Repositioning of anti-viral drugs as therapy for cervical cancer.

Pharmacol Rep. 2016 Oct;68(5):983-9

Authors: Sharma S, Baksi R, Agarwal M

Abstract
BACKGROUND: Increase in expression of eIF4E (Eukaryotic translation initiation factor 4E) protein is mediated by oncogenic proteins of Human Papilloma Virus (HPV). Increased expression of eIF4E plays an important role in HPV induced carcinogenesis. Ribavirin and Indinavir are known inhibitors of eIF4E activity.
METHODS: The effect of the drugs on HeLa cells was assessed by in vitro assays including cell viability using MTT and Neutral red assay, apoptotic potential using Caspase-3, Caspase-8 and Caspase-9 activity assays and MMP-2 and MMP-9 secretion by determination of Gelatinase activity. The in vivo effect of Ribavirin treatment on tumor volume was assessed in human xenograft in immunocompromised C57BL/6 mice.
RESULTS: In vitro analyses indicate that Ribavirin and Indinavir reduce viability of HeLa cells, induce apoptosis and decrease secretion of MMPs. Treatment with Ribavirin at a dose of 50mg/kg and 100mg/kg daily led to significant decrease in tumor volume in vivo.
CONCLUSION: The study thus provides evidence that Ribavirin and Indinavir can be explored as therapy against HPV-18 induced cervical cancer.

PMID: 27379616 [PubMed - indexed for MEDLINE]

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

PLoS Negl Trop Dis. 2017 Mar 17;11(3):e0005472

Authors: Reigada C, Valera-Vera EA, Sayé M, Errasti AE, Avila CC, Miranda MR, Pereira CA

Abstract
Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6-10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

PMID: 28306713 [PubMed - as supplied by publisher]

Heter-LP: A heterogeneous label propagation algorithm and its application in drug repositioning.

J Biomed Inform. 2017 Mar 11;:

Authors: Lotfi Shahreza M, Ghadiri N, Rasoul Mousavi S, Varshosaz J, Green JR

Abstract
Drug repositioning offers an effective solution to drug discovery, saving both time and resources by finding new indications for existing drugs. Typically, a drug takes effect via its protein targets in the cell. As a result, it is necessary for drug development studies to conduct an investigation into the interrelationships of drugs, protein targets, and diseases. Although previous studies have made a strong case for the effectiveness of integrative network-based methods for predicting these interrelationships, little progress has been achieved in this regard within drug repositioning research. Moreover, the interactions of new drugs and targets (lacking any known targets and drugs, respectively) cannot be accurately predicted by most established methods. In this paper, we propose a novel semi-supervised heterogeneous label propagation algorithm named Heter-LP, which applies both local and global network features for data integration. To predict drug-target, disease-target, and drug-disease associations, we use information about drugs, diseases, and targets as collected from multiple sources at different levels. Our algorithm integrates these various types of data into a heterogeneous network and implements a label propagation algorithm to find new interactions. Statistical analyses of 10-fold cross-validation results and experimental analyses support the effectiveness of the proposed algorithm.

PMID: 28300647 [PubMed - as supplied by publisher]

FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model.

J Transl Med. 2017 Mar 15;15(1):58

Authors: Szymiczek A, Pastorino S, Larson D, Tanji M, Pellegrini L, Xue J, Li S, Giorgi C, Pinton P, Takinishi Y, Pass HI, Furuya H, Gaudino G, Napolitano A, Carbone M, Yang H

Abstract
BACKGROUND: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet.
METHODS: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo.
RESULTS: We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity.
CONCLUSIONS: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.

PMID: 28298211 [PubMed - in process]

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"drug repositioning" OR "drug repurposing"

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7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2017/03/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Computational Discovery of Niclosamide Ethanolamine, A Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells in Vitro and in Mice by Inhibiting CDC37 Signaling.

Gastroenterology. 2017 Mar 08;:

Authors: Chen B, Wei W, Ma L, Yang B, Gill RM, Chua MS, Butte AJ, So S

Abstract
BACKGROUND & AIMS: Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC).
METHODS: We searched public databases of mRNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are downregulated in HCCs and reduce expression of genes upregulated in HCCs using a non-parametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In 1 model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated beta catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored.
RESULTS: Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more toxic to HCCs than primary hepatocytes. Oral administration of NEN to mice significantly slowed growth of genetically induced liver tumors and patient-derived xenografts, whereas niclosamide did not, coinciding with the observed greater bioavailability of NEN compared with niclosamide. The combination of NEN and sorafenib was more effective at slowing growth of patient-derived xenografts than either agent alone. In HepG2 cells and in patient-derived xenografts, administration of niclosamide or NEN increased expression of 20 genes downregulated in HCC and reduced expression of 29 genes upregulated in the 274-gene HCC signature. Administration of NEN to mice with patient-derived xenografts reduced expression of proteins in the Wnt-beta catenin, STAT3, AKT-mTOR, EGFR-Ras-Raf signaling pathways. Using immunoprecipitation assays, we found NEN to bind cell division cycle 37 (CDC37) protein and disrupt its interaction with heat shock protein 90 (HSP90).
CONCLUSIONS: In a bioinformatics search for agents that alter the HCC-specific gene expression pattern, we identified the anthelmintic niclosamide as a potential anti-tumor agent. Its ethanolamine salt, with greater bioavailability, was more effective than niclosamide at slowing the growth of genetically induced liver tumors and patient-derived xenografts in mice. Both agents disrupted interaction between CDC37 and HSP90 in HCC cells, with concomitant inhibition of their downstream signaling pathways. NEN might be effective for treatment of patients with HCC.

PMID: 28284560 [PubMed - as supplied by publisher]

Support for phosphoinositol 3 kinase and mTOR inhibitors as treatment for lupus using in-silico drug-repurposing analysis.

Arthritis Res Ther. 2017 Mar 11;19(1):54

Authors: Toro-Domínguez D, Carmona-Sáez P, Alarcón-Riquelme ME

Abstract
BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with few treatment options. Current therapies are not fully effective and show highly variable responses. In this regard, large efforts have focused on developing more effective therapeutic strategies. Drug repurposing based on the comparison of gene expression signatures is an effective technique for the identification of new therapeutic approaches. Here we present a drug-repurposing exploratory analysis using gene expression signatures from SLE patients to discover potential new drug candidates and target genes.
METHODS: We collected a compendium of gene expression signatures comprising peripheral blood cells and different separate blood cell types from SLE patients. The Lincscloud database was mined to link SLE signatures with drugs, gene knock-down, and knock-in expression signatures. The derived dataset was analyzed in order to identify compounds, genes, and pathways that were significantly correlated with SLE gene expression signatures.
RESULTS: We obtained a list of drugs that showed an inverse correlation with SLE gene expression signatures as well as a set of potential target genes and their associated biological pathways. The list includes drugs never or little studied in the context of SLE treatment, as well as recently studied compounds.
CONCLUSION: Our exploratory analysis provides evidence that phosphoinositol 3 kinase and mammalian target of rapamycin (mTOR) inhibitors could be potential therapeutic options in SLE worth further future testing.

PMID: 28284231 [PubMed - in process]

MOST: most-similar ligand based approach to target prediction.

BMC Bioinformatics. 2017 Mar 11;18(1):165

Authors: Huang T, Mi H, Lin CY, Zhao L, Zhong LL, Liu FB, Zhang G, Lu AP, Bian ZX, for MZRW Group

Abstract
BACKGROUND: Many computational approaches have been used for target prediction, including machine learning, reverse docking, bioactivity spectra analysis, and chemical similarity searching. Recent studies have suggested that chemical similarity searching may be driven by the most-similar ligand. However, the extent of bioactivity of most-similar ligands has been oversimplified or even neglected in these studies, and this has impaired the prediction power.
RESULTS: Here we propose the MOst-Similar ligand-based Target inference approach, namely MOST, which uses fingerprint similarity and explicit bioactivity of the most-similar ligands to predict targets of the query compound. Performance of MOST was evaluated by using combinations of different fingerprint schemes, machine learning methods, and bioactivity representations. In sevenfold cross-validation with a benchmark Ki dataset from CHEMBL release 19 containing 61,937 bioactivity data of 173 human targets, MOST achieved high average prediction accuracy (0.95 for pKi ≥ 5, and 0.87 for pKi ≥ 6). Morgan fingerprint was shown to be slightly better than FP2. Logistic Regression and Random Forest methods performed better than Naïve Bayes. In a temporal validation, the Ki dataset from CHEMBL19 were used to train models and predict the bioactivity of newly deposited ligands in CHEMBL20. MOST also performed well with high accuracy (0.90 for pKi ≥ 5, and 0.76 for pKi ≥ 6), when Logistic Regression and Morgan fingerprint were employed. Furthermore, the p values associated with explicit bioactivity were found be a robust index for removing false positive predictions. Implicit bioactivity did not offer this capability. Finally, p values generated with Logistic Regression, Morgan fingerprint and explicit activity were integrated with a false discovery rate (FDR) control procedure to reduce false positives in multiple-target prediction scenario, and the success of this strategy it was demonstrated with a case of fluanisone. In the case of aloe-emodin's laxative effect, MOST predicted that acetylcholinesterase was the mechanism-of-action target; in vivo studies validated this prediction.
CONCLUSIONS: Using the MOST approach can result in highly accurate and robust target prediction. Integrated with a FDR control procedure, MOST provides a reliable framework for multiple-target inference. It has prospective applications in drug repurposing and mechanism-of-action target prediction.

PMID: 28284192 [PubMed - in process]

Topical phenytoin for the treatment of neuropathic pain.

J Pain Res. 2017;10:469-473

Authors: Kopsky DJ, Keppel Hesselink JM

Abstract
We developed and tested a new putative analgesic cream, based on the anticonvulsant phenytoin in patients suffering from treatment refractory neuropathic pain. The use of commercial topical analgesics is not widespread due to the facts that capsaicin creams or patches can give rise to side effects, such as burning, and analgesic patches (e.g., lidocaine 5% patches) have complex handling, especially for geriatric patients. Only in a few countries, compounded creams based on tricyclic antidepressants or other (co-)analgesics are available. Such topical analgesic creams, however, are easy to administer and have a low propensity for inducing side effects. We, therefore, developed a new topical cream based on 5% and 10% phenytoin and described three successfully treated patients suffering from neuropathic pain. All patients were refractory to a number of other analgesics. In all patients, phenytoin cream was effective in reducing pain completely, without any side effects, and the tolerability was excellent. The onset of action of the phenytoin creams was within 30 minutes. Phenytoin cream might become a new treatment modality of the treatment of neuropathic pain.

PMID: 28280381 [PubMed - in process]

Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.

J Hematol Oncol. 2017 Mar 09;10(1):67

Authors: Yoshida GJ

Abstract
The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.

PMID: 28279189 [PubMed - in process]

Drugs in clinical development for the treatment of amyotrophic lateral sclerosis.

Expert Opin Investig Drugs. 2017 Mar 06;:

Authors: Martinez A, Palomo Ruiz MD, Perez DI, Gil C

Abstract
INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clin ical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert Opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.

PMID: 28277881 [PubMed - as supplied by publisher]

Exploring the epigenetic drug discovery landscape.

Expert Opin Drug Discov. 2017 Feb 28;:1-18

Authors: Prachayasittikul V, Prathipati P, Pratiwi R, Phanus-Umporn C, Malik AA, Schaduangrat N, Seenprachawong K, Wongchitrat P, Supokawej A, Prachayasittikul V, Wikberg JE, Nantasenamat C

Abstract
INTRODUCTION: Epigenetic modification has been implicated in a wide range of diseases and the ability to modulate such systems is a lucrative therapeutic strategy in drug discovery. Areas covered: This article focuses on the concepts and drug discovery aspects of epigenomics. This is achieved by providing a survey of the following concepts: (i) factors influencing epigenetics, (ii) diseases arising from epigenetics, (iii) epigenetic enzymes as druggable targets along with coverage of existing FDA-approved drugs and pharmacological agents, and (iv) drug repurposing/repositioning as a means for rapid discovery of pharmacological agents targeting epigenetics. Expert opinion: Despite significant interests in targeting epigenetic modifiers as a therapeutic route, certain classes of target proteins are heavily studied while some are less characterized. Thus, such orphan target proteins are not yet druggable with limited report of active modulators. Current research points towards a great future with novel drugs directed to the many complex multifactorial diseases of humans, which are still often poorly understood and difficult to treat.

PMID: 28276705 [PubMed - as supplied by publisher]

Some leopards can change their spots: potential repositioning of stem cell reprogramming compounds as anti-cancer agents.

Cell Biol Toxicol. 2016 06;32(3):157-68

Authors: Kim WH, Shen H, Jung DW, Williams DR

PMID: 27156576 [PubMed - indexed for MEDLINE]

A Receptor Tyrosine Kinase Inhibitor, Dovitinib (TKI-258), Enhances BMP-2-Induced Osteoblast Differentiation In Vitro.

Mol Cells. 2016 May 31;39(5):389-94

Authors: Lee Y, Bae KJ, Chon HJ, Kim SH, Kim SA, Kim J

Abstract
Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.

PMID: 27025387 [PubMed - indexed for MEDLINE]

Value added medicines: what value repurposed medicines might bring to society?

J Mark Access Health Policy. 2017;5(1):1264717

Authors: Toumi M, Rémuzat C

Abstract
Background & objectives: Despite the wide interest surrounding drug repurposing, no common terminology has been yet agreed for these products and their full potential value is not always recognised and rewarded, creating a disincentive for further development. The objectives of the present study were to assess from a wide perspective which value drug repurposing might bring to society, but also to identify key obstacles for adoption of these medicines and to discuss policy recommendations. Methods: A preliminary comprehensive search was conducted to assess how the concept of drug repurposing was described in the literature. Following completion of the literature review, a primary research was conducted to get perspective of various stakeholders across EU member states on drug repurposing (healthcare professionals, regulatory authorities and Health Technology Assessment (HTA) bodies/payers, patients, and representatives of the pharmaceutical industry developing medicines in this field). Ad hoc literature review was performed to illustrate, when appropriate, statements of the various stakeholders. Results: Various nomenclatures have been used to describe the concept of drug repurposing in the literature, with more or less broad definitions either based on outcomes, processes, or being a mix of both. In this context, Medicines for Europe (http://www.medicinesforeurope.com/value-added-medicines/) established one single terminology for these medicines, known as value added medicines, defined as 'medicines based on known molecules that address healthcare needs and deliver relevant improvements for patients, healthcare professionals and/or payers'. Stakeholder interviews highlighted three main potential benefits for value added medicines: (1) to address a number of medicine-related healthcare inefficiencies related to irrational use of medicines, non-availability of appropriate treatment options, shortage of mature products, geographical inequity in medicine access; (2) to improve healthcare system efficiency; and (3) to contribute to sustainability of healthcare systems through economic advantages. Current HTA framework, generic stigma, and pricing rules, such as internal reference pricing or tendering processes in place in some countries, were reported as the current key hurdles preventing the full recognition of value added medicines' benefits, discouraging manufacturers from bringing such products to the market. Discussion & conclusions: There is currently a gap between increasing regulatory authority interest in capturing value added medicines' benefits and the resistance of HTA bodies/payers, who tend to ignore this important segment of the pharmaceutical field. This situation calls for policy changes to foster appropriate incentives to enhance value recognition of value added medicines and deliver the expected benefit to society. Policy changes from HTA perspective should include: absence of any legislative barriers preventing companies from pursuing HTA; HTA requirements proportionate to potential reward; HTA decision-making framework taking into account the specific characteristics of value added medicines; eligibility for early HTA dialogues; Policy changes from pricing perspective should encompass: tenders/procurement policies allowing differentiation from generic medicines; eligibility for early entry agreement; non-systematic implementation of external and internal reference pricing policies; recognition of indication-specific pricing. At the same time, the pharmaceutical industry should engage all the stakeholders (patients, healthcare providers, HTA bodies/payers) in early dialogues to identify their expectations and to ensure the developed value added medicines address their needs.

PMID: 28265347 [PubMed - in process]

Loss of BRCA1 in the cells of origin of ovarian cancer induces glycolysis: A window of opportunity for ovarian cancer chemoprevention.

Cancer Prev Res (Phila). 2017 Mar 06;:

Authors: Chiyoda T, Hart PC, Eckert MA, McGregor SM, Lastra RR, Hamamoto R, Nakamura Y, Yamada SD, Olopade OI, Lengyel E, Romero IL

Abstract
Mutations in the breast cancer susceptibility gene 1 (BRCA1) are associated with an increased risk of developing epithelial ovarian cancer. However, beyond the role of BRCA1 in DNA repair, little is known about other mechanisms by which BRCA1 impairment promotes carcinogenesis. Given that altered metabolism is now recognized as important in the initiation and progression of cancer, we asked whether loss of BRCA1 changes metabolism in the cells of origin of ovarian cancer. The findings show that silencing BRCA1 in ovarian surface epithelial and fallopian tube cells increased glycolysis. Furthermore, when these cells were transfected with plasmids carrying deleterious BRCA1 mutations (5382insC or the P1749R), there was an increase in hexokinase-2 (HK2), a key glycolytic enzyme. This effect was mediated by MYC and the signal transducer and activator of transcription 3 (STAT3). To target the metabolic phenotype induced by loss of BRCA1, a drug repurposing approach was used and aspirin was identified as an agent that counteracted the increase in HK2 and the increase in glycolysis induced by BRCA1 impairment. Evidence from this study indicates that the tumor suppressor functions of BRCA1 extend beyond DNA repair to include metabolic endpoints and identifies aspirin as an ovarian cancer chemopreventive agent capable of reversing the metabolic derangements caused by loss of BRCA1.

PMID: 28264838 [PubMed - as supplied by publisher]

Deep learning-based drug-target interaction prediction.

J Proteome Res. 2017 Mar 06;:

Authors: Wen M, Zhang Z, Niu S, Sha H, Yang R, Yun Y, Lu H

Abstract
Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug target interaction (DTI) can speed up the experimental work which is expensive and time-consuming by providing most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side-effect. Traditionally, the performance of DTI prediction heavily depends on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the target into different classes, we developed a deep learning-based algorithmic framework named DeepDTIs. It firstly abstracts representation from raw input descriptors using unsupervised pre-training, then applies known label pairs of interaction to build a classification model. Comparing with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

PMID: 28264154 [PubMed - as supplied by publisher]

Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations.

PLoS One. 2017;12(3):e0173303

Authors: Matthews H, Deakin J, Rajab M, Idris-Usman M, Nirmalan NJ

Abstract
The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26-32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product.

PMID: 28257497 [PubMed - in process]

EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain.

J Pain Res. 2017;10:439-443

Authors: Keppel Hesselink JM, Schatman ME

Abstract
EMA401 is an old molecule, synthesized by Parke-Davis in the last century and characterized at that time as an AT2R antagonist. Professor Maree Smith and her group from the University of Queensland (Australia) patented the drug and many related derivatives and other compounds with high affinity for the AT2R for the indication neuropathic pain in 2004, an example of drug repositioning. After some years of university work, the Australian biotech company Spinifex Pharmaceuticals took over further research and development and characterized the S-enantiomer, code name EMA401, and related compounds in a variety of animal models for neuropathic and cancer pain. EMA401 was selected as the lead compound, based on high selectivity for the AT2R and good oral bioavailability (33%). EMA401, however, was only administered once in a chronic neuropathic pain model, and no data have been published in other pain models, or during steady state, although such data were available for the racemate EMA400 and some related compounds (EMA200, EMA400). A pilot phase IIa study demonstrated the efficacy and safety of the drug taken twice daily as two capsules of 50 mg (400 mg/day). In 2015, Novartis took over the clinical development. Two phase IIb studies designed by Spinifex Pharmaceuticals were put on hold, probably because Novartis wanted to improve the clinical design or collect additional preclinical data. Further data are eagerly awaited, especially since EMA401 is first-in-class in neuropathic pain.

PMID: 28255254 [PubMed - in process]