Translational Research in Cancer

Translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies concerning the molecular pathways involved in tumorigenesis. Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. The vast majority of cancer cases are due to environmental risk factors. Many of these environmental factors are controllable lifestyle choices. Experimental cancer treatments are studied in clinical trials to compare the proposed treatment to the best existing treatment through translational research. The key features of the book include: 1) New screening for the development of radioprotectors: radioprotection and anti-cancer effect of β-Glucan (Enterococcus faecalis) 2) Translational perspective on hepatocellular carcinoma 3) Brachytherapy for endometrial cancer 4) Discovery of small molecule inhibitors for histone methyltransferases in cance

Targeting the Colchicine Binding Site on Tubulin to Overcome Multidrug Resistance and Anticancer Efficacy of Selective Survivin Inhibitors

Tubulin inhibitors are widely used as chemotherapeutic agents, and their successis attributed to their ability to target microtubule dynamics and disrupt critical cellular functions including cell signaling, motility, intracellular trafficking, and mitosis. Interference with microtubule dynamics consequently disrupts mitotic progression and ultimately leads to apoptosis, validating microtubule dynamics as an excellent target for anticancer agents. While this class of drug has proven to be effective against many cancer types, the clinical efficacy of current tubulin inhibitors is often limited by the development of multidrug resistance. The most common form of resistance to these agents arises from the overexpression of drug efflux transporters. Extensive research efforts have attempted to develop colchicine binding site inhibitors, which are reported to be significantly less susceptible to multidrug resistance and have therapeutic advantages over agents that target the taxane and vinca alkaloid site. Herein, we evaluated the anticancer activity of novel small-molecules that target the colchicine binding site, focusing on the most promising compounds from several structural scaffolds including indolyl-imidazopyridines (DJ95 and DJ101), VERU-111 analogs with a modified indole moiety (10ab and 10bb) or 3,4,5-trimethoxyphenyl moiety (13f), and heterocyclic pyrimidines (4a, 6a, 5a, and 5b). We demonstrated the cytotoxic potency of these compounds against a variety of cancer cell lines, including malignant melanomas, taxaneresistant prostate cancer cells, and drug efflux pump-overexpressing cell lines. Their mechanism of action was revealed through tubulin polymerization inhibition, disruption of microtubule networks and mitotic spindle formation, and confirmed through X-ray crystallography, which detailed their specific molecular interactions with tubulin in the colchicine binding pocket. Furthermore, these compounds exhibited hallmark characteristics of colchicine binding site agents, such as arresting cells in the G2/M phase of the cell cycle, inducing apoptosis in a concentration-dependent manner, and impeding cancer cell proliferation and migration. Finally, the compounds were efficacious in vivo against melanoma and taxane-resistant prostate cancer xenograft tumors. Several agents were evaluated for ability to prevent melanoma metastases to the lungs in experimental mouse models, and they potently inhibited the development metastatic foci. Safety assessment by pharmacological profiling demonstrated minimal interactions to physiologically important targets and pathophysiological analysis of major organs from the in vivo treatment groups did not expose apparent drug-related injury. Several of the investigated compounds also demonstrated vascular disrupting properties by targeting tumor vasculature and inhibiting capillary-like network formation of endothelial cells. Ultimately, these compounds exhibit strong anticancer efficacy, specifically target the colchicine binding site, and have great potential as cancer therapeutics, particularly for multidrug resistance phenotypes. Another target we explored for anticancer intervention was survivin. Survivin is the smallest member the inhibitor of apoptosis protein family and its overexpression in tumor cells is been positively correlated with the development of multidrug resistance and radiation resistance. Because it is differentially expressed in healthy tissues and tumors, it is an attractive therapeutic target. Using the scaffold of UC-112, which was previously identified through virtual screening, we evaluated a series of analogs designed to optimize potency and improve selectivity to survivin over other inhibitor of apoptosis proteins. We identified compound 10f, which was highly cytotoxic to melanoma and Pglycoprotein overexpressing cell lines, induced apoptotic cascades in a concentrationdependent manner, specifically downregulated survivin protein levels, and significantly inhibited tumor growth in vivo. Ultimately, these results validated our in-depth biological investigation of novel scaffolds of survivin inhibitors and verified the anticancer efficacy of 10f

Drug Repurposing

This book focuses on various aspects and applications of drug repurposing, the understanding of which is important for treating diseases. Due to the high costs and time associated with the new drug discovery process, the inclination toward drug repurposing is increasing for common as well as rare diseases. A major focus of this book is understanding the role of drug repurposing to develop drugs for infectious diseases, including antivirals, antibacterial and anticancer drugs, as well as immunotherapeutics

Natural Medicine in Therapy

Enter For a long time, natural medicine has been used as a therapeutic therapy based on generations of indigenous practices. Today the rise in natural remedies has been largely driven by public demand and billions of dollars are spent annually on herbal medicines. It is therefore important to document the effectiveness of natural medicine, its potential side effects, and potential interactions

Automatic discovery of drug mode of action and drug repositioning from gene expression data

2009 - 2010The identification of the molecular pathway that is targeted by a compound, combined with the dissection of the following reactions in the cellular environment, i.e. the drug mode of action, is a key challenge in biomedicine. Elucidation of drug mode of action has been attempted, in the past, with different approaches. Methods based only on transcriptional responses are those requiring the least amount of information and can be quickly applied to new compounds. On the other hand, they have met with limited success and, at the present, a general, robust and efficient gene-expression based method to study drugs in mammalian systems is still missing. We developed an efficient analysis framework to investigate the mode of action of drugs by using gene expression data only. Particularly, by using a large compendium of gene expression profiles following treatments with more than 1,000 compounds on different human cell lines, we were able to extract a synthetic consensual transcriptional response for each of the tested compounds. This was obtained by developing an original rank merging procedure. Then, we designed a novel similarity measure among the transcriptional responses to each drug, endingending up with a “drug similarity network”, where each drug is a node and edges represent significant similarities between drugs. By means of a novel hierarchical clustering algorithm, we then provided this network with a modular topology, contanining groups of highly interconnected nodes (i.e. network communities) whose exemplars form secondlevel modules (i.e. network rich-clubs), and so on. We showed that these topological modules are enriched for a given mode of action and that the hierarchy of the resulting final network reflects the different levels of similarities among the composing compound mode of actions. Most importantly, by integrating a novel drug X into this network (which can be done very quickly) the unknown mode of action can be inferred by studying the topology of the subnetwork surrounding X. Moreover, novel potential therapeutic applications can be assigned to safe and approved drugs, that are already present in the network, by studying their neighborhood (i.e. drug repositioning), hence in a very cheap, easy and fast way, without the need of additional experiments. By using this approach, we were able to correctly classify novel anti-cancer compounds; to predict and experimentally validate an unexpected similarity in the mode of action of CDK2 inhibitors and TopoIsomerase inhibitors and to predict that Fasudil, a known and FDA-approved cardiotonic agent, could be repositioned as novel enhancer of cellular autophagy. Due to the extremely safe profile of this drug and its potential ability to traverse the blood-brain barrier, this could have strong implications in the treatment of several human neurodegenerative disorders, such as Huntington and Parkinson diseases. [edited by author]IX n.s