The isoquinoline alkaloid berberine inhibits human cytomegalovirus replication by interfering with the viral Immediate Early-2 (IE2) protein transactivating activity.

Antiviral Res. 2019 Feb 07;:

Authors: Luganini A, Mercorelli B, Messa L, Palù G, Gribaudo G, Loregian A

Abstract
The identification and validation of new small molecules able to inhibit the replication of human cytomegalovirus (HCMV) remains a priority to develop alternatives to the currently used DNA polymerase inhibitors, which are often burdened by long-term toxicity and emergence of cross-resistance. To contribute to this advancement, here we report on the characterization of the mechanism of action of a bioactive plant-derived alkaloid, berberine (BBR), selected in a previous drug repurposing screen expressly devised to identify early inhibitors of HCMV replication. Low micromolar concentrations of BBR were confirmed to suppress the replication of different HCMV strains, including clinical isolates and strains resistant to approved DNA polymerase inhibitors. Analysis of the HCMV replication cycle in infected cells treated with BBR then revealed that the bioactive compound compromised the progression of virus cycle at a stage prior to viral DNA replication and Early (E) genes expression, but after Immediate-Early (IE) proteins expression. Mechanistic studies in fact highlighted that BBR interferes with the transactivating functions of the viral IE2 protein, thus impairing efficient E gene expression and the progression of HCMV replication cycle. Finally, the mechanism of the antiviral activity of BBR appears to be conserved among different CMVs, since BBR suppressed murine CMV (MCMV) replication and inhibited the transactivation of the prototypic MCMV E1 gene by the IE3 protein, the murine homolog of IE2. Together, these observations warrant for further experimentation to obtain proof of concept that BBR could represent an attractive candidate for alternative anti-HCMV therapeutic strategies.

PMID: 30738836 [PubMed - as supplied by publisher]

PI3K inhibitors protect against glucocorticoid-induced skin atrophy.

EBioMedicine. 2019 Feb 05;:

Authors: Agarwal S, Mirzoeva S, Readhead B, Dudley JT, Budunova I

Abstract
BACKGROUND: Skin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids.
METHODS: Using drug repurposing approach, we screened LINCS library (http://lincsproject.org/LINCS/) to identify repressors of REDD1/FKBP51 expression. Candidate compounds were tested for their ability to inhibit glucocorticoid-induced REDD1/FKBP51 expression in human primary/immortalized keratinocytes and in mouse skin. Reporter gene expression, microarray, and chromatin immunoprecipitation were employed to evaluate effect of these inhibitors on the glucocorticoid receptor (GR) signaling.
FINDINGS: Bioinformatics analysis unexpectedly identified phosphoinositide-3-kinase (PI3K)/mTOR/Akt inhibitors as a pharmacological class of REDD1/FKBP51 repressors. Selected PI3K/mTOR/Akt inhibitors-Wortmannin (WM), LY294002, AZD8055, and two others indeed blocked REDD1/FKBP51expression in human keratinocytes. PI3K/mTOR/Akt inhibitors also modified global effect of glucocorticoids on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted GR phosphorylation; nuclear translocation; and GR loading on REDD1/FKBP51 gene promoters. Further, topical application of LY294002 together with glucocorticoid fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and skin atrophy but did not alter the anti-inflammatory activity of FA in ear edema test.
INTERPRETATION: Our results built a strong foundation for development of safer GR-targeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors. FUND: Work is supported by NIH grants R01GM112945, R01AI125366, and HESI-THRIVE foundation.

PMID: 30737086 [PubMed - as supplied by publisher]

Old Drugs and New Targets as an Outlook for the Treatment of Tuberculosis.

Curr Med Chem. 2018;25(38):5142-5167

Authors: Zitko J, Doležal M

Abstract
BACKGROUND: Despite of the globally positive trends in the epidemiology of tuberculosis, the increasing rates of drug-resistant strains are urging to introduce new antituberculars into clinical practice. Development of a new chemical entity from hit to marketed drug is an extremely time and resources consuming process with uncertain outcome. Repurposing of clinically used drugs can be a cheaper alternative to develop new drugs effective in the treatment of tuberculosis.
OBJECTIVE: To extract the latest information on new mechanisms of action described or proposed for clinically used antitubercular drugs. To identify drugs from various pharmacodynamic groups as candidates for repurposing to become effective in combatting tuberculosis. Attention will be paid to elucidate the connection between repurposed drugs and new antituberculars in clinical practice or in clinical trials.
METHODS: Scientific databases were searched for the keywords.
RESULTS: We reviewed the latest aspects of usage and new mechanisms of action for both first-line and second-line antitubercular drugs in clinical practice. Further, we found that surprisingly large number of clinically used drugs from various pharmacodynamic groups have potential to be used in the treatment of tuberculosis, including antimicrobial drugs not typically used against tuberculosis, statins, CNS drugs (tricyclic phenothiazines, antidepressants, anticonvulsants), non-steroidal anti-inflammatory drugs, kinase inhibitors, and others (metformin, disulfiram, verapamil, lansoprazole). Repurposed drugs may become effective antituberculars, acting either by direct effects on mycobacteria or as adjunct, host-directed therapy.
CONCLUSION: In this review, we showed that proper research of old drugs is a very efficient tool to develop new antituberculars.

PMID: 28933298 [PubMed - indexed for MEDLINE]

EXPRESS: Drug Repositioning in Pulmonary Arterial Hypertension: Challenges and Opportunities.

Pulm Circ. 2019 Feb 07;:2045894019832226

Authors: Grinnan D, Trankle C, Andruska A, Bloom B, Spiekerkoetter EF

Abstract

PMID: 30729869 [PubMed - as supplied by publisher]

Computational drug repurposing for inflammatory bowel disease using genetic information.

Comput Struct Biotechnol J. 2019;17:127-135

Authors: Grenier L, Hu P

Abstract
As knowledge of the genetics behind inflammatory bowel disease (IBD) has continually improved, there has been a demand for methods that can use this data in a clinically significant way. Genome-wide association analyses for IBD have identified 232 risk genetic loci for the disorder. While identification of these risk loci enriches our understanding of the underlying biology of the disorder, their identification does not serve a clinical purpose. A potential use of this genetic information is to look for potential IBD drugs that target these loci in a procedure known as drug repurposing. The demand for new drug treatments for IBD is high due to the side effects and high costs of current treatments. We hypothesize that IBD genetic variants obtained from GWAS and the candidate genes prioritized from the variants have a causal relationship with IBD drug targets. A computational drug repositioning study was done due to its efficiency and inexpensiveness compared to traditional in vitro or biochemical approaches. Our approach for drug repurposing was multi-layered; it not only focused on the interactions between drugs and risk IBD genes, but also the interactions between drugs and all of the biological pathways the risk genes are involved in. We prioritized IBD candidate genes using identified genetic variants and identified potential drug targets and drugs that can be potentially repositioned or developed for IBD using the identified candidate genes. Our analysis strategy can be applied to repurpose drugs for other complex diseases using their risk genes identified from genetic analysis.

PMID: 30728920 [PubMed]

Data mining for mutation-specific targets in acute myeloid leukemia.

Leukemia. 2019 Feb 06;:

Authors: Benard B, Gentles AJ, Köhnke T, Majeti R, Thomas D

Abstract
Three mutation-specific targeted therapies have recently been approved by the FDA for the treatment of acute myeloid leukemia (AML): midostaurin for FLT3 mutations, enasidenib for relapsed or refractory cases with IDH2 mutations, and ivosidenib for cases with an IDH1 mutation. Together, these agents offer a mutation-directed treatment approach for up to 45% of de novo adult AML cases, a welcome deluge after a prolonged drought. At the same time, a number of computational tools have recently been developed that promise to further accelerate progress in mutation-specific therapy for AML and other cancers. Technical advances together with comprehensively annotated AML tissue banks have resulted in the availability of large and complex data sets for exploration by the end-user, including (i) microarray gene expression, (ii) exome sequencing, (iii) deep sequencing data of sub-clone heterogeneity, (iv) RNA sequencing of gene expression (bulk and single cell), (v) DNA methylation and chromatin, (vi) and germline quantitative trait loci. Yet few clinicians or experimental hematologists have the time or the training to access or analyze these repositories. This review summarizes the data sets and bioinformatic tools currently available to further the discovery of mutation-specific targets with an emphasis on web-based applications that are open, accessible, user-friendly, and do not require coding experience to navigate. We show examples of how available data can be mined to identify potential targets using synthetic lethality, drug repurposing, epigenetic sub-grouping, and proteomic networks while also highlighting strengths and limitations and the need for superior models for validation.

PMID: 30728456 [PubMed - as supplied by publisher]

Drug development for cryptococcosis treatment: what can patents tell us?

Mem Inst Oswaldo Cruz. 2019 Jan 31;114:e180391

Authors: Santos-Gandelman J, Machado-Silva A

Abstract
BACKGROUND: Cryptococcosis is one of the most devastating fungal infections in humans. Despite the disease's clinical importance, current therapy is based on limited antifungals that are either toxic, inefficient, unavailable worldwide, or that quickly lead to resistance.
OBJECTIVES: The goal of this study was to provide insight into the future of cryptococcosis treatment by describing the patent scenario in this field.
METHODS: We identified and analysed patent documents revealing compounds with anti-cryptococcal activity supported by experimental evidence.
FINDINGS: Patenting in this field has been historically low, with an overall tendency of increase since 2012. Most applications are single filings, suggesting that they do not encompass strategic inventions requiring broad protection. Research and development essentially took place in China and the United States, which also represent the main countries of protection. Both academic and corporate institutions contributed to patenting in this field. Universities are the leading actors, with the highest patent family counts.
CONCLUSION: The low number of patents in this field indicates that efforts to mitigate the unmet needs for cryptococcosis treatment remain insufficient. Without investment to drive research and innovation, patients will likely continue to face inadequate assistance. Given the current scenario characterised by poor funding and low interest for technological development, drug repurposing may be the best alternative for cryptococcosis treatment.

PMID: 30726342 [PubMed - in process]

Potential for Drug Repositioning of Midazolam for Dentin Regeneration.

Int J Mol Sci. 2019 Feb 04;20(3):

Authors: Karakida T, Onuma K, Saito MM, Yamamoto R, Chiba T, Chiba R, Hidaka Y, Fujii-Abe K, Kawahara H, Yamakoshi Y

Abstract
Drug repositioning promises the advantages of reducing costs and expediting approvalschedules. An induction of the anesthetic and sedative drug; midazolam (MDZ), regulatesinhibitory neurotransmitters in the vertebrate nervous system. In this study we show the potentialfor drug repositioning of MDZ for dentin regeneration. A porcine dental pulp-derived cell line(PPU-7) that we established was cultured in MDZ-only, the combination of MDZ with bonemorphogenetic protein 2, and the combination of MDZ with transforming growth factor-beta 1. Thedifferentiation of PPU-7 into odontoblasts was investigated at the cell biological and genetic level.Mineralized nodules formed in PPU-7 were characterized at the protein and crystal engineeringlevels. The MDZ-only treatment enhanced the alkaline phosphatase activity and mRNA levels ofodontoblast differentiation marker genes, and precipitated nodule formation containing a dentinspecificprotein (dentin phosphoprotein). The nodules consisted of randomly orientedhydroxyapatite nanorods and nanoparticles. The morphology, orientation, and chemicalcomposition of the hydroxyapatite crystals were similar to those of hydroxyapatite that hadtransformed from amorphous calcium phosphate nanoparticles, as well as the hydroxyapatite inhuman molar dentin. Our investigation showed that a combination of MDZ and PPU-7 cellspossesses high potential of drug repositioning for dentin regeneration.

PMID: 30720745 [PubMed - in process]

Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis.

Antimicrob Agents Chemother. 2019 Feb 04;:

Authors: Puri S, Kumar R, Rojas IG, Salvatori O, Edgerton M

Abstract
Candida albicans, the causative agent of mucosal infections including oropharyngeal candidiasis (OPC) as well as bloodstream infections is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth. Here we evaluated the role of iron-limitation using deferasirox (an FDA approved iron chelator for treatment of patients with iron overload) during murine OPC; and assessed deferasirox-treated C. albicans for its interaction with human oral epithelial (OE), neutrophils, and antimicrobial peptides. Therapeutic deferasirox treatment significantly reduced salivary iron levels while a non-significant reduction in fungal burden was observed. Preventive treatment that allowed for two additional days of drug administration in our murine model, resulted in significant reduction of C. albicans colony forming units (CFU)/g of tongue tissue, a significant reduction in salivary iron levels, and significantly reduced neutrophil-mediated inflammation. C. albicans harvested from tongues of animals undergoing preventive treatment had differential expression of 106 genes, including those involved in iron metabolism, adhesion, and response to host innate immunity. Moreover, deferasirox-treated C. albicans cells had two-fold reduction in survival in neutrophil phagosomes (with greater susceptibility to oxidative stress); and reduced adhesion and invasion of OE cells, in vitro Thus deferasirox treatment has the potential to alleviate OPC by affecting C. albicans gene expression and reducing virulence.

PMID: 30718249 [PubMed - as supplied by publisher]

Drug repurposing against arabinosyl transferase (EmbC) of Mycobacterium tuberculosis: Essential dynamics and free energy minima based binding mechanics analysis.

Gene. 2019 Feb 01;:

Authors: Singh A, Somvanshi P, Grover A

Abstract
Arabinosyl tranferases (embA, embB, embC) are the key enzymes responsible for biogenesis of arabinan domain of arabinogalactan (AG) and lipoarabinomannan (LAM), two major heteropolysaccharide constituents of the peculiar mycobacterial cell envelope. EmbC is predominantly responsible for LAM synthesis and has been commonly associated with Ethambutol resistance. We have screened the FDA library against EmbC to reposition a drug better than Ethambutol with higher binding affinity to Embc. High throughput virtual screening followed by extra precision docking using Glide gave two best leads i.e. Terlipressin and Amikacin with docking score of -11.39 kcal/mol and -10.71 kcal/mol, respectively. Binding mechanics of the selected drugs was elucidated through long range molecular dynamics simulations (100 ns) using binding free energy rescoring, essential dynamics and free energy minima based approaches, thus revealing the most stable binding modes of Terlipressin with EmbC. Our study establishes the EmbC binding potential of the repurposed drugs Terlipressin and Amikacin.

PMID: 30716439 [PubMed - as supplied by publisher]

Conserved Disease Modules Extracted From Multilayer Heterogeneous Disease and Gene Networks for Understanding Disease Mechanisms and Predicting Disease Treatments.

Front Genet. 2018;9:745

Authors: Yu L, Yao S, Gao L, Zha Y

Abstract
Disease relationship studies for understanding the pathogenesis of complex diseases, diagnosis, prognosis, and drug development are important. Traditional approaches consider one type of disease data or aggregating multiple types of disease data into a single network, which results in important temporal- or context-related information loss and may distort the actual organization. Therefore, it is necessary to apply multilayer network model to consider multiple types of relationships between diseases and the important interplays between different relationships. Further, modules extracted from multilayer networks are smaller and have more overlap that better capture the actual organization. Here, we constructed a weighted four-layer disease-disease similarity network to characterize the associations at different levels between diseases. Then, a tensor-based computational framework was used to extract Conserved Disease Modules (CDMs) from the four-layer disease network. After filtering, nine significant CDMs were reserved. The statistical significance test proved the significance of the nine CDMs. Comparing with modules got from four single layer networks, CMDs are smaller, better represent the actual relationships, and contain potential disease-disease relationships. KEGG pathways enrichment analysis and literature mining further contributed to confirm that these CDMs are highly reliable. Furthermore, the CDMs can be applied to predict potential drugs for diseases. The molecular docking techniques were used to provide the direct evidence for drugs to treat related disease. Taking Rheumatoid Arthritis (RA) as a case, we found its three potential drugs Carvedilol, Metoprolol, and Ramipril. And many studies have pointed out that Carvedilol and Ramipril have an effect on RA. Overall, the CMDs extracted from multilayer networks provide us with an impressive understanding disease mechanisms from the perspective of multi-layer network and also provide an effective way to predict potential drugs for diseases based on its neighbors in a same CDM.

PMID: 30713550 [PubMed]

AS602801 Sensitizes Ovarian Cancer Stem Cells to Paclitaxel by Down-regulating MDR1.

Anticancer Res. 2019 Feb;39(2):609-617

Authors: Yamamoto M, Suzuki S, Togashi K, Sanomachi T, Seino S, Kitanaka C, Okada M

Abstract
BACKGROUND/AIM: AS602801, an anti-cancer stem cell (CSC) candidate drug, sensitizes ovarian CSCs to paclitaxel and carboplatin by reducing the expression of survivin, an anti-apoptotic protein. The aim of the study was to examine the effect of AS602801 on the expression of multi drug resistance protein 1 (MDR1).
MATERIALS AND METHODS: Using two ovarian CSC lines, A2780 CSLC and TOV-21G CSLC, mechanisms other than survivin down-regulation were examined by comparing the effects of AS602801 and YM155, an inhibitor of survivin. After screening for the expression of ATP-binding cassette (ABC) transporters with or without AS602801 treatment, the sensitivity of cells to paclitaxel, carboplatin, and cisplatin was examined following knockdown of the ABC transporter.
RESULTS: The combinational effect of AS602801 on paclitaxel was less dependent on survivin than the effect on carboplatin. AS602801 reduced the expression of MDR1, an ABC transporter. Knockdown of MDR1 sensitized the cells to paclitaxel, but not to carboplatin or cisplatin.
CONCLUSION: AS602801 chemosensitized ovarian CSCs to paclitaxel by reducing the expression of MDR1.

PMID: 30711936 [PubMed - in process]

Repurposing ibuprofen to control Staphylococcus aureus biofilms.

Eur J Med Chem. 2019 Jan 24;166:197-205

Authors: Oliveira IM, Borges A, Borges F, Simões M

Abstract
Drug repurposing arises as an interesting alternative to overcome the limited efficacy of current available antibiotics by reducing time, cost and risk associated with drug innovation. In this study, the activity of ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), was evaluated on the control of pre-established adhered cells (2 h) and 24 h old biofilms of Staphylococcus aureus. Bacterial adhesion was performed by S. aureus CECT 976, while biofilm formation was also performed by the antibiotic-resistant strains: SA1199B, RN4220 and XU212. The treatment with ibuprofen promoted metabolic reductions up to 80% and total loss of culturability of adhered cells and 24 h old biofilms. Ibuprofen demonstrated moderate efficacy to remove biofilms of S. aureus CECT 976 (removal ≤ 40%), but did not display removal action against the antibiotic-resistant strains. Antibacterial activity (inhibitory and bactericidal) and mode of action of ibuprofen were also assessed using different bacterial physiological indices. Minimum inhibitory and bactericidal concentrations of the four S. aureus strains ranged between 500 and 2000 mg L-1 and 1400 - >2000 mg L-1, respectively. After S. aureus CECT 976 incubation with ibuprofen, cell permeation to propidium iodide, release of intracellular potassium and changes on cell surface hydrophobicity were observed. The overall results, demonstrate that ibuprofen can control S. aureus planktonic and sessile growth, with strong destabilizing and disrupting action on the cytoplasmic membrane.

PMID: 30711830 [PubMed - as supplied by publisher]

Repurposing host-based therapeutics to control coronavirus and influenza virus.

Drug Discov Today. 2019 Jan 31;:

Authors: Li CC, Wang XJ, Wang HR

Abstract
The development of highly effective antiviral agents has been a major objective in virology and pharmaceutics. Drug repositioning has emerged as a cost-effective and time-efficient alternative approach to traditional drug discovery and development. This new shift focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for the therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus. Host-based antiviral agents target host cellular machineries essential for viral infections or innate immune responses to interfere with viral pathogenesis. This review discusses current knowledge, prospective applications and challenges in the repurposing of clinically approved and preclinically studied drugs for newly indicated antiviral therapeutics.

PMID: 30711575 [PubMed - as supplied by publisher]

Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis.

Biochem Pharmacol. 2019 Jan 30;:

Authors: Jin Yoon Y, Han YM, Choi J, Lee YJ, Yun J, Lee SK, Woo Lee C, Soon Kang J, Chi SW, Hee Moon J, Lee S, Cho Han D, Kwon BM

Abstract
Metastasis is the leading cause of cancer mortality and cancer cell migration is an essential stage of metastasis. We identified benproperine (Benp, a clinically used antitussive drug) as an inhibitor of cancer cell migration and an anti-metastatic agent. Benp selectively inhibited cancer cell migration and invasion, which also suppressed metastasis of cancer cells in animal models. Actin-related protein 2/3 complex subunit 2(ARPC2) was identified as a molecular target of Benp by affinity column chromatography with Benp-tagged Sepharose beads. Benp bound directly to ARPC2 in cells, which was validated by pull-down assay using Benp-biotin and label-free biochemical methods such as the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). Benp inhibited Arp2/3 function, showing disruption of lamellipodial structure and inhibition of actin polymerization. Unlike Arp2/3 inhibitors, Benp selectively inhibited the migration of cancer cells but not normal cells. ARPC2-knockdown cancer cells showed defective cell migration and suppressed metastasis in an animal model. Therefore, ARPC2 is a potential target for anti-metastatic therapy, and Benp has the clinical potential to block metastasis. Furthermore, Benp is a useful agent for studying the functions of the Arp2/3 complex in cancer cell migration and metastasis.

PMID: 30710516 [PubMed - as supplied by publisher]

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens.

Orphanet J Rare Dis. 2019 Feb 01;14(1):27

Authors: Armao D, Bouldin TW, Bailey RM, Hooper JE, Bharucha DX, Gray SJ

Abstract
Giant axonal neuropathy (GAN; ORPHA: 643; OMIM# 256850) is a rare, hereditary, pediatric neurodegenerative disorder associated with intracellular accumulations of intermediate filaments (IFs). GAN knockout (KO) mouse models mirror the IF dysregulation and widespread nervous system pathology seen in human GAN. Validation of therapeutic efficacy and viral vector delivery systems with these GAN KO models has provided the springboard for the development of a viral vector being delivered intrathecally in an ongoing Phase I gene therapy clinical trial for the treatment of children with GAN ( https://clinicaltrials.gov/ct2/show/NCT02362438 ). During the course of a comprehensive pathologic characterization of the GAN KO mouse, we discovered the very early and unexpected involvement of the ocular lens. Light microscopy revealed the presence of intracytoplasmic inclusion bodies within lens epithelial cells. The inclusion bodies showed strong immunohistochemical positivity for glial fibrillary acidic protein (GFAP). We confirmed that intracytoplasmic inclusion bodies are also present within lens epithelial cells in human GAN. These IF inclusion bodies in lens epithelial cells are unique to GAN. Similar IF inclusion bodies in lens epithelial cells have not been reported previously in experimental animal models or human diseases. Since current paradigms in drug discovery and drug repurposing for IF-associated disorders are often hindered by lack of validated targets, our findings suggest that lens epithelial cells in the GAN KO mouse may provide a potential target, in vivo and in vitro, for evaluating drug efficacy and alternative therapeutic approaches in promoting the clearance of IF inclusions in GAN and other diseases characterized by intracellular IF accumulations.

PMID: 30709364 [PubMed - in process]

Precision Medicine for Relapsed Multiple Myeloma on the Basis of an Integrative Multiomics Approach.

JCO Precis Oncol. 2018;2018:

Authors: Laganà A, Beno I, Melnekoff D, Leshchenko V, Madduri D, Ramdas D, Sanchez L, Niglio S, Perumal D, Kidd BA, Miotto R, Shaknovich R, Chari A, Cho HJ, Barlogie B, Jagannath S, Dudley JT, Parekh S

Abstract
Purpose: Multiple myeloma (MM) is a malignancy of plasma cells, with a median survival of 6 years. Despite recent therapeutic advancements, relapse remains mostly inevitable, and the disease is fatal in the majority of patients. A major challenge in the treatment of patients with relapsed MM is the timely identification of treatment options in a personalized manner. Current approaches in precision oncology aim at matching specific DNA mutations to drugs, but incorporation of genome-wide RNA profiles has not yet been clinically assessed.
Methods: We have developed a novel computational platform for precision medicine of relapsed and/or refractory MM on the basis of DNA and RNA sequencing. Our approach expands on the traditional DNA-based approaches by integrating somatic mutations and copy number alterations with RNA-based drug repurposing and pathway analysis. We tested our approach in a pilot precision medicine clinical trial with 64 patients with relapsed and/or refractory MM.
Results: We generated treatment recommendations in 63 of 64 patients. Twenty-six patients had treatment implemented, and 21 were assessable. Of these, 11 received a drug that was based on RNA findings, eight received a drug that was based on DNA, and two received a drug that was based on both RNA and DNA. Sixteen of the 21 evaluable patients had a clinical response (ie, reduction of disease marker ≥ 25%), giving a clinical benefit rate of 76% and an overall response rate of 66%, with five patients having ongoing responses at the end of the trial. The median duration of response was 131 days.
Conclusion: Our results show that a comprehensive sequencing approach can identify viable options in patients with relapsed and/or refractory myeloma, and they represent proof of principle of how RNA sequencing can contribute beyond DNA mutation analysis to the development of a reliable drug recommendation tool.

PMID: 30706044 [PubMed]

Selecting precise reference normal tissue samples for cancer research using a deep learning approach.

BMC Med Genomics. 2019 Jan 31;12(Suppl 1):21

Authors: Zeng WZD, Glicksberg BS, Li Y, Chen B

Abstract
BACKGROUND: Normal tissue samples are often employed as a control for understanding disease mechanisms, however, collecting matched normal tissues from patients is difficult in many instances. In cancer research, for example, the open cancer resources such as TCGA and TARGET do not provide matched tissue samples for every cancer or cancer subtype. The recent GTEx project has profiled samples from healthy individuals, providing an excellent resource for this field, yet the feasibility of using GTEx samples as the reference remains unanswered.
METHODS: We analyze RNA-Seq data processed from the same computational pipeline and systematically evaluate GTEx as a potential reference resource. We use those cancers that have adjacent normal tissues in TCGA as a benchmark for the evaluation. To correlate tumor samples and normal samples, we explore top varying genes, reduced features from principal component analysis, and encoded features from an autoencoder neural network. We first evaluate whether these methods can identify the correct tissue of origin from GTEx for a given cancer and then seek to answer whether disease expression signatures are consistent between those derived from TCGA and from GTEx.
RESULTS: Among 32 TCGA cancers, 18 cancers have less than 10 matched adjacent normal tissue samples. Among three methods, autoencoder performed the best in predicting tissue of origin, with 12 of 14 cancers correctly predicted. The reason for misclassification of two cancers is that none of normal samples from GTEx correlate well with any tumor samples in these cancers. This suggests that GTEx has matched tissues for the majority cancers, but not all. While using autoencoder to select proper normal samples for disease signature creation, we found that disease signatures derived from normal samples selected via an autoencoder from GTEx are consistent with those derived from adjacent samples from TCGA in many cases. Interestingly, choosing top 50 mostly correlated samples regardless of tissue type performed reasonably well or even better in some cancers.
CONCLUSIONS: Our findings demonstrate that samples from GTEx can serve as reference normal samples for cancers, especially those do not have available adjacent tissue samples. A deep-learning based approach holds promise to select proper normal samples.

PMID: 30704474 [PubMed - in process]

Drug Repurposing Campaigns for Human Cytomegalovirus Identify a Natural Compound Targeting the Immediate-Early 2 (IE2) Protein: A Comment on "The Natural Flavonoid Compound Deguelin Inhibits HCMV Lytic Replication within Fibroblasts".

Viruses. 2019 Jan 29;11(2):

Authors: Mercorelli B, Luganini A, Palù G, Gribaudo G, Loregian A

Abstract
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that establishes a lifelong persistence in the host through both chronic and latent states of infection [...].

PMID: 30699923 [PubMed - in process]

Adenylate kinase 4 modulates oxidative stress and stabilizes HIF-1α to drive lung adenocarcinoma metastasis.

J Hematol Oncol. 2019 Jan 29;12(1):12

Authors: Jan YH, Lai TC, Yang CJ, Lin YF, Huang MS, Hsiao M

Abstract
BACKGROUND: Adenylate kinase 4 (AK4) has been identified as a biomarker of metastasis in lung cancer. However, the impacts of AK4 on metabolic genes and its translational value for drug repositioning remain unclear.
METHODS: Ingenuity upstream analyses were used to identify potential transcription factors that regulate the AK4 metabolic gene signature. The expression of AK4 and its upstream regulators in lung cancer patients was examined via immunohistochemistry. Pharmacological and gene knockdown/overexpression approaches were used to investigate the interplay between AK4 and its upstream regulators during epithelial-to-mesenchymal transition (EMT). Drug candidates that reversed AK4-induced gene expression were identified by querying a connectivity map. Orthotopic xenograft mouse models were established to evaluate the therapeutic efficacy of drug candidates for metastatic lung cancer.
RESULTS: We found that HIF-1α is activated in the AK4 metabolic gene signature. IHC analysis confirmed this positive correlation, and the combination of both predicts worse survival in lung cancer patients. Overexpression of AK4 exaggerates HIF-1α protein expression by increasing intracellular ROS levels and subsequently induces EMT under hypoxia. Attenuation of ROS production with N-acetylcysteine abolishes AK4-induced invasion potential under hypoxia. Pharmacogenomics analysis of the AK4 gene signature revealed that withaferin-A could suppress the AK4-HIF-1α signaling axis and serve as a potent anti-metastatic agent in lung cancer.
CONCLUSIONS: Overexpression of AK4 promotes lung cancer metastasis by enhancing HIF-1α stability and EMT under hypoxia. Reversing the AK4 gene signature with withaferin-A may serve as a novel therapeutic strategy to treat metastatic lung cancer.

PMID: 30696468 [PubMed - in process]