Kevin Grimes, Postdoctoral Faculty Sponsor
Failure to demonstrate efficacy and safety issues are important reasons that drugs do not reach the market. An incomplete understanding of how drugs exert their effects hinders regulatory and pharmaceutical industry projections of a drug's benefits and risks. Signaling pathways mediate drug response and while many signaling molecules have been characterized for their contribution to disease or their role in drug side effects, our knowledge of these pathways is incomplete. To better understand all signaling molecules involved in drug response and the phenotype associations of these molecules, we created a novel method, PathFX, a non-commercial entity, to identify these pathways and drug-related phenotypes. We benchmarked PathFX by identifying drugs' marketed disease indications and reported a sensitivity of 41%, a 2.7-fold improvement over similar approaches. We then used PathFX to strengthen signals for drug-adverse event pairs occurring in the FDA Adverse Event Reporting System (FAERS) and also identified opportunities for drug repurposing for new diseases based on interaction paths that associated a marketed drug to that disease. By discovering molecular interaction pathways, PathFX improved our understanding of drug associations to safety and efficacy phenotypes. The algorithm may provide a new means to improve regulatory and therapeutic development decisions.
View details for PubMedID 30532240
IMPACT STATEMENT: Many untreated diseases are not monogenic and are instead caused by multiple genetic defects. Because of this complexity, computational, logical, and systems understanding will be essential to discovering novel therapies. The scientist engineer is uniquely disposed to use this type of understanding to advance therapeutic discovery. This work highlights benefits of the scientist engineer perspective and underscores the potential impact of these approaches for future therapeutic development. By framing the scientist engineer's tool set and increasing awareness about this approach, this article stands to impact future therapeutic development efforts in an age of rising development costs and high drug attrition.
View details for PubMedID 30458646
Data integration stands to improve interpretation of RNAi screens which, as a result of off-target effects, typically yield numerous gene hits of which only a few validate. These off-target effects can result from seed matches to unintended gene targets (reagent-based) or cellular pathways, which can compensate for gene perturbations (biology-based). We focus on the biology-based effects and use network modeling tools to discover pathways de novo around RNAi hits. By looking at hits in a functional context, we can uncover novel biology not identified from any individual 'omics measurement. We leverage multiple 'omic measurements using the Simultaneous Analysis of Multiple Networks (SAMNet) computational framework to model a genome scale shRNA screen investigating Acute Lymphoblastic Leukemia (ALL) progression in vivo. Our network model is enriched for cellular processes associated with hematopoietic differentiation and homeostasis even though none of the individual 'omic sets showed this enrichment. The model identifies genes associated with the TGF-beta pathway and predicts a role in ALL progression for many genes without this functional annotation. We further experimentally validate the hidden genes - Wwp1, a ubiquitin ligase, and Hgs, a multi-vesicular body associated protein - for their role in ALL progression. Our ALL pathway model includes genes with roles in multiple types of leukemia and roles in hematological development. We identify a tumor suppressor role for Wwp1 in ALL progression. This work demonstrates that network integration approaches can compensate for off-target effects, and that these methods can uncover novel biology retroactively on existing screening data. We anticipate that this framework will be valuable to multiple functional genomic technologies - siRNA, shRNA, and CRISPR - generally, and will improve the utility of functional genomic studies.
View details for DOI 10.1039/c6ib00040a
View details for Web of Science ID 000379430200004
View details for PubMedID 27315426
View details for PubMedCentralID PMC5224708
Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.
View details for DOI 10.1126/scitranslmed.aax2550
View details for PubMedID 32727913
Control of microvascular network growth is critical to treatment of ischemic tissue diseases and enhancing regenerative capacity of tissue engineering implants. Conventional therapeutic strategies for inducing angiogenesis aim to deliver one or more proangiogenic cytokines or to over-express known pro-angiogenic genes, but seldom address potential compensatory or cooperative effects between signals and the overarching signaling pathways that determine successful outcomes. An emerging grand challenge is harnessing the expanding knowledge base of angiogenic signaling pathways toward development of successful new therapies. We previously performed drug optimization studies by various substitutions of a 2-(2,6-dioxo-3-piperidyl)isoindole-1,3-dione scaffold to discover novel bioactive small molecules capable of inducing growth of microvascular networks, the most potent of which we termed phthalimide neovascularization factor 1 (PNF1, formerly known as SC-3-149). We then showed that PNF-1 regulates the transcription of signaling molecules that are associated with vascular initiation and maturation in a time-dependent manner through a novel pathway compendium analysis in which transcriptional regulatory networks of PNF-1-stimulated microvascular endothelial cells are overlaid with literature-derived angiogenic pathways. In this study, we generated three analogues (SC-3-143, SC-3-263, SC-3-13) through systematic transformations to PNF1 to evaluate the effects of electronic, steric, chiral, and hydrogen bonding changes on angiogenic signaling. We then expanded our compendium analysis toward these new compounds. Variables obtained from the compendium analysis were then used to construct a PLSR model to predict endothelial cell proliferation. Our combined approach suggests mechanisms of action involving suppression of VEGF pathways through TGF-β andNR3C1 network activation.
View details for DOI 10.1007/s40883-018-0077-8
View details for Web of Science ID 000465457400004
View details for PubMedID 31008183
View details for PubMedCentralID PMC6474664
Limited efficacy and intolerable safety limit therapeutic development and identification of potential liabilities earlier in development could significantly improve this process. Computational approaches which aggregate data from multiple sources and consider the drug's pathways effects could add to identification of these liabilities earlier. Such computational methods must be accessible to a variety of users beyond computational scientists, especially regulators and industry scientists, in order to impact the therapeutic development process. We have previously developed and published PathFX, an algorithm for identifying drug networks and phenotypes for understanding drug associations to safety and efficacy. Here we present a streamlined and easy-to-use PathFX web application that allows users to search for drug networks and associated phenotypes. We have also added visualization, and phenotype clustering to improve functionality and interpretability of PathFXweb.https://www.pathfxweb.net/.Supplementary data are available at Bioinformatics online.
View details for DOI 10.1093/bioinformatics/btz419
View details for PubMedID 31114840
Clinical trial designs targeting patient subgroups with certain genetic characteristics may enhance the efficiency of developing drugs for cardiovascular disease (CVD). To evaluate the extent to which genetic knowledge translates to the CVD pipeline, we analyzed how genomic biomarkers are utilized in trials. Phase II and III trial protocols for investigational new drugs for CVD and risk factors were evaluated for prospective and exploratory genomic biomarker use; drug targets were evaluated for the presence of evidence that genetic variations can impact CVD risk or drug response. We identified 134 programs (73 unique drug targets) and 147 clinical trials. Less than 1% (n = 1/147) trials used a genomic biomarker prospectively for in-trial enrichment despite 32% (n = 23/73) of the drug targets having evidence of genetic variations. Additionally, 46% (n = 68/147) of the trials specified exploratory biomarker use. The results highlight an opportunity for more targeted CVD drug development by leveraging genomic biomarker knowledge.
View details for DOI 10.1002/cpt.1473
View details for PubMedID 31002380
Biomarkers are the pillars of precision medicine and are delivering on expectations of molecular, quantitative health. These features have made clinical decisions more precise and personalized, but require a high bar for validation. Biomarkers have improved health outcomes in a few areas such as cancer, pharmacogenetics, and safety. Burgeoning big data research infrastructure, the internet of things, and increased patient participation will accelerate discovery in the many areas that have not yet realized the full potential of biomarkers for precision health. Here we review themes of biomarker discovery, current implementations of biomarkers for precision health, and future opportunities and challenges for biomarker discovery. Impact statement Precision medicine evolved because of the understanding that human disease is molecularly driven and is highly variable across patients. This understanding has made biomarkers, a diverse class of biological measurements, more relevant for disease diagnosis, monitoring, and selection of treatment strategy. Biomarkers' impact on precision medicine can be seen in cancer, pharmacogenomics, and safety. The successes in these cases suggest many more applications for biomarkers and a greater impact for precision medicine across the spectrum of human disease. The authors assess the status of biomarker-guided medical practice by analyzing themes for biomarker discovery, reviewing the impact of these markers in the clinic, and highlight future and ongoing challenges for biomarker discovery. This work is timely and relevant, as the molecular, quantitative approach of precision medicine is spreading to many disease indications.
View details for PubMedID 29199461
Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signaling molecules. Of importance for disease is the release of ligands that activate the EGFR, such as TGFα, which is mostly carried out by ADAM17 [a member of the A-disintegrin and metalloprotease (ADAM) domain family]. EGFR ligand shedding has been linked to many diseases, in particular cancer development, growth and metastasis, as well as resistance to cancer therapeutics. Excessive EGFR ligand release can outcompete therapeutic EGFR inhibition or the inhibition of other growth factor pathways by providing bypass signaling via EGFR activation. Drugging metalloproteases directly have failed clinically because it indiscriminately affected shedding of numerous substrates. It is therefore essential to identify regulators for EGFR ligand cleavage. Here, integration of a functional shRNA genomic screen, computational network analysis, and dedicated validation tests succeeded in identifying several key signaling pathways as novel regulators of TGFα shedding in cancer cells. Most notably, a cluster of genes with NFκB pathway regulatory functions was found to strongly influence TGFα release, albeit independent of their NFκB regulatory functions. Inflammatory regulators thus also govern cancer cell growth-promoting ectodomain cleavage, lending mechanistic understanding to the well-known connection between inflammation and cancer.Implications: Using genomic screens and network analysis, this study defines targets that regulate ectodomain shedding and suggests new treatment opportunities for EGFR-driven cancers. Mol Cancer Res; 16(1); 147-61. ©2017 AACR.
View details for DOI 10.1158/1541-7786.MCR-17-0140
View details for Web of Science ID 000419147200013
View details for PubMedID 29018056
View details for PubMedCentralID PMC5859574
RNA-interference (RNAi) studies hold great promise for functional investigation of the significance of genetic variations and mutations, as well as potential synthetic lethalities, for understanding and treatment of cancer, yet technical and conceptual issues currently diminish the potential power of this approach. While numerous research groups are usefully employing this kind of functional genomic methodology to identify molecular mediators of disease severity, response, and resistance to treatment, findings are generally confounded by "off-target" effects. These effects arise from a variety of issues beyond non-specific reagent behavior, such as biological cross-talk and feedback processes so thus can occur even with specific perturbation. Interpreting RNAi results in a network framework instead of merely as individual "hits" or "targets" leverages contributions from all hit/target contributions to pathways via their relationships with other network nodes. This interpretation can ameliorate dependence upon individual reagent performance and increase confidence in biological validation. Here we provide background on RNAi studies in cancer applications, review key challenges with functional genomics, and motivate the use of network models grounded in pathway analyses.
View details for DOI 10.1016/j.semcancer.2013.06.004
View details for Web of Science ID 000323455900002
View details for PubMedID 23811269
View details for PubMedCentralID PMC3844556
Microvascular remodeling is a complex process that includes many cell types and molecular signals. Despite a continued growth in the understanding of signaling pathways involved in the formation and maturation of new blood vessels, approximately half of all compounds entering clinical trials will fail, resulting in the loss of much time, money, and resources. Most pro-angiogenic clinical trials to date have focused on increasing neovascularization via the delivery of a single growth factor or gene. Alternatively, a focus on the concerted regulation of whole networks of genes may lead to greater insight into the underlying physiology since the coordinated response is greater than the sum of its parts. Systems biology offers a comprehensive network view of the processes of angiogenesis and arteriogenesis that might enable the prediction of drug targets and whether or not activation of the targets elicits the desired outcome. Systems biology integrates complex biological data from a variety of experimental sources (-omics) and analyzes how the interactions of the system components can give rise to the function and behavior of that system. This review focuses on how systems biology approaches have been applied to microvascular growth and remodeling, and how network analysis tools can be utilized to aid novel pro-angiogenic drug discovery.
View details for DOI 10.1089/ten.teb.2009.0611
View details for Web of Science ID 000278640000008
View details for PubMedID 20121415
View details for PubMedCentralID PMC2946904
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