David B. Jackson

Molecular Health GmbH

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we...

Noradrenaline can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here we identify Src as a key regulator of phosphoproteomic signalling networks activated in response to beta-adrenergic signalling in cancer cells. The...

Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription fac...

It was Hippocrates, the father of Western medicine, who first emphasized the patient as the most important determinant of therapeutic efficacy. Although the principle of adjusting treatment to specific patient characteristics has since been the strategy of physicians, this is undermined by a population-biased approach to drug development. Therefore...

In a recent issue of PNAS, Mitchell et al. (1) reported exciting insights into the use of circulating microRNAs as biomarkers for cancer detection. Recently corroborated by similar studies, the potential now appears to extend well beyond the clinical oncology domain (2, 3). The observed specificity and simplicity of the approach are particularly st...

We improved a previous pharmacological target adverse‐event profile model to predict adverse events on FDA drug labels at the time of approval. The new model uses more drugs and features for learning as well as a new algorithm. Comparator drugs sharing similar target activities to a drug of interest were evaluated by aggregating adverse events from...

BRCA1/2 variants are prognostic biomarkers for hereditary breast and/or ovarian cancer (HBOC) syndrome and predictive biomarkers for PARP inhibition. In this study, we benchmarked the classification of BRCA1/2 variants from patients with HBOC-related cancer using MH BRCA, a novel computational technology that combines the ACMG guidelines with exper...

Immune checkpoint inhibition represents an important therapeutic option for advanced melanoma patients. Results from clinical studies have shown that treatment with the PD-1 inhibitors Pembrolizumab and Nivolumab provides improved response and survival rates. Moreover, combining Nivolumab with the CTLA-4 inhibitor Ipilimumab is superior to the resp...

Background The BRCA1/2 genes have emerged as critical biomarkers, particularly for patients with hereditary breast and ovarian cancer (HBOC). MH BRCA classifies variants based on ACMG guidelines. Clinical interpretation of NGS results by MH GUIDE provides clinicians with treatment recommendations to cancer based on expert curated biomarker knowledg...

Adverse events are a common and for the most part unavoidable consequence of therapeutic intervention. Nevertheless, available tomes of such data now provide us with an invaluable opportunity to study the relationship between human phenotype and drug-induced protein perturbations within a patient system. Deciphering the molecular basis of such adve...

Figure S1. Reporting frequencies in FAERS by MedDRA PT and DME.

Table S1. List of MedDRA‐DME key value pairs.

Data S2. Model code and data.

Data S1. Search criteria for TAE profiles FAERS.

Data S3. FDA labels current multiquery.

We present a novel approach for the molecular transformation and analysis of patient clinical phenotypes. Building on the fact that drugs perturb the function of targets/genes, we integrated data from 8.2 million clinical reports detailing drug-induced side effects with the molecular world of drug-target information. Using this dataset, we extracte...

Clinical trials can fail to detect rare adverse events (AEs). We assessed the ability of pharmacological target adverse‐event (TAE) profiles to predict AEs on US Food and Drug Administration (FDA) drug labels at least 4 years after approval. TAE profiles were generated by aggregating AEs from the FDA adverse event reporting system (FAERS) reports a...

Case reports suggest an association between second-generation antipsychotics (SGAs) and serotonin syndrome (SS). The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) was analyzed to generate hypotheses about how SGAs may interact with pharmacological targets associated with SS. FAERS was integrated with additional source...

Table S2. Analysis of matched germline and somatic mutations in selected oncogenic cancer syndrome genes (cases with sufficiently good quality sequencing data).

Table S1. List of included genes.

Table S3. Germ line variants.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly due to chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we re...

Knocking out stress: A systems-based identification of optimal drug combinations to improve ovarian cancer outcomes

Abstract Background. For many tumors, therapeutic options are sparse beyond the guidelines, especially for pancreatic cancer. At the same time, more and more biomarkers are known, informing about or supporting treatment decisions. Finally, tumor DNA analysis with next generation sequencing (NGS) is quickly becoming a routine test, at least for tumo...

Objectives: While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo’s effects on cancer cells prompted us to consider the existence of an alternative Epo recept...

Oncology is undergoing a data-driven metamorphosis. Armed with new and ever more efficient molecular and information technologies, we have entered an era where data is helping us spearhead the fight against cancer. This technology driven data explosion, often referred to as “big data”, is not only expediting biomedical discovery, but it is also rap...

s: AACR Special Conference: Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; October 17-20, 2015; Orlando, FL Background: Recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. However the lack of correlation between expre...

Abstract Introduction: To accelerate the translation of genome information in important biological and clinical insights requires systematic integration and analysis of functional genomic and proteomic information. In this way molecular landscapes of cancer patients can be characterized efficiently to impact their care. To fully rationalize the pot...

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. However the lack of correlation between expression of the canonical EpoR and rhEpo’s effects on cancer cells prompted us to consider the existence of an alternative Epo receptor...

Background Among 493 patients with early stage, lower risk (70% node negative), HER2 positive breast cancer, the 2-year DFS was 97% with adjuvant docetaxel and cyclophosphamide plus 1 year of trastuzumab (TCH) in a phase 2 study (Jones et al, Lancet Oncology 14: 1121, 2013). The objective of this work was to investigate the presence of ERBB2 specif...

Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disp...

Abstract Introduction: Molecular characterization is rapidly becoming a standard of care in clinical oncology practice. Simultaneously, growing volumes of peer-reviewed literature reporting the relationships between genomic aberrations, tumor responsiveness to treatments, and associated patient outcomes has significantly increased the challenge fac...

Objectives: Bisphosphonates, known to have beneficial effects on bone and soft tissue metastases in breast cancer, are potent inhibitors of macrophages, but effects on the microenvironment are not fully understood. We investigated the biological effect of clodronate on macrophage and endothelial cell-driven angiogenesis in ovarian cancer. Methods:...

Objective: Infusion reactions can be serious life threatening adverse events and have been associated with many drugs and biologic agents. Our objective was to report drugs associated with infusion reactions using two different data-mining methodologies. Methods: The Food and Drug Administration Adverse Event Reporting System (FAERS) was data-mined...

Background: Bladder cancer (BC) is a burdensome disease with significant morbidity, mortality, and cost. The development of novel plasma-based biomarkers for BC diagnosis and surveillance could significantly improve clinical outcomes and decrease health expenditures. Plasma miRNAs are promising biomarkers that have yet to be rigorously investigate...

The integration of increasingly diverse and disparate data about cancers into routine, clinical decision making is a major challenge for evidence-based medicine. Clearly, a comprehensive knowledge model for an indication is the mandatory basis for any evidence-based treatment prioritization. But the concepts and technologies required to collate pre...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Adverse events (AE's) are a common and unavoidable consequence of therapeutic intervention. Nevertheless, available tomes of such data now provide us with an invaluable opportunity to study the relationship between human phenotype and drug-induced protein perturbations within...

Clinical studies have demonstrated that chronic stress can influence cancer progression. However, the underlying mechanisms are not fully understood. To determine the molecular drivers of downstream signaling networks activated in response to chronic stress, we performed a phosphoproteomic analysis and determined that the non-receptor tyrosine kina...

Introduction: Recent clinical trials suggest that use of erythropoietin to treat chemotherapy-induced anemia results in enhanced tumor progression and impaired survival in certain cancer patients. Rationalizing these observations with Epo’s pleiotropic functionality and the lack of compelling evidence for Epo receptor (EpoR) involvement, we hypothe...

While current trials of anticancer agents serve to provide a population-based validation of therapeutic activity, clinical success is typically restricted to tumors of select molecular subtype. Recent insights have yielded a growing catalogue of germline and tumor-based aberrations that can predetermine whether a patient will achieve clinical benef...

miRNA correlation to EMT and RAS signature scores on mean-centered data. Pearson correlation coefficient and the associated p-value are provided.

Out of ~300 signatures tested, EMT was the most significantly associated with PC1 in colon (P < 10-135). More importantly, the up and down arms of the EMT signature were directionally correlated with PC1 (P < 10-16, Fisher Exact Test). See Additional File 2 for list of genes.

Waterfall plot of recurrence prediction of PC1 for the MCC colon dataset shows more recurrences with high signature scores than with low signature scores; similarly there fewer recurrences with low signature scores than with high signature scores.

Hierarchical cluster analysis showing expression of key genes (red and blue) and gene signatures (black) in the EMT signature for lung tumors. Genes positively correlated with the EMT signature are shown in red and genes negatively correlated with the EMT signature are shown in blue.

Waterfall and boxplot analysis's shows a differential EMT score for colon < lung < pancreas following normalization across all samples.

PC1 predicts recurrence in stages 2 and 3 of colon cancer. Data is shown for MCC dataset.

EMT signature proposed in this paper is predictive of recurrence in stage 2 and stage 3 MCC tumors.

EMT signature was derived by comparing gene expression of cell lines sorted into epithelial or mesenchymal like groups based on CDH1 and VIM expression (see Additional Figure 1). The top 200 up and down probes found most significant by ANOVA (P < 0.001) were selected to represent the EMT signature. The EMT signature contains known EMT drivers such...

Derivation of the EMT signature used to clarify the biology characterizing PC1. The EMT signature was derived from a global gene expression analysis of 93 lung cancer cell lines first segregated by differential CDH1 and VIM expression. Right panel shows the relationship between EMT signature score and CDH1 probe intensities, the left panel shows th...

Covariance matrices showing the relationship of PC1 to the same endpoints as shown in Figure 4ausing (a) independent colon dataset [21](b) EXPO dataset, (c) NKI dataset.

Ingenuity/GO Analysis produced multiple functional categories for PC1 without bringing clarity to the underlying biology. The table lists top functional gene groups in terms of significance for enrichment of genes from PC1 signature. Both, significance of enrichment p-value,(based on hyper geometric distribution) and Bonferroni-type correction e-va...

Centered abundances for 49 tumors × 416 MiR detectors.

Hierarchical cluster analysis showing expression of key genes (red and blue) and gene signatures (black) in the EMT signature for colorectal tumors. Genes positively correlated with the EMT signature are shown in red and genes negatively correlated with the EMT signature are shown in blue.

Top 5000 most variable genes (columns) on Colon cell lines (rows) sorted by PC1. PC1 is observed to be positively correlated to EMT signature score and anti-correlated to RAS signature score. Genes are clustered using Pearson correlation distance metric and Ward linkage. Heatmap shows mean-centered probe intensities.

Hierarchical cluster analysis showing expression of key genes (red and blue) and gene signatures (black) in the EMT signature for pancreatic tumors. Genes positively correlated with the EMT signature are shown in red and genes negatively correlated with the EMT signature are shown in blue.

EMT signature proposed in this paper is predictive of recurrence when applied to all tumor samples in MCC data set.

Background Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging. Methods We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 decipher...

Purpose: Urothelial carcinoma of the bladder (UC) is the 4th most common solid malignancy in men and 5th most common overall with an estimated 70,000 new cases of UC and over 14,000 deaths from the disease expected in 2010 in the United States. Although the majority of patients with invasive UC present without radiographic or clinical evidence of d...

Currently, there are some paradigm shifts in medicine, from the search for a single ideal biomarker, to the search for panels of molecules, and from a reductionistic to a systemic view, placing these molecules on functional networks. There is also a general trend to favor non-invasive biomarkers. Identifying non-invasive biomarkers in high- through...

Off-target hits of drugs can lead to serious adverse effects or, conversely, to unforeseen alternative medical utility. Selectivity profiling against large panels of potential targets is essential for the drug discovery process to minimize attrition and maximize therapeutic utility. Lately, it has become apparent that drug promiscuity (polypharmaco...

While the advent of targeted therapies has promised to revolutionize the success of cancer treatment, a critical review of clinical response rates provides a sobering perspective on the challenge at hand. New levels of discovery innovation are urgently required to redress this enormous medical need. Focusing on primary imatinib resistance in chroni...

With the advent of targeted therapies promising to revolutionise the nature and success of patient care, the field of clinical oncology is facing a highly exciting future. While much of this enthusiasm comes from the hope for improved patient outcomes, a review of clinical response/relapse rates for current therapies provides a more sobering perspe...

Molecular diversity is a hallmark of life. Unfortunately, given that the clinical benefit of a drug can only be realized under certain genetic/molecular conditions, such heterogeneity can mean the difference between survival and death. For most targeted therapies it appears that such conditions are met in only a small percentage of patients, partic...

The co-emergence of microarray technologies with systems oriented approaches to discovery is testament to the technological and conceptual advancements of recent years. By providing a platform for massively parallelized reductionism, microarrays are enabling us to examine the functional features of diverse classes of bio-system components in a cont...

Nuclear receptors are ligand-modulated transcription factors. On the basis of the completed human genome sequence, this family was thought to contain 48 functional members. However, by mining human and mouse genomic sequences, we identified FXRβ as a novel family member. It is a functional receptor in mice, rats, rabbits, and dogs but constitutes a...

The writer T.S. Eliot once mused, “Where is the knowledge we have lost in information?” [1 ]. From a biological perspective, the answer to this profound question is today having far-reaching consequences for the future of biomedical research and, in particular, the drug discovery process.

We previously described the isolation of ysl2-1 due to its genetic interaction with Δypt51/vps21, a mutant with a deletion of the coding sequence for the yeast Rab5 homolog, which regulates endocytic traffic between early and late endosomes. Here we report that Ysl2p is a novel 186.8-kDa peripheral membrane protein homologous to members of the Sec7...

Listeria monocytogenes is a food-borne pathogen with a high mortality rate that has also emerged as a paradigm for intracellular parasitism. We present and compare the genome sequences of L. monocytogenes (2,944,528 base pairs) and a nonpathogenic species, L. innocua (3,011,209 base pairs). We found a large number of predicted genes encoding surfac...

During Drosophila development Fos acts downstream from the JNK pathway. Here we show that it can also mediate ERK signaling in wing vein formation and photoreceptor differentiation. Drosophila JNK and ERK phosphorylate D-Fos with overlapping, but distinct, patterns. Analysis of flies expressing phosphorylation site point mutants of D-Fos revealed t...

We have identified and isolated mutations in the first Drosophila gene encoding a subunit of the Sec61 protein translocation channel, DSec61beta. While neither the Saccharomyces cerevisiae Sec61beta nor its functional Escherichia coli homologue are essential for viability or for protein translocation, we show that DSec61beta is essential for embryo...

Drosophila kayak mutant embryos exhibit defects in dorsal closure, a morphogenetic cell sheet movement during embryogenesis. Here we show that kayak encodes D-Fos, the Drosophila homologue of the mammalian proto-oncogene product, c-Fos. D-Fos is shown to act in a similar manner to Drosophila Jun: in the cells of the leading edge it is required for...

Decapentaplegic (Dpp) is an extracellular signal of the transforming growth factor-beta family with multiple functions during Drosophila development. For example, it plays a key role in the embryo during endoderm induction. During this process, Dpp stimulates transcription of the homeotic genes Ultrabithorax in the visceral mesoderm and labial in t...