(1):513

Authors: Wang L, Li X, Zhang L, Gao Q

Abstract
BACKGROUND: Human cancer cell lines are used in research to study the biology of cancer and to test cancer treatments. Recently there are already some large panels of several hundred human cancer cell lines which are characterized with genomic and pharmacological data. The ability to predict drug responses using these pharmacogenomics data can facilitate the development of precision cancer medicines. Although several methods have been developed to address the drug response prediction, there are many challenges in obtaining accurate prediction.
METHODS: Based on the fact that similar cell lines and similar drugs exhibit similar drug responses, we adopted a similarity-regularized matrix factorization (SRMF) method to predict anticancer drug responses of cell lines using chemical structures of drugs and baseline gene expression levels in cell lines. Specifically, chemical structural similarity of drugs and gene expression profile similarity of cell lines were considered as regularization terms, which were incorporated to the drug response matrix factorization model.
RESULTS: We first demonstrated the effectiveness of SRMF using a set of simulation data and compared it with two typical similarity-based methods. Furthermore, we applied it to the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets, and performance of SRMF exceeds three state-of-the-art methods. We also applied SRMF to estimate the missing drug response values in the GDSC dataset. Even though SRMF does not specifically model mutation information, it could correctly predict drug-cancer gene associations that are consistent with existing data, and identify novel drug-cancer gene associations that are not found in existing data as well. SRMF can also aid in drug repositioning. The newly predicted drug responses of GDSC dataset suggest that mTOR inhibitor rapamycin was sensitive to non-small cell lung cancer (NSCLC), and expression of AK1RC3 and HINT1 may be adjunct markers of cell line sensitivity to rapamycin.
CONCLUSIONS: Our analysis showed that the proposed data integration method is able to improve the accuracy of prediction of anticancer drug responses in cell lines, and can identify consistent and novel drug-cancer gene associations compared to existing data as well as aid in drug repositioning.

PMID: 28768489 [PubMed - in process]

Repurposed Therapeutic Agents Targeting the Ebola Virus: A Systematic Review.

Curr Ther Res Clin Exp. 2017;84:10-21

Authors: Sweiti H, Ekwunife O, Jaschinski T, Lhachimi SK

Abstract
BACKGROUND: The Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD.
OBJECTIVE: We aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy.
METHODS: We conducted a systematic literature search in MEDLINE, Embase, and other relevant trial registry platforms for studies published between January 1976 and January 2017. We included drug screening, preclinical studies, and clinical studies on repurposed drugs for the treatment of EVD. The risk of bias for animal studies and nonrandomized clinical studies was assessed. The quality of reporting for case series and case reports was evaluated. Finally, we selected drugs approved by established regulatory authorities, which have positive in vitro study outcomes and at least one additional animal or clinical trial.
RESULTS: We identified 3301 publications, of which 37 studies fulfilled our inclusion criteria. Studies were highly heterogeneous in terms of study type, methodology, and intervention. The risk of bias was high for 13 out of 14 animal studies. We selected 11 drugs with potential anti-EVD therapeutic effects and summarized their evidence.
CONCLUSIONS: Several established drugs may have therapeutic effects on EVD, but the quality and quantity of current scientific evidence is lacking. This review highlights the need for well-designed and conducted preclinical and clinical research to establish the efficacy of potential repurposed drugs against EVD.

PMID: 28761574 [PubMed - in process]

The Role of Common Pharmaceutical Agents on the Prevention and Treatment of Pancreatic Cancer.

Gut Liver. 2016 Sep 15;10(5):665-71

Authors: Amin S, Boffetta P, Lucas AL

Abstract
Survival from pancreatic cancer remains poor. Conventional treatment has resulted in only marginal improvements in survival compared with survival in the previous several decades. Thus, considerable interest has emerged regarding the potential use of common pharmaceutical agents as chemopreventative and chemotherapeutic options. Aspirin, metformin, statins, β-blockers, and bisphosphonates have biologically plausible mechanisms to inhibit pancreatic neoplasia, whereas dipeptidyl-peptidase 4 inhibitors may promote it. Regardless, real-world epidemiological data remain inconclusive. This review examines the hypotheses, evidence, and current state of the literature for each of these medications and their potential roles in the prevention and treatment of pancreatic cancer.

PMID: 27563018 [PubMed - indexed for MEDLINE]

Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice.

EMBO Mol Med. 2017 Jul 25;:

Authors: Wehr MC, Hinrichs W, Brzózka MM, Unterbarnscheidt T, Herholt A, Wintgens JP, Papiol S, Soto-Bernardini MC, Kravchenko M, Zhang M, Nave KA, Wichert SP, Falkai P, Zhang W, Schwab MH, Rossner MJ

Abstract
Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia-relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4-mediated mode-of-action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.

PMID: 28743784 [PubMed - as supplied by publisher]

Kinome Profiling Identifies Druggable Targets for Novel Human Cytomegalovirus (HCMV) Antivirals.

Mol Cell Proteomics. 2017 Apr;16(4 suppl 1):S263-S276

Authors: Arend KC, Lenarcic EM, Vincent HA, Rashid N, Lazear E, McDonald IM, Gilbert TS, East MP, Herring LE, Johnson GL, Graves LM, Moorman NJ

Abstract
Human cytomegalovirus (HCMV) is a significant cause of disease in immune-compromised adults and immune naïve newborns. No vaccine exists to prevent HCMV infection, and current antiviral therapies have toxic side effects that limit the duration and intensity of their use. There is thus an urgent need for new strategies to treat HCMV infection. Repurposing existing drugs as antivirals is an attractive approach to limit the time and cost of new antiviral drug development. Virus-induced changes in infected cells are often driven by changes in cellular kinase activity, which led us to hypothesize that defining the complement of kinases (the kinome), whose abundance or expression is altered during infection would identify existing kinase inhibitors that could be repurposed as new antivirals. To this end, we applied a kinase capture technique, multiplexed kinase inhibitor bead-mass spectrometry (MIB-MS) kinome, to quantitatively measure perturbations in >240 cellular kinases simultaneously in cells infected with a laboratory-adapted (AD169) or clinical (TB40E) HCMV strain. MIB-MS profiling identified time-dependent increases and decreases in MIB binding of multiple kinases including cell cycle kinases, receptor tyrosine kinases, and mitotic kinases. Based on the kinome data, we tested the antiviral effects of kinase inhibitors and other compounds, several of which are in clinical use or development. Using a novel flow cytometry-based assay and a fluorescent reporter virus we identified three compounds that inhibited HCMV replication with IC50 values of <1 μm, and at doses that were not toxic to uninfected cells. The most potent inhibitor of HCMV replication was OTSSP167 (IC50 <1.2 nm), a MELK inhibitor, blocked HCMV early gene expression and viral DNA accumulation, resulting in a >3 log decrease in virus replication. These results show the utility of MIB-MS kinome profiling for identifying existing kinase inhibitors that can potentially be repurposed as novel antiviral drugs.

PMID: 28237943 [PubMed - indexed for MEDLINE]

Antifungal adjuvants: Preserving and extending the antifungal arsenal.

Virulence. 2017 Feb 17;8(2):198-210

Authors: Butts A, Palmer GE, Rogers PD

Abstract
As the rates of systemic fungal infections continue to rise and antifungal drug resistance becomes more prevalent, there is an urgent need for new therapeutic options. This issue is exacerbated by the limited number of systemic antifungal drug classes. However, the discovery, development, and approval of novel antifungals is an extensive process that often takes decades. For this reason, there is growing interest and research into the possibility of combining existing therapies with various adjuvants that either enhance activity or overcome existing mechanisms of resistance. Reports of antifungal adjuvants range from plant extracts to repurposed compounds, to synthetic peptides. This approach would potentially prolong the utility of currently approved antifungals and mitigate the ongoing development of resistance.

PMID: 27459018 [PubMed - indexed for MEDLINE]

Repurposing auranofin as an antifungal: In vitro activity against a variety of medically important fungi.

Virulence. 2017 Feb 17;8(2):138-142

Authors: Wiederhold NP, Patterson TF, Srinivasan A, Chaturvedi AK, Fothergill AW, Wormley FL, Ramasubramanian AK, Lopez-Ribot JL

Abstract
Repositioning old drugs can significantly decrease the time and effort that it takes to develop novel antifungal therapeutics, which represents a pressing and unmet clinical need due to the devastating nature of fungal infections. We have previously described the activity of auranofin, a gold thiol compound used to treat rheumatoid arthritis, against Candida albicans biofilms. Here we evaluate its antifungal spectrum of action and describe its activity against a variety of medically important fungi.

PMID: 27268469 [PubMed - indexed for MEDLINE]

Exploration and analysis of drug modes of action through feature integration.

Mol Biosyst. 2017 Jan 31;13(2):425-431

Authors: Xin M, Fan J, Liu M, Jiang Z

Abstract
Identifying drug modes of action (MoA) is of paramount importance for having a good grasp of drug indications in clinical tests. Anticipating MoA can help to discover new uses for approved drugs. Here we first used a drug-set enrichment analysis method to discover significant biological activities in every mode of action category. Then, we proposed a new computational model, a probability ensemble approach based on Bayesian network theory, which integrated chemical, therapeutic, genomic and phenotypic properties of over a thousand of FDA approved drugs to assist with the prediction of MoA. 10-fold cross validation tests demonstrate that this method can achieve better performances than four other methods with the area under the receiver operating characteristic (ROC) curves. Finally, we further conducted a large-scale prediction for drug-MoA pairs. Using the Cardiovascular Agents category as an example, several predicted drug-MoA pairs were supported by literature resources.

PMID: 28092388 [PubMed - indexed for MEDLINE]

Drug discovery and development for rare genetic disorders.

Am J Med Genet A. 2017 Jul 21;:

Authors: Sun W, Zheng W, Simeonov A

Abstract
Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated.

PMID: 28731526 [PubMed - as supplied by publisher]

Selective Inhibition of Host Cell Signaling for Rotavirus Antivirals: PI3K/Akt/mTOR-Mediated Rotavirus Pathogenesis.

Virulence. 2017 Jul 19;:0

Authors: Kindrachuk J

PMID: 28723236 [PubMed - as supplied by publisher]

Exploring anti-malarial potential of FDA approved drugs: an in silico approach.

Malar J. 2017 Jul 18;16(1):290

Authors: Ramakrishnan G, Chandra N, Srinivasan N

Abstract
BACKGROUND: The critically important issue on emergence of drug-resistant malarial parasites is compounded by cross resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action. This aspect requires discovery of new anti-malarial compounds or formulation of new combination therapy. The current study attempts to contribute towards accelerating anti-malarial drug development efforts, by exploring the potential of existing FDA-approved drugs to target proteins of Plasmodium falciparum.
METHODS: Using comparative sequence and structure analyses, FDA-approved drugs, originally developed against other pathogens, were identified as potential repurpose-able candidates against P. falciparum. The rationale behind the undertaken approach is the likeliness of small molecules to bind to homologous targets. Such a study of evolutionary relationships between established targets and P. falciparum proteins aided in identification of approved drug candidates that can be explored for their anti-malarial potential.
RESULTS: Seventy-one FDA-approved drugs were identified that could be repurposed against P. falciparum. A total of 89 potential targets were recognized, of which about 70 are known to participate in parasite housekeeping machinery, protein biosynthesis, metabolic pathways and cell growth and differentiation, which can be prioritized for chemotherapeutic interventions. An additional aspect of prioritization of predicted repurpose-able drugs has been explored on the basis of ability of the drugs to permeate cell membranes, i.e., lipophilicity, since the parasite resides within a parasitophorous vacuole, within the erythrocyte, during the blood stages of infection. Based on this consideration, 46 of 71 FDA-approved drugs have been identified as feasible repurpose-able candidates against P. falciparum, and form a first-line for laboratory investigations. At least five of the drugs identified in the current analysis correspond to existing antibacterial agents already under use as repurposed anti-malarial agents.
CONCLUSIONS: The drug-target associations predicted, primarily by taking advantage of evolutionary information, provide a valuable resource of attractive and feasible candidate drugs that can be readily taken through further stages of anti-malarial drug development pipeline.

PMID: 28720135 [PubMed - in process]

Identification of driver copy number alterations in diverse cancer types and application in drug repositioning.

Mol Oncol. 2017 Jul 18;:

Authors: Zhou W, Zhao Z, Wang R, Han Y, Wang C, Yang F, Han Y, Liang H, Qi L, Wang C, Guo Z, Gu Y

Abstract
Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression. Our work aimed to identify the drivers (oncogenes or tumor suppressor genes) that reside in recurrently aberrant genomic regions, including a large number of genes or non-coding genes, which remain a challenge for decoding the SCNAs involved in carcinogenesis. Here, we propose a new approach to comprehensively identify drivers, using 8740 cancer samples involving 18 cancer types from The Cancer Genome Atlas (TCGA). On average, 84 drivers were revealed for each cancer type, including protein-coding genes, long non-coding RNAs (lncRNA) and microRNAs (miRNAs). We demonstrated that the drivers showed significant attributes of cancer genes, and significantly overlapped with known cancer genes, including MYC, CCND1, and ERBB2 in breast cancer, and the lncRNA PVT1 in multiple cancer types. Pan-cancer analyses of drivers revealed specificity and commonality across cancer types, and the non-coding drivers showed a higher cancer-type specificity than that of coding drivers. Some cancer types from different tissue origins were found to converge to high similarity because of the significant overlap of drivers, such as head and neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma (LUSC). The lncRNA SOX2-OT, a common driver of HNSC and LUSC, showed significant expression correlation with the oncogene SOX2. In addition, because some drivers are common in multiple cancer types and have been targeted by known drugs, we revealed that some drugs could be successfully repositioned which was validated by the datasets of drug response assays in cell lines. Our work reported a new method to comprehensively identify drivers in SCNAs across diverse cancer types, providing a feasible strategy for cancer drug repositioning as well as novel findings regarding cancer-associated non-coding RNA discovery. This article is protected by copyright. All rights reserved.

PMID: 28719033 [PubMed - as supplied by publisher]

Drugs currently under investigation for the treatment of invasive candidiasis.

Expert Opin Investig Drugs. 2017 Jul;26(7):825-831

Authors: McCarthy MW, Walsh TJ

Abstract
INTRODUCTION: The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed. Areas covered: In this paper, we explore investigational agents for the treatment of invasive candidiasis, with particular attention paid to compounds that have recently entered phase I or phase II clinical trials. Expert opinion: The antifungal drug development pipeline has been severely limited due to regulatory hurdles and a systemic lack of investment in novel compounds. However, several promising drug development strategies have recently emerged, including chemical screens involving Pathogen Box compounds, combination antifungal therapy, and repurposing of existing agents that were initially developed to treat other conditions, all of which have the potential to redefine the treatment of invasive candidiasis.

PMID: 28617137 [PubMed - indexed for MEDLINE]