Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity.

Parasitol Res. 2016 Aug 8;

Authors: Cowan N, Raimondo A, Keiser J

Abstract
Infections with soil-transmitted helminths (STHs) are considered among the most persistent global health problems. The few available drugs have limitations including low efficacy against Trichuris trichiura infections. As a starting point toward drug repositioning, we studied a set of FDA-approved oncology drugs for activity against Trichuris muris since targets relevant to cancer therapy might have a function in helminth biology. Drugs were tested in vitro on the larval and adult stage of T. muris. Compounds active in vitro were tested in the T. muris mouse model at single oral dosages of 200-400 mg/kg. Of the 114 drugs tested in vitro, 12 showed activity against T. muris larvae (>80 % drug effect at 50 μM). Ten of these drugs were also active on the adult worm stage (>80 % drug effect at 50 μM), of which six revealed IC50 values between 1.8 and 5.0 μM. Except for tamoxifen citrate, all in vitro active drugs were protein kinase inhibitors. None of the drugs tested in vivo showed efficacy, revealing worm burden reductions of 0-24 % and worm expulsion rates of 0-7.9 %. The promising in vitro activities of protein kinases could not be confirmed in vivo. Drug discovery against STH should be strengthened including the definition of compound progression criteria. Follow-up structure-activity relationship studies with modified compounds might be considered.

PMID: 27498843 [PubMed - as supplied by publisher]

Network biology concepts in complex disease comorbidities.

Nat Rev Genet. 2016 Aug 8;

Authors: Hu JX, Thomas CE, Brunak S

Abstract
The co-occurrence of diseases can inform the underlying network biology of shared and multifunctional genes and pathways. In addition, comorbidities help to elucidate the effects of external exposures, such as diet, lifestyle and patient care. With worldwide health transaction data now often being collected electronically, disease co-occurrences are starting to be quantitatively characterized. Linking network dynamics to the real-life, non-ideal patient in whom diseases co-occur and interact provides a valuable basis for generating hypotheses on molecular disease mechanisms, and provides knowledge that can facilitate drug repurposing and the development of targeted therapeutic strategies.

PMID: 27498692 [PubMed - as supplied by publisher]

Protein kinase C-δ inhibitor, Rottlerin inhibits growth and survival of mycobacteria exclusively through Shikimate kinase.

Biochem Biophys Res Commun. 2016 Aug 4;

Authors: Pandey S, Chatterjee A, Jaiswal S, Kumar S, Ramachandran R, Srivastava KK

Abstract
The molecular bases of disease provide exceptional prospect to translate research findings into new drugs. Nevertheless, to develop new and novel chemical entities takes huge amount of time and efforts, mainly due to the stringent processes. Therefore, drug repurposing is one of such strategies which is being used in recent times to identify new pharmacophores. The essential first step in discovery of the specific inhibitor with low toxicity is the identification and elucidation of pathways exclusive to target pathogen. One such target is the shikimate pathway, which is essential for algae, higher plants, bacteria and fungi. Since, this enzyme system is absent in higher eukaryotes and in mammals, the enzymes involved in the pathway provide an attractive target for the development of potentially selective and non toxic antimicrobial agents. Since, so far there is no specific inhibitor which is able to restrain mycobacterial shikimate pathway; we expanded the use of a known kinase inhibitor; Rottlerin, in order to predict the prototype in discovering the specific molecules against this enzyme. For the first time we have shown that Rottlerin inhibits extracellular mycobacteria by affecting Shikimate Kinase (SK) and this effect is further enhanced during the intracellular infection due to the added effect of PKC- δ down-regulation. The molecular docking of Rottlerin with both the mycobacterial SKs, corroborated the inhibition data, and revealed that the effects of SK, in slow and in fast grower mycobacteria are due to the changes in affinity of binding with the drug.

PMID: 27498028 [PubMed - as supplied by publisher]

Drug repositioning in SLE: crowd-sourcing, literature-mining and Big Data analysis.

Lupus. 2016 Sep;25(10):1150-70

Authors: Grammer AC, Ryals MM, Heuer SE, Robl RD, Madamanchi S, Davis LS, Lauwerys B, Catalina MD, Lipsky PE

Abstract
Lupus patients are in need of modern drugs to treat specific manifestations of their disease effectively and safely. In the past half century, only one new treatment has been approved by the US Food and Drug Administration (FDA) for systemic lupus erythematosus (SLE). In 2014-2015, the FDA approved 71 new drugs, only one of which targeted a rheumatic disease and none of which was approved for use in SLE. Repositioning/repurposing drugs approved for other diseases using multiple approaches is one possible means to find new treatment options for lupus patients. "Big Data" analysis approaches this challenge from an unbiased standpoint whereas literature mining and crowd sourcing for candidates assessed by the CoLTs (Combined Lupus Treatment Scoring) system provide a hypothesis-based approach to rank potential therapeutic candidates for possible clinical application. Both approaches mitigate risk since the candidates assessed have largely been extensively tested in clinical trials for other indications. The usefulness of a multi-pronged approach to drug repositioning in lupus is highlighted by orthogonal confirmation of hypothesis-based drug repositioning predictions by "Big Data" analysis of differentially expressed genes from lupus patient samples. The goal is to identify novel therapies that have the potential to affect disease processes specifically. Involvement of SLE patients and the scientists that study this disease in thinking about new drugs that may be effective in lupus though crowd-sourcing sites such as LRxL-STAT (www.linkedin.com/in/lrxlstat) is important in stimulating the momentum needed to test these novel drug targets for efficacy in lupus rapidly in small, proof-of-concept trials conducted by LuCIN, the Lupus Clinical Investigators Network (www.linkedin.com/in/lucinstat).

PMID: 27497259 [PubMed - in process]

Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation.

Oncotarget. 2015 Oct 13;6(31):31018-29

Authors: Lee HG, Kim H, Kim EJ, Park PG, Dong SM, Choi TH, Kim H, Chong CR, Liu JO, Chen J, Ambinder RF, Hayward SD, Park JH, Lee JM

Abstract
The constant presence of the viral genome in Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) suggests the applicability of novel EBV-targeted therapies. The antiviral nucleoside drug, ganciclovir (GCV), is effective only in the context of the viral lytic cycle in the presence of EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression. In this study, screening of the Johns Hopkins Drug Library identified gemcitabine as a candidate for combination treatment with GCV. Pharmacological induction of EBV-TK or PK in EBVaGC-originated tumor cells were used to study combination treatment with GCV in vitro and in vivo. Gemcitabine was found to be a lytic inducer via activation of the ataxia telangiectasia-mutated (ATM)/p53 genotoxic stress pathway in EBVaGC. Using an EBVaGC mouse model and a [125I] fialuridine (FIAU)-based lytic activation imaging system, we evaluated gemcitabine-induced lytic activation in an in vivo system and confirmed the efficacy of gemcitabine-GCV combination treatment. This viral enzyme-targeted anti-tumor strategy may provide a new therapeutic approach for EBVaGCs.

PMID: 26427042 [PubMed - indexed for MEDLINE]

The photosensitizer verteporfin has light-independent anti-leukemic activity for Ph-positive acute lymphoblastic leukemia and synergistically works with dasatinib.

Oncotarget. 2016 Aug 2;

Authors: Morishita T, Hayakawa F, Sugimoto K, Iwase M, Yamamoto H, Hirano D, Kojima Y, Imoto N, Naoe T, Kiyoi H

Abstract
Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, particularly from the viewpoints of microenvironmental independence. Patient-derived xenografts (PDX) are established by the transfer of primary tumor cells directly from patients into immunodeficient mice and can provide primary-like tumor cells of the amount needed at the desired time. We developed a high-throughput drug screening system using PDX cells and performed drug screening using the PDX cells of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). We established four Ph+ ALL PDX mice and performed high-throughput screening of 3440 compounds using leukemia cells from the PDX mice (PDX-cell screening). The profiles of drugs selected by PDX-cell screening were markedly different from those by screening using the Ph+ ALL cell line. We found that verteporfin, an FDA-approved drug, exhibited strong PDX cell-specific cytotoxicity. In the validation assay, its GI50 was 228 nM, 395 nM, and 538 nM in three PDX cells and 3.93 µM, 2.11 µM, and 5.61 µM in three cell lines. Although verteporfin is a photosensitizer activated by photoirradiation, its cytotoxic effects were mediated by the light-independent production of reactive oxygen species; therefore, its anti-leukemic effects were also exerted in vivo without photoirradiation. Furthermore, it exhibited synergistic effects with dasatinib, an ABL kinase inhibitor. These results indicated the potential of verteporfin as a new anti-leukemic reagent.

PMID: 27494842 [PubMed - as supplied by publisher]

Drug repurposing: a new front in the war against Staphylococcus aureus.

Future Microbiol. 2016 Aug 5;

Authors: Das S, Dasgupta A, Chopra S

Abstract
Staphylococcus aureus continues its domination of worldwide bacterial infection rates, thereby remaining a pathogen of significant public health interest. A major reason for its continued success is its ability to acquire and maintain diverse drug resistance mechanisms, leading to a paucity of antimicrobials active against it, concomitantly leading to a continuous search for new antimicrobial agents. However, with the withdrawal of the major pharmaceutical firms from the anti-infective area, drug repurposing has provided a potential boost to the drug pipeline. In this review, we provide an overview of the currently approved drugs with repurposing potential against Staphylococcus aureus, thus augmenting the classical drug discovery pathway.

PMID: 27494302 [PubMed - as supplied by publisher]

Context-specific functional module based drug efficacy prediction.

BMC Bioinformatics. 2016;17(Suppl 6):275

Authors: Hwang W, Choi J, Kwon M, Lee D

Abstract
BACKGROUND: It is necessary to evaluate the efficacy of individual drugs on patients to realize personalized medicine. Testing drugs on patients in clinical trial is the only way to evaluate the efficacy of drugs. The approach is labour intensive and requires overwhelming costs and a number of experiments. Therefore, preclinical model system has been intensively investigated for predicting the efficacy of drugs. Current computational drug sensitivity prediction approaches use general biological network modules as their prediction features. Therefore, they miss indirect effectors or the effects from tissue-specific interactions.
RESULTS: We developed cell line specific functional modules. Enriched scores of functional modules are utilized as cell line specific features to predict the efficacy of drugs. Cell line specific functional modules are clusters of genes, which have similar biological functions in cell line specific networks. We used linear regression for drug efficacy prediction. We assessed the prediction performance in leave-one-out cross-validation (LOOCV). Our method was compared with elastic net model, which is a popular model for drug efficacy prediction. In addition, we analysed drug sensitivity-associated functions of five drugs - lapatinib, erlotinib, raloxifene, tamoxifen and gefitinib- by our model.
CONCLUSIONS: Our model can provide cell line specific drug efficacy prediction and also provide functions which are associated with drug sensitivity. Therefore, we could utilize drug sensitivity associated functions for drug repositioning or for suggesting secondary drugs for overcoming drug resistance.

PMID: 27490093 [PubMed - as supplied by publisher]

Ibrutinib repurposing: from B-cell malignancies to solid tumors.

Oncoscience. 2016;3(5-6):147-8

Authors: Massó-Vallés D, Jauset T, Soucek L

PMID: 27489860 [PubMed]

Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer.

Biochem Biophys Res Commun. 2016 Mar 18;471(4):639-45

Authors: Yu M, Li R, Zhang J

Abstract
Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells.

PMID: 26902121 [PubMed - indexed for MEDLINE]

Repurposing Vitamin D as an Anticancer Drug.

Clin Oncol (R Coll Radiol). 2016 Jan;28(1):36-41

Authors: Gilbert DC, Vale C, Haire R, Coyle C, Langley RE

PMID: 26520788 [PubMed - indexed for MEDLINE]

Newly Identified Targets of Aspirin and Its Primary Metabolite, Salicylic Acid.

DNA Cell Biol. 2016 Apr;35(4):163-6

Authors: Klessig DF

Abstract
Salicylic acid (SA) is a plant hormone, which influences several physiological processes, and is a critical modulator of multiple levels of immunity in plants. Several high-throughput screens, which were developed to identify SA-binding proteins through which SA mediates its many physiological effects in plants, uncovered several novel targets of aspirin and its primary metabolite, SA, in humans. These include glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and high mobility group box 1 (HMGB1), two proteins associated with some of the most prevalent and devastating human diseases. In addition, natural and synthetic SA derivatives were discovered, which are much more potent than SA at inhibiting the disease-associated activities of these targets.

PMID: 26954428 [PubMed - indexed for MEDLINE]

Vinorelbine rescue therapy for dogs with primary urinary bladder carcinoma.

Vet Comp Oncol. 2015 Dec;13(4):443-51

Authors: Kaye ME, Thamm DH, Weishaar K, Lawrence JA

Abstract
The goal of this study was to evaluate the anti-tumour activity and toxicoses of vinorelbine as a palliative rescue therapy for dogs with primary urinary bladder carcinoma. Thirteen dogs refractory to prior chemotherapeutics and one dog naïve to chemotherapeutic treatment were enrolled. Vinorelbine (15 mg m(-2) IV) was administered intravenously along with concurrent oral anti-inflammatory drugs, if tolerated. A median of six doses of vinorelbine (range: 1-16) was administered. Two dogs (14%) had partial responses, and eight (57%) experienced stable disease. Subjective improvement in clinical signs was noted in 11 dogs (78%). Adverse events were mild and primarily haematological in nature. Median time to progression was 93 days (range: 20-239 days). Median survival time for all dogs was 187 days; median survival for 13 pre-treated dogs was 207 days. Vinorelbine may have utility in the management of canine primary urinary bladder carcinoma and should be evaluated in a prospective study.

PMID: 23981116 [PubMed - indexed for MEDLINE]

Neuropathy: A name for their pain.

Nature. 2016 Jul 14;535(7611):S10-1

Authors: Eisenstein M

PMID: 27410524 [PubMed - indexed for MEDLINE]

Screening of the Open Source Malaria Box Reveals an Early Lead Compound for the Treatment of Alveolar Echinococcosis.

PLoS Negl Trop Dis. 2016 Mar;10(3):e0004535

Authors: Stadelmann B, Rufener R, Aeschbacher D, Spiliotis M, Gottstein B, Hemphill A

Abstract
The metacestode (larval) stage of the tapeworm Echinococcus multilocularis causes alveolar echinococcosis (AE), a very severe and in many cases incurable disease. To date, benzimidazoles such as albendazole and mebendazole are the only approved chemotherapeutical treatment options. Benzimidazoles inhibit metacestode proliferation, but do not act parasiticidal. Thus, benzimidazoles have to be taken a lifelong, can cause adverse side effects such as hepatotoxicity, and are ineffective in some patients. We here describe a newly developed screening cascade for the evaluation of the in vitro efficacy of new compounds that includes assessment of parasiticidal activity. The Malaria Box from Medicines for Malaria Venture (MMV), comprised of 400 commercially available chemicals that show in vitro activity against Plasmodium falciparum, was repurposed. Primary screening was carried out at 10 μM by employing the previously described PGI assay, and resulted in the identification of 24 compounds that caused physical damage in metacestodes. Seven out of these 24 drugs were also active at 1 μM. Dose-response assays revealed that only 2 compounds, namely MMV665807 and MMV665794, exhibited an EC50 value below 5 μM. Assessments using human foreskin fibroblasts and Reuber rat hepatoma cells showed that the salicylanilide MMV665807 was less toxic for these two mammalian cell lines than for metacestodes. The parasiticidal activity of MMV665807 was then confirmed using isolated germinal layer cell cultures as well as metacestode vesicles by employing viability assays, and its effect on metacestodes was morphologically evaluated by electron microscopy. However, both oral and intraperitoneal application of MMV665807 to mice experimentally infected with E. multilocularis metacestodes did not result in any reduction of the parasite load.

PMID: 26967740 [PubMed - indexed for MEDLINE]

Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities.

FEBS J. 2016 Mar;283(6):1139-67

Authors: Bhosle A, Chandra N

Abstract
Antifolates are competitive inhibitors of dihydrofolate reductase (DHFR), a conserved enzyme that is central to metabolism and widely targeted in pathogenic diseases, cancer and autoimmune disorders. Although most clinically used antifolates are known to be target specific, some display a fair degree of cross-reactivity with DHFRs from other species. A method that enables identification of determinants of affinity and specificity in target DHFRs from different species and provides guidelines for the design of antifolates is currently lacking. To address this, we first captured the potential druggable space of a DHFR in a substructure called the 'supersite' and classified supersites of DHFRs from 56 species into 16 'site-types' based on pairwise structural similarity. Analysis of supersites across these site-types revealed that DHFRs exhibit varying extents of dissimilarity at structurally equivalent positions in and around the binding site. We were able to explain the pattern of affinities towards chemically diverse antifolates exhibited by DHFRs of different site-types based on these structural differences. We then generated an antifolate-DHFR network by mapping known high-affinity antifolates to their respective supersites and used this to identify antifolates that can be repurposed based on similarity between supersites or antifolates. Thus, we identified 177 human-specific and 458 pathogen-specific antifolates, a large number of which are supported by available experimental data. Thus, in the light of the clinical importance of DHFR, we present a novel approach to identifying differences in the druggable space of DHFRs that can be utilized for rational design of antifolates.

PMID: 26797763 [PubMed - indexed for MEDLINE]

Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations.

Sci Rep. 2015;5:12298

Authors: Lesterhuis WJ, Rinaldi C, Jones A, Rozali EN, Dick IM, Khong A, Boon L, Robinson BW, Nowak AK, Bosco A, Lake RA

Abstract
Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs, and define contextually relevant novel therapeutic targets.

PMID: 26193793 [PubMed - indexed for MEDLINE]

An integrated network platform for contextual prioritization of drugs and pathways.

Mol Biosyst. 2015 Nov;11(11):2850-9

Authors: Segura-Cabrera A, Singh N, Komurov K

Abstract
Repurposing of drugs to novel disease indications has promise for faster clinical translation. However, identifying the best drugs for a given pathological context is not trivial. We developed an integrated random walk-based network framework that combines functional biomolecular relationships and known drug-target interactions as a platform for contextual prioritization of drugs, genes and pathways. We show that the use of gene-centric or drug-centric data, such as gene expression data or a phenotypic drug screen, respectively, within this network platform can effectively prioritize drugs and pathways, respectively, to the studied biological context. We demonstrate that various genomic data can be used as contextual cues to effectively prioritize drugs to the studied context, while similarly, phenotypic drug screen data can be used to effectively prioritize genes and pathways to the studied phenotypic context. As a proof-of-principle, we showcase the use of our platform to identify known and novel drug indications against different subsets of breast cancers through contextual prioritization based on genome-wide gene expression, shRNA and drug screen and clinical survival data. The integrated network and associated methods are incorporated into the NetWalker suite for functional genomics analysis ().

PMID: 26315485 [PubMed - indexed for MEDLINE]

Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents.

Eur J Med Chem. 2016 Jul 9;122:723-730

Authors: Ramesh R, Shingare RD, Kumar V, Anand A, B S, Veeraraghavan S, Viswanadha S, Ummanni R, Gokhale R, Srinivasa Reddy D

Abstract
The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.

PMID: 27476117 [PubMed - as supplied by publisher]

A network based approach to drug repositioning identifies plausible candidates for breast cancer and prostate cancer.

BMC Med Genomics. 2016;9(1):51

Authors: Chen HR, Sherr DH, Hu Z, DeLisi C

Abstract
BACKGROUND: The high cost and the long time required to bring drugs into commerce is driving efforts to repurpose FDA approved drugs-to find new uses for which they weren't intended, and to thereby reduce the overall cost of commercialization, and shorten the lag between drug discovery and availability. We report on the development, testing and application of a promising new approach to repositioning.
METHODS: Our approach is based on mining a human functional linkage network for inversely correlated modules of drug and disease gene targets. The method takes account of multiple information sources, including gene mutation, gene expression, and functional connectivity and proximity of within module genes.
RESULTS: The method was used to identify candidates for treating breast and prostate cancer. We found that (i) the recall rate for FDA approved drugs for breast (prostate) cancer is 20/20 (10/11), while the rates for drugs in clinical trials were 131/154 and 82/106; (ii) the ROC/AUC performance substantially exceeds that of comparable methods; (iii) preliminary in vitro studies indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. We briefly discuss the biological plausibility of the candidates at a molecular level in the context of the biological processes that they mediate.
CONCLUSIONS: Our method appears to offer promise for the identification of multi-targeted drug candidates that can correct aberrant cellular functions. In particular the computational performance exceeded that of other CMap-based methods, and in vitro experiments indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. The approach has the potential to provide a more efficient drug discovery pipeline.

PMID: 27475327 [PubMed - as supplied by publisher]