Loss of Cadherin-11 in pancreatic ductal adenocarcinoma alters tumor-immune microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest forms of cancer with very few treatment options. The 5-year survival rate for PDAC is 10% following diagnosis. Cadherin 11 (Cdh11), a cell-to-cell adhesion molecule, has been suggested to promote tumor growth and immunosuppression in PDAC, and Cdh11 inhibition significantly extended survival in mice with PDAC.

ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening.

Electrostatic interactions drive biomolecular interactions and associations. Computational modeling of electrostatics in biomolecular systems, such as protein-ligand, protein-protein, and protein-DNA, has provided atomistic insights into the binding process. In drug discovery, finding biologically plausible ligand-protein target interactions is challenging as current virtual screening and adjuvant techniques such as docking methods do not provide optimal treatment of electrostatic interactions.

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines . Here, we created constitutive knockout () mouse models to study RARRES1 function .

A novel chemo-phenotypic method identifies mixtures of salpn, vitamin D3, and pesticides involved in the development of colorectal and pancreatic cancer.

Environmental chemical (EC) exposures and our interactions with them has significantly increased in the recent decades. Toxicity associated biological characterization of these chemicals is challenging and inefficient, even with available high-throughput technologies. In this report, we describe a novel computational method for characterizing toxicity, associated biological perturbations and disease outcome, called the Chemo-Phenotypic Based Toxicity Measurement (CPTM).

Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in Breast Cancer.

Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role in tumor progression and metastasis. CAFs coexist as heterogeneous populations with potentially different biological functions. Although CAFs are a major component of the breast cancer stroma, molecular and phenotypic heterogeneity of CAFs in breast cancer is poorly understood.

Curation of the Pancreatic Ductal Adenocarcinoma Subset of the Cancer Genome Atlas Is Essential for Accurate Conclusions about Survival-Related Molecular Mechanisms.

Publicly available databases, for example, The Cancer Genome Atlas (TCGA), containing clinical and molecular data from many patients are useful in validating the contribution of particular genes to disease mechanisms and in forming novel hypotheses relating to clinical outcomes. The impact of key drivers of cancer progression can be assessed by segregating a patient cohort by certain molecular features and constructing survival plots using the associated clinical data. However, conclusions drawn from this straightforward analysis are highly dependent on the quality and source of tissue samples, as demonstrated through the pancreatic ductal adenocarcinoma (PDAC) subset of TCGA.

Differential prioritization of therapies to subtypes of triple negative breast cancer using a systems medicine method.

Triple negative breast cancer (TNBC) is a group of cancers whose heterogeneity and shortage of effective drug therapies has prompted efforts to divide these cancers into molecular subtypes. Our computational platform, entitled GenEx-TNBC, applies concepts in systems biology and polypharmacology to prioritize thousands of approved and experimental drugs for therapeutic potential against each molecular subtype of TNBC. Using patient-based and cell line-based gene expression data, we constructed networks to describe the biological perturbation associated with each TNBC subtype at multiple levels of biological action.

Metabolomic and Lipidomic Profiling Identifies The Role of the RNA Editing Pathway in Endometrial Carcinogenesis.

Endometrial cancer (EC) remains the most common malignancy of the genital tract among women in developed countries. Although much research has been performed at genomic, transcriptomic and proteomic level, there is still a significant gap in the metabolomic studies of EC. In order to gain insights into altered metabolic pathways in the onset and progression of EC carcinogenesis, we used high resolution mass spectrometry to characterize the metabolomic and lipidomic profile of 39 human EC and 17 healthy endometrial tissue samples.

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools.

Background: While establishing efficacy in translational models and humans through clinically-relevant endpoints for disease is of great interest, assessing the potential toxicity of a putative therapeutic drug is critical. Toxicological assessments in the pre-clinical discovery phase help to avoid future failure in the clinical phases of drug development. Many in vitro assays exist to aid in modular toxicological assessment, such as hepatotoxicity and genotoxicity.

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.

Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation.

MSD-MAP: A Network-Based Systems Biology Platform for Predicting Disease-Metabolite Links.

Background: Cancer-associated metabolites result from cell-wide mechanisms of dysregulation. The field of metabolomics has sought to identify these aberrant metabolites as disease biomarkers, clues to understanding disease mechanisms, or even as therapeutic agents.

Objective: This study was undertaken to reliably predict metabolites associated with colorectal, esophageal, and prostate cancers.

A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis.

Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/β-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter β-catenin nuclear localization and directly suppress β-catenin/TCF mediated transcriptional activity.

DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression-based drug repurposing.

Background: The targeting of disease-related proteins is important for drug discovery, and yet target-based discovery has not been fruitful. Contextualizing overall biological processes is critical to formulating successful drug-disease hypotheses. Network pharmacology helps to overcome target-based bottlenecks through systems biology analytics, such as protein-protein interaction (PPI) networks and pathway regulation.

Harnessing Polypharmacology with Computer-Aided Drug Design and Systems Biology.

The ascent of polypharmacology in drug development has many implications for disease therapy, most notably in the efforts of drug discovery, drug repositioning, precision medicine and combination therapy. The single- target approach to drug development has encountered difficulties in predicting drugs that are both clinically efficacious and avoid toxicity. By contrast, polypharmacology offers the possibility of a controlled distribution of effects on a biological system.

RepurposeVS: A Drug Repurposing-Focused Computational Method for Accurate Drug-Target Signature Predictions.

We describe here RepurposeVS for the reliable prediction of drug-target signatures using X-ray protein crystal structures. RepurposeVS is a virtual screening method that incorporates docking, drug-centric and protein-centric 2D/3D fingerprints with a rigorous mathematical normalization procedure to account for the variability in units and provide high-resolution contextual information for drug-target binding. Validity was confirmed by the following: (1) providing the greatest enrichment of known drug binders for multiple protein targets in virtual screening experiments, (2) determining that similarly shaped protein target pockets are predicted to bind drugs of similar 3D shapes when RepurposeVS is applied to 2,335 human protein targets, and (3) determining true biological associations in vitro for mebendazole (MBZ) across many predicted kinase targets for potential cancer repurposing.

Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and growth inhibition of breast cancer cells and cancer stem-like cells.

Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression.

βII-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin.

Unlabelled: βII-Spectrin (SPTBN1) is an adapter protein for Smad3/Smad4 complex formation during transforming growth factor beta (TGF-β) signal transduction. Forty percent of SPTBN1(+/-) mice spontaneously develop hepatocellular carcinoma (HCC), and most cases of human HCC have significant reductions in SPTBN1 expression. In this study, we investigated the possible mechanisms by which loss of SPTBN1 may contribute to tumorigenesis.

Big data: the next frontier for innovation in therapeutics and healthcare.

Advancements in genomics and personalized medicine not only effect healthcare delivery from patient and provider standpoints, but also reshape biomedical discovery. We are in the era of the '-omics', wherein an individual's genome, transcriptome, proteome and metabolome can be scrutinized to the finest resolution to paint a personalized biochemical fingerprint that enables tailored treatments, prognoses, risk factors, etc. Digitization of this information parlays into 'big data' informatics-driven evidence-based medical practice.

Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies.

Cadherin-11 (CDH11), associated with epithelial to mesenchymal transformation in development, poor prognosis malignancies and cancer stem cells, is also a major therapeutic target in rheumatoid arthritis (RA). CDH11 expressing basal-like breast carcinomas and other CDH11 expressing malignancies exhibit poor prognosis. We show that CDH11 is increased early in breast cancer and ductal carcinoma in-situ.

Genome-wide multi-omics profiling of colorectal cancer identifies immune determinants strongly associated with relapse.

The use and benefit of adjuvant chemotherapy to treat stage II colorectal cancer (CRC) patients is not well understood since the majority of these patients are cured by surgery alone. Identification of biological markers of relapse is a critical challenge to effectively target treatments to the ~20% of patients destined to relapse. We have integrated molecular profiling results of several "omics" data types to determine the most reliable prognostic biomarkers for relapse in CRC using data from 40 stage I and II CRC patients.

Drug repurposing: translational pharmacology, chemistry, computers and the clinic.

The process of discovering a pharmacological compound that elicits a desired clinical effect with minimal side effects is a challenge. Prior to the advent of high-performance computing and large-scale screening technologies, drug discovery was largely a serendipitous endeavor, as in the case of thalidomide for erythema nodosum leprosum or cancer drugs in general derived from flora located in far-reaching geographic locations. More recently, de novo drug discovery has become a more rationalized process where drug-target-effect hypotheses are formulated on the basis of already known compounds/protein targets and their structures.

Predicting new indications for approved drugs using a proteochemometric method.

The most effective way to move from target identification to the clinic is to identify already approved drugs with the potential for activating or inhibiting unintended targets (repurposing or repositioning). This is usually achieved by high throughput chemical screening, transcriptome matching, or simple in silico ligand docking. We now describe a novel rapid computational proteochemometric method called "train, match, fit, streamline" (TMFS) to map new drug-target interaction space and predict new uses.

Quantitative measurement of human papillomavirus type 16 e5 oncoprotein levels in epithelial cell lines by mass spectrometry.

The high-risk human papillomavirus type 16 (HPV-16) E5 protein (16E5) induces tumors in a transgenic mouse model and may contribute to early stages of cervical carcinogenesis. Although high-risk E5 expression is generally thought to be lost during the progression to cervical carcinoma following integration of HPV DNA into the host genome, episomal viral DNA has been documented in a subset of HPV-16-positive malignant lesions. Numerous studies have shown that transcripts that could potentially encode 16E5 are present in cervical biopsy specimens and cervical cancer cell lines, but the presence of E5 protein has been demonstrated in only two reports that have not been corroborated.