Inventing new therapies without reinventing the wheel: the power of drug repurposing.

Br J Pharmacol. 2018 Jan;175(2):165-167

Authors: Papapetropoulos A, Szabo C

Abstract
LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

PMID: 29313889 [PubMed - in process]

Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480.

Oncotarget. 2017 Dec 12;8(65):109319-109331

Authors: Gudernova I, Balek L, Varecha M, Kucerova JF, Bosakova MK, Fafilek B, Palusova V, Uldrijan S, Trantirek L, Krejci P

Abstract
Many tyrosine kinase inhibitors (TKIs) have failed to reach human use due to insufficient activity in clinical trials. However, the failed TKIs may still benefit patients if their other kinase targets are identified by providing treatment focused on syndromes driven by these kinases. Here, we searched for novel targets of AZD1480, an inhibitor of JAK2 kinase that recently failed phase two cancer clinical trials due to a lack of activity. Twenty seven human receptor tyrosine kinases (RTKs) and 153 of their disease-associated mutants were in-cell profiled for activity in the presence of AZD1480 using a newly developed RTK plasmid library. We demonstrate that AZD1480 inhibits ALK, LTK, FGFR1-3, RET and TRKA-C kinases and uncover a physical basis of this specificity. The RTK activity profiling described here facilitates inhibitor repurposing by enabling rapid and efficient identification of novel TKI targets in cells.

PMID: 29312610 [PubMed]

Drug Repositioning of Proton Pump Inhibitors for Enhanced Efficacy and Safety of Cancer Chemotherapy.

Front Pharmacol. 2017;8:911

Authors: Ikemura K, Hiramatsu S, Okuda M

Abstract
Proton pump inhibitors (PPIs), H+/K+-ATPase inhibitors, are the most commonly prescribed drugs for the treatment of gastroesophageal reflux and peptic ulcer diseases; they are highly safe and tolerable. Since PPIs are frequently used in cancer patients, studies investigating interactions between PPIs and anticancer agents are of particular importance to achieving effective and safe cancer chemotherapy. Several studies have revealed that PPIs inhibit not only the H+/K+-ATPase in gastric parietal cells, but also the vacuolar H+-ATPase (V-ATPase) overexpressed in tumor cells, as well as the renal basolateral organic cation transporter 2 (OCT2) associated with pharmacokinetics and/or renal accumulation of various drugs, including anticancer agents. In this mini-review, we summarize the current knowledge regarding the impact of PPIs on the efficacy and safety of cancer chemotherapeutics via inhibition of targets other than the H+/K+-ATPase. Co-administration of clinical doses of PPIs protected kidney function in patients receiving cisplatin and fluorouracil, presumably by decreasing accumulation of cisplatin in the kidney via OCT2 inhibition. In addition, co-administration or pretreatment with PPIs could inhibit H+ transport via the V-ATPase in tumor cells, resulting in lower extracellular acidification and intracellular acidic vesicles to enhance the sensitivity of the tumor cells to the anticancer agents. In the present mini-review, we suggest that PPIs enhance the efficacy and safety of anticancer agents via off-target inhibition (e.g., of OCT2 and V-ATPase), rather than on-target inhibition of the H+/K+-ATPase. The present findings should provide important information to establish novel supportive therapy with PPIs during cancer chemotherapy.

PMID: 29311921 [PubMed]

Encouraging New Uses for Old Drugs.

JAMA. 2017 Dec 26;318(24):2421-2422

Authors: Sachs RE, Ginsburg PB, Goldman DP

PMID: 29204602 [PubMed - indexed for MEDLINE]

Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets.

Drug Resist Updat. 2016 May;26:10-27

Authors: Mudduluru G, Walther W, Kobelt D, Dahlmann M, Treese C, Assaraf YG, Stein U

Abstract
The increasing unraveling of the molecular basis of cancer offers manifold novel options for intervention strategies. However, the discovery and development of new drugs for potential clinical applications is a tremendously time-consuming and costly process. Translating a novel lead candidate compound into an approved clinical drug takes often more than a decade, and the success rate is very low due to versatile efforts including defining its pharmacokinetics, pharmacodynamics, side effects as well as lack of sufficient efficacy. Thus, strategies are needed to minimize time and costs, while maximizing success rates. A very attractive strategy for novel cancer therapeutic options is the repositioning of already approved drugs. These medicines, approved for the treatment of non-malignant disorders, have already passed some early costs and time, have been tested in humans and are ready for clinical trials as anti-cancer drugs. Here we discuss the repositioning of nonsteroidal anti-inflammatory drugs (NSAID), statins, anti-psychotic drugs, anti-helminthic drugs and vitamin D as anti-tumor agents. We focus on their novel actions and potential for inhibition of cancer growth and metastasis by interfering with target molecules and pathways, which drive these malignant processes. Furthermore, important pre-clinical and clinical data are reviewed herein, which elucidate their therapeutic mechanisms which enable their repositioning for cancer therapy and disruption of metastasis.

PMID: 27180307 [PubMed - indexed for MEDLINE]

Distinct effects of HIV protease inhibitors and ERAD inhibitors on zygote to ookinete transition of the malaria parasite.

Mol Biochem Parasitol. 2018 Jan 03;:

Authors: Goulielmaki E, Kaforou S, Venugopal K, Loukeris TG, Siden-Kiamos I, Koussis K

Abstract
In an effort to eradicate malaria, new interventions are proposed to include compound/vaccine development against pre-erythrocytic, erythrocytic and mosquito stages of Plasmodium. Drug repurposing might be an alternative approach to new antimalarials reducing the cost and the time required for drug development. Previous in vitro studies have examined the effects of protease inhibitors on different stages of the Plasmodium parasite, although the clinical relevance of this remains unclear. In this study we tested the putative effect of three HIV protease inhibitors, two general aspartyl protease inhibitors and three AAA-p97 ATPase inhibitors on the zygote to ookinete transition of the Plasmodium parasite. Apart from the two general aspartyl inhibitors, all other compounds had a profound effect on the development of the parasites. HIVPIs inhibited zygote to ookinete conversion by 75%-90%, while the three AAA-p97 ATPase inhibitors blocked conversion by 50%-90% at similar concentrations, while electron microscopy highlighted nuclear and structural abnormalities. Our results highlight a potential of HIV protease inhibitors and p97 inhibitors as transmission blocking agents for the eradication of malaria.

PMID: 29305880 [PubMed - as supplied by publisher]

The Hippo pathway in normal development and cancer.

Pharmacol Ther. 2018 Jan 02;:

Authors: Maugeri-Saccà M, De Maria R

Abstract
The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption.

PMID: 29305295 [PubMed - as supplied by publisher]

Drug knowledge bases and their applications in biomedical informatics research.

Brief Bioinform. 2018 Jan 03;:

Authors: Zhu Y, Elemento O, Pathak J, Wang F

Abstract
Recent advances in biomedical research have generated a large volume of drug-related data. To effectively handle this flood of data, many initiatives have been taken to help researchers make good use of them. As the results of these initiatives, many drug knowledge bases have been constructed. They range from simple ones with specific focuses to comprehensive ones that contain information on almost every aspect of a drug. These curated drug knowledge bases have made significant contributions to the development of efficient and effective health information technologies for better health-care service delivery. Understanding and comparing existing drug knowledge bases and how they are applied in various biomedical studies will help us recognize the state of the art and design better knowledge bases in the future. In addition, researchers can get insights on novel applications of the drug knowledge bases through a review of successful use cases. In this study, we provide a review of existing popular drug knowledge bases and their applications in drug-related studies. We discuss challenges in constructing and using drug knowledge bases as well as future research directions toward a better ecosystem of drug knowledge bases.

PMID: 29304188 [PubMed - as supplied by publisher]

Establishing A Preclinical Multidisciplinary Board for Brain Tumors.

Clin Cancer Res. 2018 Jan 04;:

Authors: Nimmervoll B, Boulos N, Bianski BM, Dapper J, DeCuypere M, Shelat AA, Terranova S, Terhune HE, Gajjar A, Patel YT, Freeman BB, Onar-Thomas A, Stewart CF, Roussel MF, Guy RK, Merchant TE, Calabrese C, Wright KD, Gilbertson RJ

Abstract
PURPOSE: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies.  It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors.  Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.  Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC).  Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic and efficacy studies were used to triage active compounds for combination preclinical trials with 'standard-of-care' surgery and radiotherapy.
RESULTS: Mouse models displayed distinct patterns of response to surgery, irradiation and chemotherapy that varied with tumor subtype.  Repurposing screens identified three hour infusions of gemcitabine as a relatively non-toxic and efficacious treatment of SEP and CPC.  Combination neurosurgery, fractionated irradiation and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.
CONCLUSIONS:  We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing.  Post-irradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.

PMID: 29301833 [PubMed - as supplied by publisher]

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"

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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 2018/01/05

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.

Predicting drug-disease interactions by semi-supervised graph cut algorithm and three-layer data integration.

BMC Med Genomics. 2017 Dec 28;10(Suppl 5):79

Authors: Wu G, Liu J, Wang C

Abstract
BACKGROUND: Prediction of drug-disease interactions is promising for either drug repositioning or disease treatment fields. The discovery of novel drug-disease interactions, on one hand can help to find novel indictions for the approved drugs; on the other hand can provide new therapeutic approaches for the diseases. Recently, computational methods for finding drug-disease interactions have attracted lots of attention because of their far more higher efficiency and lower cost than the traditional wet experiment methods. However, they still face several challenges, such as the organization of the heterogeneous data, the performance of the model, and so on.
METHODS: In this work, we present to hierarchically integrate the heterogeneous data into three layers. The drug-drug and disease-disease similarities are first calculated separately in each layer, and then the similarities from three layers are linearly fused into comprehensive drug similarities and disease similarities, which can then be used to measure the similarities between two drug-disease pairs. We construct a novel weighted drug-disease pair network, where a node is a drug-disease pair with known or unknown treatment relation, an edge represents the node-node relation which is weighted with the similarity score between two pairs. Now that similar drug-disease pairs are supposed to show similar treatment patterns, we can find the optimal graph cut of the network. The drug-disease pair with unknown relation can then be considered to have similar treatment relation with that within the same cut. Therefore, we develop a semi-supervised graph cut algorithm, SSGC, to find the optimal graph cut, based on which we can identify the potential drug-disease treatment interactions.
RESULTS: By comparing with three representative network-based methods, SSGC achieves the highest performances, in terms of both AUC score and the identification rates of true drug-disease pairs. The experiments with different integration strategies also demonstrate that considering several sources of data can improve the performances of the predictors. Further case studies on four diseases, the top-ranked drug-disease associations have been confirmed by KEGG, CTD database and the literature, illustrating the usefulness of SSGC.
CONCLUSIONS: The proposed comprehensive similarity scores from multi-views and multiple layers and the graph-cut based algorithm can greatly improve the prediction performances of drug-disease associations.

PMID: 29297383 [PubMed - in process]

Pharmacophore anchor models of flaviviral NS3 proteases lead to drug repurposing for DENV infection.

BMC Bioinformatics. 2017 Dec 28;18(Suppl 16):548

Authors: Pathak N, Lai ML, Chen WY, Hsieh BW, Yu GY, Yang JM

Abstract
BACKGROUND: Viruses of the flaviviridae family are responsible for some of the major infectious viral diseases around the world and there is an urgent need for drug development for these diseases. Most of the virtual screening methods in flaviviral drug discovery suffer from a low hit rate, strain-specific efficacy differences, and susceptibility to resistance. It is because they often fail to capture the key pharmacological features of the target active site critical for protein function inhibition. So in our current work, for the flaviviral NS3 protease, we summarized the pharmacophore features at the protease active site as anchors (subsite-moiety interactions).
RESULTS: For each of the four flaviviral NS3 proteases (i.e., HCV, DENV, WNV, and JEV), the anchors were obtained and summarized into 'Pharmacophore anchor (PA) models'. To capture the conserved pharmacophore anchors across these proteases, were merged the four PA models. We identified five consensus core anchors (CEH1, CH3, CH7, CV1, CV3) in all PA models, represented as the "Core pharmacophore anchor (CPA) model" and also identified specific anchors unique to the PA models. Our PA/CPA models complied with 89 known NS3 protease inhibitors. Furthermore, we proposed an integrated anchor-based screening method using the anchors from our models for discovering inhibitors. This method was applied on the DENV NS3 protease to screen FDA drugs discovering boceprevir, telaprevir and asunaprevir as promising anti-DENV candidates. Experimental testing against DV2-NGC virus by in-vitro plaque assays showed that asunaprevir and telaprevir inhibited viral replication with EC50 values of 10.4 μM & 24.5 μM respectively. The structure-anchor-activity relationships (SAAR) showed that our PA/CPA model anchors explained the observed in-vitro activities of the candidates. Also, we observed that the CEH1 anchor engagement was critical for the activities of telaprevir and asunaprevir while the extent of inhibitor anchor occupation guided their efficacies.
CONCLUSION: These results validate our NS3 protease PA/CPA models, anchors and the integrated anchor-based screening method to be useful in inhibitor discovery and lead optimization, thus accelerating flaviviral drug discovery.

PMID: 29297305 [PubMed - in process]

Repositioning drugs by targeting network modules: a Parkinson's disease case study.

BMC Bioinformatics. 2017 Dec 28;18(Suppl 14):532

Authors: Yue Z, Arora I, Zhang EY, Laufer V, Bridges SL, Chen JY

Abstract
BACKGROUND: Much effort has been devoted to the discovery of specific mechanisms between drugs and single targets to date. However, as biological systems maintain homeostasis at the level of functional networks robustly controlling the internal environment, such networks commonly contain multiple redundant mechanisms designed to counteract loss or perturbation of a single member of the network. As such, investigation of therapeutics that target dysregulated pathways or processes, rather than single targets, may identify agents that function at a level of the biological organization more relevant to the pathology of complex diseases such as Parkinson's Disease (PD). Genome-wide association studies (GWAS) in PD have identified common variants underlying disease susceptibility, while gene expression microarray data provide genome-wide transcriptional profiles. These genomic studies can illustrate upstream perturbations causing the dysfunction in signaling pathways and downstream biochemical mechanisms leading to the PD phenotype. We hypothesize that drugs acting at the level of a gene expression module specific to PD can overcome the lack of efficacy associated with targeting a single gene in polygenic diseases. Thus, this approach represents a promising new direction for module-based drug discovery in human diseases such as PD.
RESULTS: We built a framework that integrates GWAS data with gene co-expression modules from tissues representing three brain regions-the frontal gyrus, the lateral substantia, and the medial substantia in PD patients. Using weighted gene correlation network analysis (WGCNA) software package in R, we conducted enrichment analysis of data from a GWAS of PD. This led to the identification of two over-represented PD-specific gene co-expression network modules: the Brown Module (Br) containing 449 genes and the Turquoise module (T) containing 905 genes. Further enrichment analysis identified four functional pathways within the Br module (cellular respiration, intracellular transport, energy coupled proton transport against the electrochemical gradient, and microtubule-based movement), and one functional pathway within the T module (M-phase). Next, we utilized drug-protein regulatory relationship databases (DMAP) and developed a Drug Effect Sum Score (DESS) to evaluate all candidate drugs that might restore gene expression to normal level across the Br and T modules. Among the drugs with the 12 highest DESS scores, 5 had been reported as potential treatments for PD and 6 hold potential repositioning applications.
CONCLUSION: In this study, we present a systems pharmacology framework which draws on genetic data from GWAS and gene expression microarray data to reposition drugs for PD. Our innovative approach integrates gene co-expression modules with biomolecular interaction network analysis to identify network modules critical to the PD pathway and disease mechanism. We quantify the positive effects of drugs in a DESS score that is based on known drug-target activity profiles. Our results illustrate that this modular approach is promising for repositioning drugs for use in polygenic diseases such as PD, and is capable of addressing challenges of the hindered gene target in drug repositioning approaches to date.

PMID: 29297292 [PubMed - in process]

The Immunogenetics of Psoriasis and Implications for Drug Repositioning.

Int J Mol Sci. 2017 Dec 08;18(12):

Authors: Xu X, Zhang HY

Abstract
Psoriasis is a genetically-regulated, T lymphocyte-mediated autoimmune skin disease that causes systemic damage, seriously affecting patient quality of life and survival. Psoriasis treatments, which aim to control the disease's development, are greatly limited because its etiology and pathogenesis have not yet been fully elucidated. A large number of studies have demonstrated that immunogenetic elements are the most important factors responsible for psoriasis susceptibility. This paper delineates the immunogenetic mechanisms of psoriasis and provides useful information with regards to performing drug repositioning for the treatment of psoriasis.

PMID: 29292715 [PubMed - in process]

Deal watch: IL-2 focus switches to stimulating Tregs.

Nat Rev Drug Discov. 2017 09 01;16(9):595

Authors: Cully M

PMID: 28860582 [PubMed - indexed for MEDLINE]

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors.

Int J Mol Sci. 2017 Dec 28;19(1):

Authors: Choi J, Lee YM, Jee JG

Abstract
Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors.

PMID: 29283382 [PubMed - in process]

Synergic in vitro combinations of artemisinin, pyrimethamine and methylene blue against Neospora caninum.

Vet Parasitol. 2018 Jan 15;249:92-97

Authors: Pereira LM, de Luca G, Abichabki NLM, Bronzon da Costa CM, Yatsuda AP

Abstract
Neospora caninum is a member of Apicomplexa phylum, the causative agent of neosporosis. The neosporosis combat is not well established and several strategies related to vaccine, chemotherapy and immune modulation are under development. In this work, we evaluated the effects of artemisinin (Art), methylene blue (MB) and pyrimethamine (Pyr) alone or associated, on N. caninum proliferation and elimination using LacZ tagged tachyzoites. The reactive oxygen species (ROS) production after incubation with Art were also performed. Our results indicate that combinations of classical antimalarial drugs improve the parasite control, allowing the use of three drugs in a single dose. Additionally, artemisinin demonstrated distinct ROS production patterns in intra and extracellular N. caninum forms. The drug repurposing appears as a suitable approach, allowing a fast and safe method to evaluate old drugs but novel candidates against neosporosis.

PMID: 29279093 [PubMed - in process]

Repurposing Medications for Hospice/Palliative Care Symptom Control Is No Longer Sufficient: A Manifesto for Change.

J Pain Symptom Manage. 2017 Mar;53(3):533-539

Authors: Currow DC, Abernethy AP, Fallon M, Portenoy RK

Abstract
The World Health Organization essential medications list for hospice/palliative care reflects that, with the judicious use of currently available medications, the majority of symptoms can be lessened, and some controlled completely. Even with optimal use of current medications, symptom control is still unacceptable for many people. Currently available medications offer great benefit to a minority of patients, some benefit to an additional group, and no benefit or harms to others. In symptom control, development of new drugs is advancing at a glacial pace, contrasting to the rapid advances seen in many other disciplines. Specialists in palliative care should agree on several principles consequently: 1) Access to symptom-control drugs codified in the World Health Organization Essential Medicines list deserves the strongest support from national policies and professional guidelines, especially in resource-challenged countries. 2) The optimal use of currently available symptom-control drugs cannot yield acceptably high rates of net benefits. 3) There is a compelling need to identify patient subgroups that are likely to benefit from available medications and provide rigorous empirical support for indications, dosing, and route of administration for clinical practice. 4) New therapies are needed requiring an accelerated effort to investigate further the pathophysiology, neurobiology, and pharmacogenetics of distressing symptoms, and factors contributing to variations in drug response. This development requires a lengthy lead time. 5) Smarter ways to promote new knowledge into practice are needed as no drug will be suitable for all patients. We need to improve clinical characterization and biomarker technology to bring the best drugs to the right patients every time.

PMID: 28042066 [PubMed - indexed for MEDLINE]

Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma.

Hepatology. 2017 Dec 26;:

Authors: Nepal C, O'Rourke CJ, Oliveira DV, Taranta A, Shema S, Gautam P, Calderaro J, Barbour A, Raggi C, Wennerberg K, Wang XW, Lautem A, Roberts LR, Andersen JB

Abstract
Intrahepatic cholangiocarcinoma (iCCA) remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients, and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, 'undetermined'). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, co-mutation profiles and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all 3 mutations ('undetermined') harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.
CONCLUSION: Stratification of iCCA patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) that influence pharmacologic response in drug repositioning protocols. This genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. This article is protected by copyright. All rights reserved.

PMID: 29278425 [PubMed - as supplied by publisher]