A meta-metastasis analysis identifies pan-cancer markers and therapeutic targets
Poster - AACR 2017
Metastasis is a leading cause of cancer-associated deaths across several cancer types, yet the molecular details of its development have not been fully elucidated. Transcriptomic analysis can provide insight into the gene expression changes in the tumor that confer metastatic potential even during early stages of tumorigenesis. Here, by leveraging RNA-Seq data collected by The Cancer Genome Atlas (TCGA), we systematically identified mechanisms consistently associated with metastasis in primary tumors from 4844 patients across 13 different cancer types via comparison of primary tumors from patients with primary site, node-negative disease with no recorded distant metastasis (N0 not M1) compared to primary tumors from patients with node-positive disease (N1, N2, or N3). Differentially expressed genes were first determined within each cancer type, to reduce tissue- or disease-specific effects. Subsequently, via meta-analysis, we combine these results to identify commonality across 13 different types of cancer. Next, using a proprietary drug prediction algorithm called Drugfinder, we identified drug candidates that can target metastasis across all cancer types and within specific cancer types.
The international MAQC Society launches to enhance reproducibility of high-throughput technologies
doi:10.1038/nbt.4029 Nature Biotechnology 35, 1127–1128(2017)
Reproducibility is a fundamental hallmark of good science. The US Food and Drug Administration (FDA)-led Microarray and Sequencing Quality Control (MAQC/SEQC) consortia conducted three projects 1,2,3 to assess the reliability and reproducibility of genomics technologies, including microarrays, genome-wide association studies, and next-generation sequencing. Here, we announce that this decade-long effort has led to the formation of a new international society, the Massive Analysis and Quality Control (MAQC) Society (http://www.maqcsociety.org), which is dedicated to quality control and analysis of massive data generated from high-throughput technologies for enhanced reproducibility.
Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice
JCI Insight. 2017;2(23):e95665. doi:10.1172/jci.insight.95665.
Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks). Early treatment improved motor coordination and reduced anxiety- and depressive-like phenotypes in YAC128 mice, but it did not rescue striatal and corpus callosum atrophy. Late treatment, conversely, only improved depressive-like symptoms. RNA-seq analysis revealed that early pridopidine treatment reversed striatal transcriptional deficits, upregulating disease-specific genes that are known to be downregulated during HD, a finding that is experimentally confirmed herein. This suggests that pridopidine exerts beneficial effects at the transcriptional level. Taken together, our findings support continued clinical development of pridopidine for HD, particularly in the early stages of disease, and provide valuable insight into the potential therapeutic mode of action of pridopidine.
Proteomic Profiling Reveals Targetable Pathways in MGUS (SLAMF6, TNFRSF8, TIMP1, TRL2) That May Contribute to Disease Progression Blood 2017 130:3805;
Poster - ASH 2017
Monoclonal gammopathy of undetermined significance (MGUS), is a pre-malignant plasma cell disorder that affects roughly 4% of the population older than 55 and is associated with a 1% per year risk of progression to multiple myeloma (MM). Successfully intercepting disease progression from MGUS to MM requires a deeper understanding of MGUS biology, identification of prognostic biomarkers and potential targets for interception. With these aims, a cohort of samples were profiled from the Olmstead County Study, which followed >20,000 subjects for over 20 years as they aged and developed a variety of diseases, including MGUS and MM (Kyle, et al. Oncology 2011). Samples were utilized from 2 cohorts: 1) healthy normal individuals with no subsequent diagnosis of plasma cell disorder, and 2) healthy normal individuals who go on to develop MGUS, with a second sample at the time of MGUS diagnosis. Broad proteomic profiling was performed on these samples, to identify pathways involved in the early stages of MGUS disease biology.
Compositional differences between Copaxone and Glatopa are reflected in altered immunomodulation ex vivo in a mouse model.
doi: 10.1111/nyas.13547 Annals of the New York Academy of Science
Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration-approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7-11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.
Transcriptomic analysis of the YAC128 HD mouse model shows disease mechanisms are ameliorated by pridopidine.
Poster - Society for Neuroscience
Huntington Disease (HD) is a neurodegenerative disorder hallmarked by the expression of a mutant form of the huntingtin gene (mHtt). A therapeutic goal for HD treatment involves the restoration of neurobiological pathways disrupted by mHtt. Pridopidine, an investigational HD drug candidate, has been shown to improve motor symptoms in both preclinical models as well as in HD patients. While originally described as a dopaminergic stabilizer, in vitro binding studies show highest affinity of pridopidine to the sigma-1 receptor. We previously reported that pridopidine upregulates BDNF, glucocorticoid receptor (GR), and dopamine 1 receptor (D1R) signaling pathways in WT rat striatum. To expand on these findings and explore molecular changes specific to HD, we repeated this study in a YAC128 HD mouse model whereby mice were treated with pridopidine or vehicle starting at postnatal week 6 and sacrificed after 11.5 months of age. We then performed RNAseq data analysis on the striatum. We identified 1346 differentially expressed genes (DEGs) in vehicle treated YAC128 mice vs. healthy controls, 221 DEGs in YAC128 mice treated with 30 mg/kg of pridopidine vs. vehicle, and 73 DEGs in YAC128 mice treated with 10 mg/kg of pridopidine vs. vehicle (all adj.p<0.05). In addition, the previously reported pridopidine-induced upregulation of BDNF, GR, and D1R pathways was confirmed after treatment with either dose (adj.p<0.05), and alternatively spliced genes after 30 mg/kg of pridopidine compared to YAC128 vehicle are enriched for the BDNF pathway (adj.p<0.05). Further, pathway analysis of DEGs after 30 mg/kg dosage revealed enrichment for biological processes related to synaptic transmission, including upregulation in the key HD-impaired processes – cAMP and calcium signaling (adj.p<0.05). Lastly, since mHtt was shown to induce neurotoxicity by promoting M1 microglia that secrete proinflammatory cytokines, enrichment analysis tested for microglial markers. Treatment with 30 mg/kg of pridopidine led to the downregulation of genes associated with M1 activation (adj.p<0.05). To summarize, pridopidine induces transcriptional modifications reversing genes in HD-impaired pathways involved in neuronal transmission and protection in the YAC128 striatum.
A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis
Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone’s mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials.
Drug repurposing from the perspective of pharmaceutical companies
doi: 10.1111/bph.13798 British Journal of Pharmacology
Drug repurposing holds the potential to bring medications with known safety profiles to new patient populations. Numerous examples exist for the identification of new indications for existing molecules, most stemming from serendipitous findings or focused recent efforts specifically limited to the mode of action of a specific drug. In recent years, the need for new approaches to drug research and development, combined with the advent of big data repositories and associated analytical methods, has generated interest in developing systematic approaches to drug repurposing. A variety of innovative computational methods to enable systematic repurposing screens, experimental as well as through in silico approaches, have emerged. An efficient drug repurposing pipeline requires the combination of access to molecular data, appropriate analytical expertise to enable robust insights, expertise and experimental set-up for validation and clinical development know-how. In this review, we describe some of the main approaches to systematic repurposing and discuss the various players in this field and the need for strategic collaborations to increase the likelihood of success in bringing existing molecules to new indications, as well as the current advantages, considerations and challenges in repurposing as a drug development strategy pursued by pharmaceutical companies.
Pharmacogenomics strategies to optimize treatments for multiple sclerosis: Insights from clinical research.
PMID: 26952809 DOI: 10.1016/j.pneurobio.2016.02.001 Progress in Neurobiology
Multiple sclerosis (MS) is a chronic, progressive, disabling disorder characterized by immune-mediated demyelination, inflammation, and neurodegenerative tissue damage in the central nervous system (CNS), associated with frequent exacerbations and remissions of neurologic symptoms and eventual permanent neurologic disability. While there are several MS therapies that are successful in reducing MS relapses, none have been effective in treating all patients. The specific response of an individual patient to any one of the MS therapies remains largely unpredictable, and physicians and patients are forced to use a trial and error approach when deciding on treatment regimens. A priori markers to predict the optimal benefit-to-risk profile of an individual MS patient would greatly facilitate the decision-making process, thereby helping the patient receive the most optimal treatment early on in the disease process. Pharmacogenomic methods evaluate how a person’s genetic and genomic makeup affects their response to therapeutics. This review focuses on how pharmacogenomics studies are being used to identify biologically relevant differences in MS treatments and provide characterization of the predictive clinical response patterns. As pharmacogenomics research is dependent on the availability of longitudinal clinical research, studies concerning glatiramer acetate and the interferon beta products which have the majority of published long term data to date are described in detail. These studies have provided considerable insight in the prognostic markers associated with MS disease and potential predictive markers of safety and beneficial response.
Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors
DOI: 10.1016/j.ccell.2016.11.006 Cancer Cell. PMID: 27960087
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.