Malignant glioma drug discovery – targeting protein kinases

Abstract

Malignant gliomas are uncommon, but extremely lethal, cancers. Current standard-of-care includes surgery, radiation and chemotherapy, but recent research has generated a shift towards targeting the aberrant signal transduction components that underlie the pathogenesis of malignant gliomas. Protein kinases are a family of enzymes that are key elements in signal transduction-regulated cellular homeostasis subdivided based on their catalytic activity into tyrosine kinases and serine/threonine kinases. Protein kinases can be deregulated by several mechanisms, including genomic rearrangement, mutations of oncogenes or loss of tumour suppressor genes and overexpression or mutation of growth factor receptors to contribute to cancer initiation and maintenance. In malignant gliomas, several protein kinases are commonly over activated and may represent new therapeutic targets. Two main classes of agents targeting protein kinases are monoclonal antibodies and small-molecule inhibitors. In clinical trials, these molecularly targeted therapies have demonstrated limited efficacy as single agents in unselected malignant glioma patient populations. Several mechanisms of the failure of targeted agent monotherapies have been elucidated as new therapeutic strategies have emerged to overcome the resistance. Multi-targeted kinase inhibitors and combinations of single-targeted kinase inhibitors with one another or with traditional cytotoxics may increase treatment efficacy. Identification of biomarkers of response or resistance will be of paramount importance to enrich patients for specific targeted agents based on their genetic/molecular signature. In this review, the authors discuss the role of protein kinases in malignant glioma and how to target aberrant protein kinases with novel therapeutics.

Network target for screening synergistic drug combinations with application to traditional Chinese medicine

“…Thus, we assume that the more important the agent gene as a network node is, the stronger effect on the disease the agent will produce. To determine the importance of an agent gene as a node in the network, we propose a node importance score, ( IP ( v ), here v denotes a vertex / node), by integrating degree [26], betweenness [27] and closeness [28], three network centrality indexes that have been used to define the network properties of drug targets separately or collectively [29]. Moreover, we suppose that if an agent pair produces synergy, their agent genes should be adjacent in the network.…”

Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening

“…Despite these drawbacks, phenotypic screening has successfully identified PZQ and other vital anthelmintics (e.g., albendazole and ivermectin) that are in medical use today. Most often, the compounds originated in the animal health sector as part of its discovery programs to identify veterinary anti-parasitics [46],[47].…”

Bioactivity of miltefosine against aquatic stages of Schistosoma mansoni, Schistosoma haematobium and their snail hosts, supported by scanning electron microscopy

“…The schistosomicidal in vitro bioassay used here followed the main procedure previously described by [30] and [31]. Thus, the schistosome material Schistosoma mansoni (Sambon) and S. haematobium (Bilharz) was obtained from the Schistosome Biological Supply Centre (SBSC), Theodor Bilharz Research Institute (TBRI), Cairo, Egypt.…”