A Real-world Toxicity Atlas Shows that Adverse Events of Combination Therapies Commonly Result in Additive Interactions.

PURPOSE: Combination therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in a real-world setting. EXPERIMENTAL DESIGN: We provide here a proof-of-concept study using 15 million patient records from the FDA Adverse Event Reporting System (FAERS). Complex adverse event frequencies of drugs or their combinations were visualized as heat maps onto a two-dimensional grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heat maps. In addition, statistical synergy analyses were performed on the basis of BLISS independence or χ2 testing. RESULTS: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug-associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically. CONCLUSIONS: Our study provides a framework for analyzing adverse events and suggests that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.

Review: A Roadmap to Use Nonstructured Data to Discover Multitarget Cancer Therapies.

Therapy resistance to single agents has led to the realization that combination therapies could become the cornerstone of cancer treatment. To operationalize the selection of effective and safe multitarget therapies, we propose to integrate chemical and preclinical therapeutic information with clinical efficacy and toxicity data, allowing a new perspective on the drug target landscape. To assess the feasibility of this approach, we evaluated the publicly available chemical, preclinical, and clinical therapeutic data, and we addressed some potential limitations while integrating the data. First, by mapping available structured data from the main biomedical resources, we noticed that there is only a 1.7% overlap between drugs in chemical, preclinical, or clinical databases. Especially, the limited amount of structured data in the clinical domain hinders linking drugs to clinical aspects such as efficacy and side effects. Second, to overcome the abovementioned knowledge gap between the chemical, preclinical, and clinical domain, we suggest information extraction from scientific literature and other unstructured resources through natural language processing models, where BioBERT and PubMedBERT are the current state-of-the-art approaches. Finally, we propose that knowledge graphs can be used to link structured data, scientific literature, and electronic health records, to come to meaningful interpretations. Together, we expect this richer knowledge will lower barriers toward clinical application of personalized combination therapies with high efficacy and limited adverse events.

The tyrosine kinase inhibitor nilotinib targets the discoidin domain receptor DDR2 in calcific aortic valve stenosis.

BACKGROUND AND PURPOSE: Tyrosine kinase inhibitors (TKI) used to treat chronic myeloid leukaemia (CML) have been associated with cardiovascular side effects, including reports of calcific aortic valve stenosis. The aim of this study was to establish the effects of first and second generation TKIs in aortic valve stenosis and to determine the associated molecular mechanisms. EXPERIMENTAL APPROACH: Hyperlipidemic APOE*3Leiden.CETP transgenic mice were treated with nilotinib, imatinib or vehicle. Human valvular interstitial cells (VICs) were isolated and studied in vitro. Gene expression analysis was perfromed in aortic valves from 64 patients undergoing aortic valve replacement surgery. KEY RESULTS: Nilotinib increased murine aortic valve thickness. Nilotinib, but not imatinib, promoted calcification and osteogenic activation and decreased autophagy in human VICs. Differential tyrosine kinase expression was detected between healthy and calcified valve tissue. Transcriptomic target identification revealed that the discoidin domain receptor DDR2, which is preferentially inhibited by nilotinib, was predominantly expressed in human aortic valves but markedly downregulated in calcified valve tissue. Nilotinib and selective DDR2 targeting in VICs induced a similar osteogenic activation, which was blunted by increasing the DDR2 ligand, collagen. CONCLUSIONS AND IMPLICATIONS: These findings suggest that inhibition of DDR2 by nilotinib promoted aortic valve thickening and VIC calcification, with possible translational implications for cardiovascular surveillance and possible personalized medicine in CML patients.

Oncostatin M reduces atherosclerosis development in APOE*3Leiden.CETP mice and is associated with increased survival probability in humans.

OBJECTIVE: Previous studies indicate a role for Oncostatin M (OSM) in atherosclerosis and other chronic inflammatory diseases for which inhibitory antibodies are in development. However, to date no intervention studies with OSM have been performed, and its relation to coronary heart disease (CHD) has not been studied. APPROACH AND RESULTS: Gene expression analysis on human normal arteries (n = 10) and late stage/advanced carotid atherosclerotic arteries (n = 127) and in situ hybridization on early human plaques (n = 9) showed that OSM, and its receptors, OSM receptor (OSMR) and Leukemia Inhibitory Factor Receptor (LIFR) are expressed in normal arteries and atherosclerotic plaques. Chronic OSM administration in APOE*3Leiden.CETP mice (n = 15/group) increased plasma E-selectin levels and monocyte adhesion to the activated endothelium independently of cholesterol but reduced the amount of inflammatory Ly-6CHigh monocytes and atherosclerotic lesion size and severity. Using aptamer-based proteomics profiling assays high circulating OSM levels were shown to correlate with post incident CHD survival probability in the AGES-Reykjavik study (n = 5457). CONCLUSIONS: Chronic OSM administration in APOE*3Leiden.CETP mice reduced atherosclerosis development. In line, higher serum OSM levels were correlated with improved post incident CHD survival probability in patients, suggesting a protective cardiovascular effect.

Inflammatory cytokine oncostatin M induces endothelial activation in macro- and microvascular endothelial cells and in APOE*3Leiden.CETP mice.

AIMS: Endothelial activation is involved in many chronic inflammatory diseases, such as atherosclerosis, and is often initiated by cytokines. Oncostatin M (OSM) is a relatively unknown cytokine that has been suggested to play a role in both endothelial activation and atherosclerosis. We comprehensively investigated the effect of OSM on endothelial cell activation from different vascular beds and in APOE*3Leiden.CETP mice. METHODS AND RESULTS: Human umbilical vein endothelial cells, human aortic endothelial cells and human microvascular endothelial cells cultured in the presence of OSM express elevated MCP-1, IL-6 and ICAM-1 mRNA levels. Human umbilical vein endothelial cells and human aortic endothelial cells additionally expressed increased VCAM-1 and E-selectin mRNA levels. Moreover, ICAM-1 membrane expression is increased as well as MCP-1, IL-6 and E-selectin protein release. A marked increase was observed in STAT1 and STAT3 phosphorylation indicating that the JAK/STAT pathway is involved in OSM signaling. OSM signals through the LIF receptor alfa (LIFR) and the OSM receptor (OSMR). siRNA knockdown of the LIFR and the OSMR revealed that simultaneous knockdown is necessary to significantly reduce MCP-1 and IL-6 secretion, VCAM-1 and E-selectin shedding and STAT1 and STAT3 phosphorylation after OSM stimulation. Moreover, OSM administration to APOE*3Leiden.CETP mice enhances plasma E-selectin levels and increases ICAM-1 expression and monocyte adhesion in the aortic root area. Furthermore, Il-6 mRNA expression was elevated in the aorta of OSM treated mice. CONCLUSION: OSM induces endothelial activation in vitro in endothelial cells from different vascular beds through activation of the JAK/STAT cascade and in vivo in APOE*3Leiden.CETP mice. Since endothelial activation is an initial step in atherosclerosis development, OSM may play a role in the initiation of atherosclerotic lesion formation.

The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and Ponatinib Activate Coagulation in a Translational Mouse Model.

Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the vascular adverse effects of three generations of TKIs in a translational model for atherosclerosis, the APOE*3Leiden.CETP mouse. Mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (10 and 30 mg/kg QD) or ponatinib (3 and 10 mg/kg QD), giving similar drug exposures as in CML-patients. Cardiovascular risk factors were analyzed longitudinally, and histopathological analysis of atherosclerosis and transcriptome analysis of the liver was performed. Imatinib and ponatinib decreased plasma cholesterol (imatinib, -69%, p < 0.001; ponatinib 3 mg/kg, -37%, p < 0.001; ponatinib 10 mg/kg-44%, p < 0.001) and atherosclerotic lesion area (imatinib, -78%, p < 0.001; ponatinib 3 mg/kg, -52%, p = 0.002; ponatinib 10 mg/kg, -48%, p = 0.006), which were not affected by nilotinib. In addition, imatinib increased plaque stability. Gene expression and pathway analysis demonstrated that ponatinib enhanced the mRNA expression of coagulation factors of both the contact activation (intrinsic) and tissue factor (extrinsic) pathways. In line with this, ponatinib enhanced plasma levels of FVII, whereas nilotinib increased plasma FVIIa activity. While imatinib showed a beneficial cardiovascular risk profile, nilotinib and ponatinib increased the cardiovascular risk through induction of a pro-thrombotic state.

Expression and clinical relevance of paired box protein 7 and sex determining region Y-box 2 in canine corticotroph pituitary adenomas.

Pituitary-dependent hypercortisolism is a common endocrinopathy in dogs, caused by an adrenocorticotrophic hormone secreting pituitary tumour of the anterior or intermediate lobe. The prognosis of intermediate lobe adenomas is worse than that of anterior lobe adenomas, indicating the possible usefulness of melanotropic markers as prognosticators. Another possible origin of pituitary adenomas is found in cancer stem cells. The aim of the present study was to investigate the expression of melanotroph specific transcription factor paired box protein 7 (Pax7) and stem cell marker and reprogramming factor sex determining region Y-box 2 (Sox2) and to relate their expression to clinical parameters. The mean ± SD of labelling index (LI) for Pax7 was 8.6% ± 21.7% in the adenomas; 1/6 controls had positive staining (LI, 15.2%). For Sox2, the LI in the adenomas was 16.9% ± 15.2% and 19.5% ± 11.6% in the controls. Pax7 expression was significantly higher in enlarged pituitaries, compared to non-enlarged pituitaries (P = 0.05), but Pax7 or Sox2 immunopositivity did not correlate to other clinical parameters such as histological diagnosis, survival time or disease-free interval. Gene expression of Pax7 target genes, such as proconvertase 2 (PC2), pro-opiomelanocortin (POMC), and dopamine D2 receptor (DRD2), was significantly lower in the adenoma samples compared to normal tissue, indicating that Pax7 signalling was not activated in adenomas. It was suggested that Pax7 and Sox2 remain interesting targets for molecular investigations into their role in pituitary tumorigenesis, but were unsuitable as clinical prognosticators in dogs.