Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

<p>Background: Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target.</p> <p>Methods: The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated.</p> <p>Results: No growth defect under low and elevated oxygen tension, no up-or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10(Delta gdha) parasite lines. Further, the fate of the carbon skeleton of [(13)C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of a-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites.</p> <p>Conclusions: First, the data support the conclusion that D10(Delta gdha) parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite development.</p&gt

In-silico Predictive Mutagenicity Model Generation Using Supervised Learning Approaches

With the advent of High Throughput Screening techniques, it is feasible to filter possible leads from a mammoth chemical space that can act against a particular target and inhibit its action. Virtual screening complements the in-vitro assays which are costly and time consuming. This process is used to sort biologically active molecules by utilizing the structural and chemical information of the compounds and the target proteins in order to screen potential hits. Various data mining and machine learning tools utilize Molecular Descriptors through the knowledge discovery process using classifier algorithms that classify the potentially active hits for the drug development process.
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Practical considerations for optimal designs in clinical dose finding studies

Determining an adequate dose level for a drug and, more broadly, characterizing its dose response relationship, are key objectives in the clinical development of any medicinal drug. If the dose is set too high, safety and tolerability problems are likely to result, while selecting too low a dose makes it difficult to establish adequate efficacy in the confirmatory phase, possibly leading to a failed program. Hence, dose finding studies are of critical importance in drug development and need to be planned carefully. In this paper we focus on practical considerations for establishing efficient study designs to estimate target doses of interest. We consider optimal designs for both the estimation of the minimum effective dose (MED) and the dose achieving 100p% of the maximum treatment effect (EDp). These designs are compared with D-optimal designs for a given dose response model. Extensions to robust designs accounting for model uncertainty are also discussed. A case study is used to motivate and illustrate the methods from this paper. --dose finding,robust designs,model uncertainty,minimum effective dose,dose response,target dose estimation,sample size

Biomarker-Drug and Liquid Biopsy Co-development for Disease Staging and Targeted Therapy: Cornerstones for Alzheimer's Precision Medicine and Pharmacology.

Systems biology studies have demonstrated that different (epi)genetic and pathophysiological alterations may be mapped onto a single tumor's clinical phenotype thereby revealing commonalities shared by cancers with divergent phenotypes. The success of this approach in cancer based on analyses of traditional and emerging body fluid-based biomarkers has given rise to the concept of liquid biopsy enabling a non-invasive and widely accessible precision medicine approach and a significant paradigm shift in the management of cancer. Serial liquid biopsies offer clues about the evolution of cancer in individual patients across disease stages enabling the application of individualized genetically and biologically guided therapies. Moreover, liquid biopsy is contributing to the transformation of drug research and development strategies as well as supporting clinical practice allowing identification of subsets of patients who may enter pathway-based targeted therapies not dictated by clinical phenotypes alone. A similar liquid biopsy concept is emerging for Alzheimer's disease, in which blood-based biomarkers adaptable to each patient and stage of disease, may be used for positive and negative patient selection to facilitate establishment of high-value drug targets and counter-measures for drug resistance. Going beyond the "one marker, one drug" model, integrated applications of genomics, transcriptomics, proteomics, receptor expression and receptor cell biology and conformational status assessments during biomarker-drug co-development may lead to a new successful era for Alzheimer's disease therapeutics. We argue that the time is now for implementing a liquid biopsy-guided strategy for the development of drugs that precisely target Alzheimer's disease pathophysiology in individual patients

miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

Multidrug resistance (MDR) remains one of the most significant obstacles in breast cancer treatment, and this process often involves dysregulation of a great number of microRNAs (miRNAs). Some miRNAs are indicators of drug resistance and confer resistance to chemotherapeutic drugs, although our understanding of this complex process is still incomplete. We have used a combination of miRNA profiling and real-time PCR in two drug-resistant derivatives of MCF-7 and Cal51 cells. Experimental modulation of miR expression has been obtained by retroviral transfection. Taxol and doxorubicin IC50 values were obtained by short-term drug sensitivity assays. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays and the levels of apoptosis-related proteins bcl-2 and bax by real-time PCR and Western blot. miR target was studied using transient transfection of luciferase constructs with the 3 untranslated regions (UTR) of target mRNAs. Small interfering RNA-mediated genetic knock-down was performed in MDR cells and its modulatory effect on apoptosis examined. The effect of miRNA on tumorigenicity and tumor drug response was studied in mouse xenografts. miRNA profiling of two drug-resistant breast cancer cell models indicated that miR-218 was down-regulated in both MCF-7/A02 and CALDOX cells. Ectopic expression of miR-218 resensitized both drug-resistant cell lines to doxorubicin and taxol due to an increase in apoptosis. miR-218 binds survivin (BIRC5) mRNA 3-UTR and down-regulated reporter luciferase activity. Experimental down-regulation of survivin by RNA interference in drug-resistant cells did mimic the sensitization observed when miRNA-218 was up-regulated. In addition, resensitization to taxol was also observed in mouse tumor xenografts from cells over-expressing miR-218. miR-218 is involved in the development of MDR in breast cancer cells via targeting survivin and leading to evasion of apoptosis. Targeting miR-218 and survivin may thus provide a potential strategy for reversing drug resistance in breast cancer

PARP inhibition: a promising therapeutic target in ovarian cancer

Ovarian cancer is burdened by the highest mortality rate among gynecological cancers. Gold standard is represented by the association of platinum-taxane -based chemotherapy and radical surgery. Despite several adjustments occurred in cytotoxic drug in last decades, most patients continue to relapse, and no significant enhancement has been reached in the overall survival. The development of drug resistance and the recurrence of disease have prompted the investigations of other targets that can be used in the treatment of ovarian cancers. Among such targets, polyadenosine diphosphate-ribose polymerase (PARP) represents a novel way to target specific patways involved in tumor growth. PARP accelerates the reaction of the polyADP-ribosylation of proteins implicated in DNA repair. PARP inhibitors have shown activity in cancers with BRCA mutations, with other deficient DNA repair genes or signaling pathways that modulate DNA repair, or in association with DNA damaging agents not involved in DNA repair dysfunction. A number of inhibitors for PARP has been developed, and such drugs are under investigation in clinical trials to identify their impact in the treatment of ovarian cancers. This review aims to summarize the recent researches and clinical progress on PARP inhibitors as novel target agents in ovarian cancer

The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases