Drugs For New Indications Research Articles

Abstract PL08-04: High-throughput drug screens in cancer cell models to enable precision cancer medicine

Abstract Alterations in cancer genomes strongly influence clinical responses to therapy and can be used as molecular biomarkers of response to targeted agents. However, the identification of biomarkers for effective patient stratification remains a considerable challenge for the development of effective therapies. We are performing large-scale drug sensitivity screens using genetically characterised in vitro cellular models of human cancer. Cancer cells are profiled for differential sensitivity to clinical, pre-clinical and experimental anti-cancer compounds and drug response is linked with genomic features. We aim to identify the molecular features of cancer cells which impact on drug sensitivity and resistance, and investigate the molecular rationale for the observed sensitivity. This provides insights into mechanism of drug action, identifies opportunities for re-purposing existing drugs for new indications, and enables the identification of biomarkers to facilitate the development of targeted cancer therapies. I will describe results from our recent analysis of how cancer-driving alterations identified from the analysis of 11,000 patient tumours correlate with response to 265 compounds profiled in a panel of 1,000 human cancer cell-lines. This comprehensive analysis provides an initial glimpse of the landscape of pharmacogenomic interactions operative in human cancer, and is a resource to identify novel therapeutic possibilities for selected cancer sub-populations. Citation Format: Mathew Garnett. High-throughput drug screens in cancer cell models to enable precision cancer medicine. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL08-04.

Target-Based Drug Repositioning Using Large-Scale Chemical-Protein Interactome Data.

Drug repositioning, or the identification of new indications for known drugs, is a useful strategy for drug discovery. In this study, we developed novel computational methods to predict potential drug targets and new drug indications for systematic drug repositioning using large-scale chemical-protein interactome data. We explored the target space of drugs (including primary targets and off-targets) based on chemical structure similarity and phenotypic effect similarity by making optimal use of millions of compound-protein interactions. On the basis of the target profiles of drugs, we constructed statistical models to predict new drug indications for a wide range of diseases with various molecular features. The proposed method outperformed previous methods in terms of interpretability, applicability, and accuracy. Finally, we conducted a comprehensive prediction of the drug-target-disease association network for 8270 drugs and 1401 diseases and showed biologically meaningful examples of newly predicted drug targets and drug indications. The predictive model is useful to understand the mechanisms of the predicted drug indications.

An FDA-Drug Library Screen for Compounds with Bioactivities against Meticillin-Resistant Staphylococcus aureus (MRSA).

The lack of new antibacterial drugs entering the market and their misuse have resulted in the emergence of drug-resistant bacteria, posing a major health crisis worldwide. In particular, meticillin-resistant Staphylococcus aureus (MRSA), a pathogen responsible for numerous human infections, has become endemic in hospitals worldwide. Drug repurposing, the finding of new therapeutic indications for approved drugs, is deemed a plausible solution to accelerate drug discovery and development in this area. Towards this end, we screened 1163 drugs approved by the Food and Drug Administration (FDA) for bioactivities against MRSA in a 10 μM single-point assay. After excluding known antibiotics and antiseptics, six compounds were identified and their MICs were determined against a panel of clinical MRSA strains. A toxicity assay using human keratinocytes was also conducted to gauge their potential for repurposing as topical agents for treating MRSA skin infections.

Editorial: The Vital Role of Randomized Controlled Trials in Arthritis & Rheumatology

Editorial: The Vital Role of Randomized Controlled Trials in <i>Arthritis &amp; Rheumatology</i>

Repurpose terbutaline sulfate for amyotrophic lateral sclerosis using electronic medical records.

Prediction of new disease indications for approved drugs by computational methods has been based largely on the genomics signatures of drugs and diseases. We propose a method for drug repositioning that uses the clinical signatures extracted from over 13 years of electronic medical records from a tertiary hospital, including >9.4 M laboratory tests from >530,000 patients, in addition to diverse genomics signatures. Cross-validation using over 17,000 known drug–disease associations shows this approach outperforms various predictive models based on genomics signatures and a well-known “guilt-by-association” method. Interestingly, the prediction suggests that terbutaline sulfate, which is widely used for asthma, is a promising candidate for amyotrophic lateral sclerosis for which there are few therapeutic options. In vivo tests using zebrafish models found that terbutaline sulfate prevents defects in axons and neuromuscular junction degeneration in a dose-dependent manner. A therapeutic potential of terbutaline sulfate was also observed when axonal and neuromuscular junction degeneration have already occurred in zebrafish model. Cotreatment with a β2-adrenergic receptor antagonist, butoxamine, suggests that the effect of terbutaline is mediated by activation of β2-adrenergic receptors.

Systematic evaluation of connectivity map for disease indications.

BackgroundConnectivity map data and associated methodologies have become a valuable tool in understanding drug mechanism of action (MOA) and discovering new indications for drugs. One of the key ideas of connectivity map (CMAP) is to measure the connectivity between disease gene expression signatures and compound-induced gene expression profiles. Despite multiple impressive anecdotal validations, only a few systematic evaluations have assessed the accuracy of this aspect of CMAP, and most of these utilize drug-to-drug matching to transfer indications across the two drugs.MethodsTo assess CMAP methodologies in a more direct setting, namely the power of classifying known drug-disease relationships, we evaluated three CMAP-based methods on their prediction performance against a curated dataset of 890 true drug-indication pairs. The disease signatures were generated using Gene Logic BioExpress™ system and the compound profiles were derived from the Connectivity Map database (CMAP, build 02, http://www.broadinstitute.org/CMAP/).ResultsThe similarity scoring algorithm called eXtreme Sum (XSum) performs better than the standard Kolmogorov-Smirnov (KS) statistic in terms of the area under curve and can achieve a four-fold enrichment at 0.01 false positive rate level, with AUC = 2.2E-4, P value = 0.0035.ConclusionConnectivity map can significantly enrich true positive drug-indication pairs given an effective matching algorithm.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0095-1) contains supplementary material, which is available to authorized users.

NMR spectroscopy-based metabolic profiling of drug-induced changes in vitro can discriminate between pharmacological classes.

Drug-induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances, as well as to support drug repurposing, i.e., identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the "Connectivity Map" (CMap). However, the potential of similar exercises at the metabolite level is still largely unexplored. Only recently, the first high-throughput metabolomic assay pilot study was published, which involved screening the metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here, we report results from a separately developed metabolic profiling assay, which leverages (1)H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of the most-tested drugs, according to their respective pharmacological class. A more-advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (3 metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this type of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information-rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.

Expanding the scope of drug repurposing in pediatrics: The Children's Pharmacy Collaborative™

Drug repurposing is the use of 'old' drugs for new indications, avoiding the need for time- and cost-intensive toxicity studies. This approach should be particularly attractive for pediatrics, but its use in this population has been limited. One obstacle has been the lack of a comprehensive database of drugs for which there already is at least one indication in children. We describe the development of The Children's Pharmacy Collaborative, which should grow over time, serve as a resource for professionals and families, and stimulate drug-repurposing efforts for a range of pediatric disorders.

Recycling existing drugs for cancer therapy: delivering low cost cancer care.

Recycling existing drugs for cancer therapy: delivering low cost cancer care.

Are biologic treatments a potential approach to wear- and corrosion-related problems?

WHERE ARE WE NOW?: Biological treatments, defined as any nonsurgical intervention whose primary mechanism of action is reducing the host response to wear and/or corrosion products, have long been postulated as solutions for osteolysis and aseptic loosening of total joint arthroplasties. Despite extensive research on drugs that target the inflammatory, osteoclastic, and osteogenic responses to wear debris, no biological treatment has emerged as an approved therapy. We review the extensive preclinical research and modest clinical research to date, which has led to the central conclusion that the osteoclast is the primary target. We also allude to the significant changes in health care, unabated safety concerns about chronic immunosuppressive/antiinflammatory therapies, industry's complete lack of interest in developing an intervention for this condition, and the practical issues that have narrowly focused the possibilities for a biologic treatment for wear debris-induced osteolysis. WHERE DO WE NEED TO GO?: Based on the conclusions from research, and the economic, regulatory, and practical issues that limit the future directions toward the development of a biologic treatment, there are a few rational approaches that warrant investigation. These largely focus on FDA-approved osteoporosis therapies that target the osteoclast (bisphosphonates and anti-RANK ligand) and recombinant parathyroid hormone (teriparatide) prophylactic treatment to increase osseous integration of the prosthesis to overcome high-risk susceptibility to aseptic loosening. The other roadblock that must be overcome if there is to be an approved biologic therapy to prevent the progression of periprosthetic osteolysis and aseptic loosening is the development of radiological measures that can quantify a significant drug effect in a randomized, placebo-controlled clinical trial. We review the progress of volumetric quantification of osteolysis in animal studies and clinical pilots. HOW DO WE GET THERE?: Accepting the aforementioned rigid boundaries, we describe the emergence of repurposing FDA-approved drugs for new indications and public (National Institutes of Health, FDA, Centers for Disease Control and Prevention) and private (universities and drug and device manufactures) partnerships as the future roadmap for clinical translation. In the case of biologic treatments for wear debris-induced osteolysis, this will involve combined federal and industry funding of multicenter clinical trials that will be run by thought leaders at large medical centers.

Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection.

Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies.

Drugs acting on central nervous system (CNS) targets as leads for non-CNS targets.

Innovative drug discovery approaches are currently needed to rejuvenate the shrinking product pipelines of the pharmaceutical companies across the globe. Here a theme is presented – the use of central nervous system (CNS) drugs as leads for non-CNS targets. The approach is related to the use of existing drugs for new indications. Suitable chemical modifications of the CNS drugs abolish their CNS penetration. These novel analogs may then be screened for activity against non-CNS targets. Careful selection of the appropriate structural modifications remains the key to success.

Estrogen Receptor Antagonists Are Anti-Cryptococcal Agents That Directly Bind EF Hand Proteins and Synergize with Fluconazole In Vivo

ABSTRACTCryptococcosis is an infectious disease of global significance for which new therapies are needed. Repurposing previously developed drugs for new indications can expedite the translation of new therapies from bench to beside. Here, we characterized the anti-cryptococcal activity and antifungal mechanism of estrogen receptor antagonists related to the breast cancer drugs tamoxifen and toremifene. Tamoxifen and toremifene are fungicidal and synergize with fluconazole and amphotericin B in vitro. In a mouse model of disseminated cryptococcosis, tamoxifen at concentrations achievable in humans combines with fluconazole to decrease brain burden by ~1 log10. In addition, these drugs inhibit the growth of Cryptococcus neoformans within macrophages, a niche not accessible by current antifungal drugs. Toremifene and tamoxifen directly bind to the essential EF hand protein calmodulin, as determined by thermal shift assays with purified C. neoformans calmodulin (Cam1), prevent Cam1 from binding to its well-characterized substrate calcineurin (Cna1), and block Cna1 activation. In whole cells, toremifene and tamoxifen block the calcineurin-dependent nuclear localization of the transcription factor Crz1. A large-scale chemical genetic screen with a library of C. neoformans deletion mutants identified a second EF hand-containing protein, which we have named calmodulin-like protein 1 (CNAG_05655), as a potential target, and further analysis showed that toremifene directly binds Cml1 and modulates its ability to bind and activate Cna1. Importantly, tamoxifen analogs (idoxifene and methylene-idoxifene) with increased calmodulin antagonism display improved anti-cryptococcal activity, indicating that calmodulin inhibition can be used to guide a systematic optimization of the anti-cryptococcal activity of the triphenylethylene scaffold.

Drugs acting on central nervous system (CNS) targets as leads for non-CNS targets

Innovative drug discovery approaches are currently needed to rejuvenate the shrinking product pipelines of the pharmaceutical companies across the globe. Here a theme is presented – the use of central nervous system (CNS) drugs as leads for non-CNS targets. The approach is related to the use of existing drugs for new indications. Suitable chemical modifications of the CNS drugs abolish their CNS penetration. These novel analogs may then be screened for activity against non-CNS targets. Careful selection of the appropriate structural modifications remains the key to success.

Abstract B19: Phenothiazines induce cytotoxicity and enhance chemotherapy-induced cell death signaling in acute myeloid leukemia.

Abstract Acute myeloid leukemia (AML) is a hematological malignancy characterized by a clonal proliferation of myeloid precursor cells. Acquired genetic aberrations have been linked to leukemogenic events such as blocked differentiation and deregulated proliferation. Conventional chemotherapeutic regimens used for AML typically involve anthracyclines and cytarabine, often resulting in complete remission (CR), although relapsing disease with a resistant phenotype is still common. Thus, novel therapeutic strategies are clearly needed. We have shown that the CD33-targeted drug gemtuzumab ozogamicin (GO) can induce significant DNA double strand break (dsbs) formation and activate pro-apoptotic signaling via Bak, Bax, and Caspase-3 in AML. The interest in using “old” FDA-approved drugs for new indications is increasing. We have previously reported that phenothiazines, compounds in clinical use for psychiatric disorders, have the capacity to increase chemotherapy-induced cell death by increasing DNA damage signaling and block DNA repair in solid tumor cells. Here we evaluated the effect of phenothiazines as mono therapy, and in combination with different classes of chemotherapeutics, on AML cells representing different leukemic subtypes. A panel of structurally different phenothiazines (trifluoperazine, thiothixene, chlorpromazine, triflupromazine, fluphenazine, cis-flupenthixol, prochlorperazine, and hydroxyzine) was evaluated for induction of in vitro cytotoxicity in the AML cell lines HL60, Kasumi-1, KG1a, and NB4, representing different AML subtypes. When used as mono therapy trifluoperazine (TFP) was the most efficient cell death inducing phenothiazine. Next the effect of phenothiazines on chemotherapy-induced responses was examined. A sub toxic dose of TFP, causing a 10% reduction in cell viability, was used in combination with the chemotherapeutics daunorubicin or GO. Pre-incubating AML cells for 1h with TFP increased GO-induced cytoxicity by up to 45%. Interestingly, a greater sensitization of chemotherapy-induced cell kill was observed in GO-resistant Kasumi-1 cells than in responsive HL-60 cells. In line with previous results in solid tumor malignancies we found that TFP increased chemotherapy-induced DNA damage signaling, Bak/Bax and caspase-3 activation also in the AML cells examined, suggesting increased DNA damage signaling to be operative. In conclusion, we show that AML cells are differentially sensitive to a panel of phenothiazines when used in mono therapy and can potentiate different classes of chemotherapeutics by increasing DNA damage response signaling. Thus, this may be a promising treatment option for AML which needs to be further explored by analyzing AML patient derived cells, studies which are ongoing within our group. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B19. Citation Format: Petra Haag, Katarzyna Zielinska-Chomej, Therese Juntti, Lena Kanter, Rolf Lewensohn, Leif Stenke, Kristina Viktorsson. Phenothiazines induce cytotoxicity and enhance chemotherapy-induced cell death signaling in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B19.

Solving the Problem of New Uses

One of the most dramatic public-policy failures in biomedical research is the lack of incentives for industry to develop new therapeutic uses (“indications”) for existing drugs once generics are available. Policymakers and commentators are well aware of this “problem of new uses,” but fail to appreciate its magnitude. Over the past decade, this gap in the incentives for pharmaceutical R&D has become one of the greatest barriers to medical progress. Recent technological advances have allowed researchers to identify hundreds of potential new indications for older drugs that could address critical unmet medical needs. And researchers are poised to discover hundreds more. Developing new indications for existing drugs is much faster, cheaper, and less risky than developing new drugs, and therefore offers the single most promising avenue for delivering new medical treatments to the public. However, pharmaceutical companies invariably lose interest in developing new uses for existing drugs when patients have access to low-cost generics. This article explores the nature and source of this gap in the incentives for developing new medical treatments, showing that it ultimately stems from a simple information problem. At present, the government encourages drug development by granting firms temporary monopoly rights that block generic manufacturers from making or selling imitations of their drugs. The government also makes available an alternative type of monopoly protection for new indications that applies to the act of taking or administering a drug for a new therapeutic use. The latter monopoly rights could provide the appropriate incentives for developing new uses of existing drugs. However, pharmaceutical companies cannot enforce these rights without knowing when physicians prescribe the drug for the patented indication as opposed to some other use. If the government established an infrastructure for pharmaceutical companies to monitor the prescribed indications when pharmacists fill a prescription, those firms would possess the information necessary to enforce patents on new indications, thereby solving the problem of new uses. This article argues that the government could easily create such an infrastructure through the expanding use of e-prescribing software and electronic medical records.

Drug repositioning for orphan genetic diseases through Conserved Anticoexpressed Gene Clusters (CAGCs)

BackgroundThe development of new therapies for orphan genetic diseases represents an extremely important medical and social challenge. Drug repositioning, i.e. finding new indications for approved drugs, could be one of the most cost- and time-effective strategies to cope with this problem, at least in a subset of cases. Therefore, many computational approaches based on the analysis of high throughput gene expression data have so far been proposed to reposition available drugs. However, most of these methods require gene expression profiles directly relevant to the pathologic conditions under study, such as those obtained from patient cells and/or from suitable experimental models. In this work we have developed a new approach for drug repositioning, based on identifying known drug targets showing conserved anti-correlated expression profiles with human disease genes, which is completely independent from the availability of ‘ad hoc’ gene expression data-sets.ResultsBy analyzing available data, we provide evidence that the genes displaying conserved anti-correlation with drug targets are antagonistically modulated in their expression by treatment with the relevant drugs. We then identified clusters of genes associated to similar phenotypes and showing conserved anticorrelation with drug targets. On this basis, we generated a list of potential candidate drug-disease associations. Importantly, we show that some of the proposed associations are already supported by independent experimental evidence.ConclusionsOur results support the hypothesis that the identification of gene clusters showing conserved anticorrelation with drug targets can be an effective method for drug repositioning and provide a wide list of new potential drug-disease associations for experimental validation.

Wither the Cooperative Groups?

The cooperative groups sponsored by the National Cancer Institute (NCI) were formed beginning in the mid-1950s and have provided a publicly funded standing infrastructure to conduct cancer clinical trials ever since (Appendix Fig A1, online only). The accomplishments of the US cooperative groups, often in collaboration with similar organizations in Europe and Canada, are notable for the development of curative therapies for most pediatric cancers; the introduction of effective combined modality treatments for many diseases, including head and neck cancer, cervical cancer, esophageal cancer, non–small-cell lung cancer, and anal cancer; the development of adjuvant chemotherapy as a standard of care for many solid tumors, particularly breast cancer and colorectal cancer; and the introduction of chemoprevention strategies for patients at high risk of developing breast and prostate cancer. The groups have also worked collaboratively with the pharmaceutical industry to introduce new cancer drugs into medical practice and to develop new indications for already approved drugs. Indeed, more than 20 new indications for cancer drugs have resulted directly from cooperative group studies. Clinical trials performed by the cooperative groups have also provided important insights into optimal scheduling and sequencing of chemotherapy drugs and the preferred route of drug administration that have established new standards of care, such as the introduction of dose-dense chemotherapy as part of adjuvant treatment of breast cancer and the demonstration of improved survival when intraperitoneal administration of chemotherapy is used for treatment of ovarian cancer. Importantly, cooperative groups have also rigorously evaluated purported advances in cancer care that were popularized by single individuals or centers and, in some cases, such as high-dose chemotherapy and autologous stem-cell transplant for breast cancer, have proven them ineffective. Finally, many important advances in supportive care for patients with cancer have come from cooperative group studies, such as the recent demonstration of the value of duloxetine to relieve symptoms of chemotherapyinduced painful peripheral neuropathy. In the current era of molecular medicine, the cooperative group biospecimen repositories, populated with specimens from clinical trial participants who received uniform treatments and have welldocumented outcomes, are invaluable resources for the development of new prognostic, predictive, and response biomarkers across a range of cancer types. These repositories will support a new generation of biomarker-driven clinical trials currently in development by the cooperative groups. And, with the heightened public interest in comparative effectiveness and cost, the cooperative groups, as publicly funded entities free from commercial bias, are ideally positioned to directly compare therapeutic approaches or drugs from competing commercial firms, combine drugs from different sponsors, develop treatments for rare diseases with small commercial markets, and rigorously examine the cost effectiveness of new treatments and their impact on patient quality of life. Beyond their scientific contributions, the cooperative groups have developed many of the standard methods to conduct multicenter clinical trials, extended clinical trials to community oncologists, and provided a fertile training ground for generations of clinical investigators and countless research staff. Despite their many contributions to cancer care and research, the cooperative groups have been subjected to scrutiny and criticism for nearly their entire existence. In the last 15 years alone, no fewer than five committees have been convened by NCI or at the request of NCI to evaluate the cooperative group program. Most recently the Institute of Medicine (IOM) of the National Academy of Sciences produced a report at the request of the NCI entitled, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program,” which identified the many challenges faced by the cooperative groups at the present time, including stagnant funding; inefficient and redundant processes; excessive and complex government oversight, with many layers of review performed by multiple agencies; long delays in the launch of clinical trials; and increasing competition from the pharmaceutical industry for patient accrual to studies. When the IOM report was issued, the time required to activate a phase III trial in the cooperative groups averaged nearly 2 years, and JOURNAL OF CLINICAL ONCOLOGY S P E C I A L A R T I C L E VOLUME 32 NUMBER 3 JANUARY 2

Should be NICE have a Spanish NICE?

Cancer is the second leading cause of death in Spain, accounting for 25 % of all deaths. One out of three men and one out of four women will have a cancer during their lives, a proportion that will increase with progressive ageing of the general population. The direct cost of cancer in our country was €3.8 billion in 2002–2003, which represents 6.5 % of the total health budget (59.3 billion) [1] and is similar to that of other European countries. The percentage ranges from 4.1 in Holland to 7 % in Sweden, through 5.6 % in UK and 5 % in the USA [2]. However, the change over time is alarming: for instance, in the USA the direct medical expense of cancer has increased from about $27 billion in 1990 to more than $90 billion in 2008 [3]. There are no figures for Spain in this regard, although the expense has at least doubled. The main reason for this trend is the increasing cost of new drugs, the use of drugs in new indications and the incorporation of modern technologies to the clinic. Cost escalation seems to be out of proportion considering the small benefit that brings in many instances. For example, the incorporation of new agents to the classical combination 5-fluorouracil and leucovorin in colorectal cancer has doubled survival, but at the expense of a 340-fold increase in cost [4]. As a result, therapy for the commonest types of cancer may mean €30,000–60,000 per drug and patient, with a minor impact on survival. The inevitable question rises whether our society can afford increasing health costs. Considering also the current economical crisis, with national and regional restrictions as the norm, measures to guarantee the sustainability of the health system are warranted. Doctors may contribute by prescribing according to treatment guidelines. We should select patients with higher chances of benefit, hence the need for progress in the field of predictive biomarkers. Likewise, treatments administered with low evidence of activity or in extreme situations should be avoided [5]. Independent investigation should be supported, particularly when evaluating new indications for conventional drugs and low-cost technologies. Thorough evaluation of new technologies should be performed to avoid those yielding a marginal benefit. Along with above mentioned and other similar measures [3], cost streamlining and selective funding are the main factors that prevent overuse as a way to guarantee sustainability of the health system. The problem is how to achieve this and not produce inequality in a regionally fragmented health system. There are important differences in patient access to antineoplastic treatment in Spain, so some drugs are provided in some regions but not in others. Even if a drug has been approved for use in a given region, every single hospital has the legal authority to decide about its use, regardless of medical criteria. As a consequence, access to a given drug may be granted in a centre but denied in a nearby institution because of local economical constraints. Considering this landscape, it would be reasonable to support the creation of a nation-wide agency to evaluate and decide about the financing of drugs, with binding effect on regional health systems and hospitals in terms of reimbursement, coverage level and price. This would avoid inequality and the need for re-evaluation at every region and every single hospital. In this regard, the National Institute for Health and Clinical Excellence (NICE) was set up in 1999 in the UK to reduce variation in the availability and quality of the British National Health System J. Feliu (&) E. Espinosa Medical Oncology Service, La Paz Hospital, P de la Castellana, 261-28046 Madrid, Spain e-mail: jaimefeliu@hotmail.com; jaime.feliu@salud.madrid.org

ChemInform Abstract: Drug Repositioning by Structure‐Based Virtual Screening

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