Kinase inhibition-related adverse events predicted from in vitro kinome and clinical trial data

BackgroundKinase inhibition is an increasingly popular strategy for pharmacotherapy of human diseases. Although many of these agents have been described as “targeted therapy”, they will typically inhibit multiple kinases with varying potency. Pre-clinical model testing has not predicted the numerous significant toxicities identified during clinical development. The purpose of this study was to develop a bioinformatics-based method to predict specific adverse events (AEs) in humans associated with the inhibition of particular kinase targets (KTs).MethodsThe AE frequencies of protein kinase inhibitors (PKIs) were curated from three sources (PubMed, Thompson Physician Desk Reference and PharmGKB), and affinities of 38 PKIs for 317 kinases, representing >50% of the predicted human kinome, were collected from published in vitro assay results. A novel quantitative computational method was developed to predict associations between KTs and AEs that included a whole panel of 71 AEs and 20 PKIs targeting 266 distinct kinases with K_d < 10 μM. The method calculated an unbiased, kinome-wide association score via linear algebra on (i) the normalized frequencies of AEs associated with 20 PKIs and (ii) the negative log-transformed dissociation constant of kinases targeted by these PKIs. Finally, a reference standard was calculated by applying Fisher’s exact test to the co-occurrence of indexed Pubmed terms (p ? 0.05, and manually verified) for AE and associated kinase targets (AE–KT) pairs from standard literature search techniques. We also evaluated the enrichment of predictions between the quantitative method and the literature search by Fisher’s exact testing.ResultsWe identified significant associations among already empirically well established pairs of AEs (e.g. diarrhea and rash) and KTs (e.g. EGFR). The following less well recognized AE–KT pairs had similar association scores: diarrhea-(DDR1;ERBB4), rash-ERBB4, and fatigue-(CSF1R;KIT). With no filtering, the association score identified 41 prioritized associations involving 7 AEs and 19 KTs. Among them, eight associations were reported in the literature review. There were only 78 out of a total of 4522 AE–KT pairs meeting the evaluation threshold, indicating a strong association between the predicted and the text mined AE–KT pairs (p = 3 × 10^?7). As many of these drugs remain in development, a larger volume of more detailed data on AE–PKI associations is accessible only through non-public databases. These prediction models will be refined with these data and validated through dedicated prospective human studies.Conclusion and future directionsOur in silico method can predict associations between kinase targets and AE frequencies in human patients. Refining this method should lead to improved clinical development of protein kinase inhibitors, a large new class of therapeutics. http://www.lussierlab.org/publication/PAS/.     

The effect of amygdala kindling on hippocampal neurogenesis coincides with decreased reelin and DISC1 expression in the adult dentate gyrus

Temporal lobe seizures can induce the proliferation and abnormal migration of newly generated dentate granule cells, but little is known about the molecular mechanisms that govern these pathological events. Reelin and DISC1 (disrupted‐in‐schizophrenia 1) are proteins that play a regulatory role in the maturation and integration of new neurons in the developing and adult brain. In this study, we examined whether amygdala kindling results in aberrant neurogenesis and altered expression of reelin and DISC1 in the adult dentate gyrus. Using doublecortin immunohistochemistry, we found that short‐term kindling (i.e., 30 electrical stimulations) significantly increased the number of immature neurons in the dentate subgranular zone (SGZ), whereas long‐term kindling (i.e., 99 electrical stimulations) did not. However, doublecortin‐labeled neurons in long‐term kindled rats showed greater dendritic complexity than they did in short‐term kindled or control rats. We also found that long‐term kindling decreased the number of reelin‐positive cells and decreased DISC1 expression in the dentate granule cell layer and subgranular zone. Interestingly, kindling‐induced changes in reelin and DISC1 expression coincided with the appearance of ectopically located Prox1‐labeled granule cells in the hilus. These effects occurred independently of alterations in granule cell layer length, dentate volume, or the number of hilar neurons. Taken together, these findings suggest a novel role for DISC1 in the pathophysiology of temporal lobe epilepsy and further suggest that changes in reelin and DISC1 expression may contribute to aberrant neurogenesis in the kindling model. © 2009 Wiley‐Liss, Inc.     

Left-handedness and longevity in primates.

In the present research we used the rhesus macaque to model the decline in the incidence of left-handedness that has been noted in the aged human population. We found a significant group-level bias towards use of the left hand among young-adult macaques, and a significant group-level bias towards use of the right hand among aged macaques. The distribution of hand preference across age classes cannot be explained through simple elimination of left-handed subjects in the aged population. Rather, our data are consistent with a maturational view positing increased use of the right hand with increased age. Similar findings across phylogenetically diverse primate taxa suggest that this phenomenon is an evolutionarily ancient trait. Greater use of the left hand in male versus female macaques indicates that sex differences in hand preference are also deeply rooted in our primate origins.     

Occult malignant breast lesions in 114 patients: relationship to age and the presence of microcalcifications

This study evaluates the mammographic findings in 352 patients, aged 30-85 years, who underwent spot localization and biopsy for evaluation of nonpalpable breast abnormalities. Malignancy was found at biopsy in 114 cases. The mammographic appearance (specifically, whether grouped microcalcifications, mass, or both were present) was correlated with patient age and histologic findings (specifically, whether the pathologic changes were infiltrating or noninfiltrating in nature). The prevalence of malignant conditions increased directly with age. The presence of grouped microcalcifications as the sole indicator of malignancy was seen in 100% (seven of seven) of the patients in the 30-39-year age group, 64% (18 of 28) in the 40-49-year age group, 37% (11 of 30) in the 50-59-year age group, 30% (seven of 23) in the 60-69-year age group, and 23% (six of 26) in the 70-85-year age group. Of the 49 tumors that were manifested solely as microcalcifications, 34 (69%) were noninfiltrating. The finding of grouped microcalcifications should be aggressively investigated, since it may indicate noninfiltrating carcinoma in an early stage, when the potential for cure is greatest.