Current Drug Targets (v.18, #1)
Meet Our Editorial Board Member by Hongmin Sun (1-1).
Editorial (Thematic Issue: The Predictive Pathology in the Target Therapy Era) by Renato Franco, Monica Cantile (2-3).
Predictive Diagnostic Pathology in the Target Therapy Era in Breast Cancer by Caterina Marchio, Davide Balmativola, Roberta Castiglione, Laura Annaratone, Anna Sapino (4-12).
Treatment strategies in oncology are nowadays largely based on the “target therapy model”, which allows to personalize the cure of each patient depending on distinctive host and disease features. As a general concept “targeted drugs” are effective only when the tumor exhibits the “target”, which in breast cancer pathology may correspond to the expression of estrogen receptors and/or of HER2. These biomarkers are evaluated on breast cancer tissues by companion diagnostic tests, however, evidence suggests that the first step in breast cancer predictive pathology is still represented by morphology. For instance, histological types, such as tubular and cribriform carcinomas, define patients who may not need any treatments other than surgical excision. Neoadjuvant studies have shown that patients affected by lobular carcinomas are not likely to have any beneficial effects from chemotherapy. The second step in prediction is represented by immunophenotyping. If the immunohistochemical evaluation of four markers (estrogen and progesterone receptors, HER2 and Ki67) remains the best practice for breast cancer predictive pathology, molecular pathology has certainly reshaped the way we approach breast cancer diagnosis. The aim of this review is to discuss current knowledge in predictive pathology for the management of breast cancer patients, focusing on the benefits and drawbacks of traditional tools and of novel improvements of molecular biology.
Does Immunohistochemistry Represent a Robust Alternative Technique in Determining Drugable Predictive Gene Alterations in Non-Small Cell Lung Cancer? by Giulio Rossi, Moira Ragazzi, Ione Tamagnini, Maria C. Mengoli, Giada Vincenzi, Fausto Barbieri, Silvia Piccioli, Alessandra Bisagni, Tiziana Vavala, Luisella Righi, Silvia Novello, Francesco Gelsomino, Marcello Tiseo (13-26).
Immunohistochemistry (IHC) is a widely-tested, low-cost and rapid ancillary technique available in all laboratories of pathology. This method is generally used for diagnostic purposes, but several studies have investigated the sensitivity and specificity of different immunohistochemical antibodies as a surrogate test in the determination of predictive biomarkers in non-small cell lung cancer (NSCLC), particularly for Epidermal Growth Factor Receptor (EGFR) gene mutations, Anaplastic Lymphoma Kinase (ALK) gene and ROS1 rearrangements. In this review, a critical examination of the works comparing the consistency of IHC expression and conventional molecular techniques to identify genetic alterations with predictive value in NSCLC is discussed. Summarizing, data on sensitivity and specificity of antibodies against ALK and ROS1 are very consistent and time has come to trust in IHC at least as a cost-effective screening tool to identify patients with rearranged tumors in clinical practice. On the other hand, mutant-specific antibodies against EGFR demonstrate a good specificity but a lowto- fair sensitivity, raising some cautions on their employment as robust predictive biomarkers. A brief comment on preliminary experiences with antibodies against BRAF, RET, HER2 and c-MET is also included.
LncRNA HOTAIR as Prognostic Circulating Marker and Potential Therapeutic Target in Patients with Tumor Diseases by Gerardo Botti, Laura Marra, Maria Gabriella Malzone, Annamaria Anniciello, Chiara Botti, Renato Franco, Monica Cantile (27-34).
In the recent years the importance of the role played by non-coding RNA on the regulation of gene expression was increased by numerous studies. The research mainly focused on small ncRNAs, such as miRNAs, while the functions of long non-coding RNA (lncRNA) have been much less studied. lncRNAs can be transcribed from intergenic, intragenic or specific chromosomal regions. Compared to miRNAs, lncRNAs have a complex secondary and tertiary structure which allows to bind proteins, RNA, DNA and to carry out their regulatory functions. Several studies showed that extracellular ncRNAs can circulate in the blood of both healthy and diseased patients. Most of the circulating ncRNAs are included in lipid or lipoprotein vesicles, such as apoptotic bodies, macrovesicles or exosomes, in which they are highly stable. The presence of circulating ncRNAs in the blood of cancer patients versus normal subjects suggested the possibility that these molecules may represent new diagnostic markers. HOTAIR is a HOX transcript antisense RNA, located in the HOXC locus, able to repress transcription in the posterior region of the HOXD locus. HOTAIR has been
Non Coding RNAs: A New Avenue for the Self-Tailoring of Blood Cancer Treatment by Gabriella Misso, Mayra Rachele Zarone, Anna Grimaldi, Maria Teresa Di Martino, Angela Lombardi, Hiromichi Kawasaki, Paola Stiuso, Pierfrancesco Tassone, Pierosandro Tagliaferri, Michele Caraglia (35-55).
Hematological malignancies, accounting for about 10% of all deaths for cancer, include various forms of leukemia, lymphoma and myeloma. At present, hematological malignancies are analyzed and classified on the basis of morphologic characteristics, cell surface markers, cytogenetic aberrations and molecular markers. Unfortunately, in most cases, standard criteria are not sufficient for both an early diagnosis and a complete classification. The latter issue hampers an optimal therapeutic choice for these patients that often display heterogeneous clinical outcomes or responses to therapy. This heterogeneity has determined a need for improved methods of analysis and novel markers for diagnosis and classification of these malignancies. Non coding RNAs act as master regulators of numerous biological processes including epigenetic response, apoptosis and cell cycle. The recent advances in cancer research have led to a spreading out in the clinical use of genomic information; in fact, several studies are investigating the prominent role of both miRNAs and lncRNAs in hematopoietic differentiation and proliferation, as well as in the development of various hematological malignancies. These investigations are mainly aimed at researching new therapeutic opportunities that could boost a reduced risk of adverse events in normal tissues. Moreover, not less important, there is also a growing interest in determining how ncRNAs are associated with clinical features. In this review we focus on the aberrant ncRNAs expression in the most common forms of blood cancers, each of which exhibits a unique signature in comparison to normal counterparts. In addition to their regulatory role and in virtue of the well known ncRNAs' capacity of modulating signal and pathway networks, herein we discuss both miRNAs' and lncRNAs' potential as new powerful biomarkers for efficient diagnosis and prediction of response for patients with hematological malignancies.
Targeting Angiogenic Pathways in Colorectal Cancer: Complexities, Challenges and Future Directions by Khurum Khan, David Cunningham, Ian Chau (56-71).
Colorectal cancer (CRC) is one of the commonest cancers in the world. During the last decade, the development of targeted therapies has given cancer treatment a novel direction in management of metastatic CRC (mCRC) and has enriched the therapeutic armamentarium in the management of this disease. In mCRC, targeting angiogenesis via the vascular endothelial growth factor (VEGF) pathway has been of particular interest based on the favourable survival benefit demonstrated by bevacizumab in clinical trials. More recently, large phase III studies have shown clinical efficacy for the new antiangiogenic agents aflibercept and regorafenib. However, the results of pre-clinical and clinical studies of other anti-angiogenic agents have been disappointing. Furthermore, the benefits from angiogenic inhibitors (AIs) in an unselected patient population are modest. Research into predictive biomarkers is therefore essential, but has, to date, been unsuccessful. Nevertheless, aflibercept and regorafenib have been shown to benefit both bevacizumab naive and refractory patients, suggesting that acquired resistance to AIs can be potentially reversed. This review describes the most recent advances in development of AIs in mCRC with particular focus on aflibercept and regorafenib, the existing challenges for the evaluation of these agents in clinical practice and potential strategies in designing clinical trials that could lead to the discovery of clinically meaningful biomarkers.
Nano-Based Anti-Tubercular Drug Delivery and Therapeutic Interventions in Tuberculosis by Rohit Sharma, Amanpreet Kaur, A. K. Sharma, Neeraj Dilbaghi, Anil K. Sharma (72-86).
Nanotechnology has shown great promise in health care offering numerous possibilities to significantly improve diagnosis of many dreadful diseases including Tuberculosis (TB). Nanomedicine has made the current drug regimen more effective against diseases particularly TB with attributes like sustained release, increased half life, higher drug concentrations at target sites, reduced toxicity and lesser side effects. However because of the severity of the disease, there is a strong urge to develop better approaches with some concomitant regimens using nano-particles to diagnose, treat and manage TB patients. The current review highlights some of the evolving strategies in the field of nanomedicine particularly drug delivery offering promising alternative for the current TB regimens. The study also emphasizes upon the need to design more effective nanocarriers which are highly specific, biocompatible and biodegradable as well.
A Perspective on Monoamine Oxidase Enzyme as Drug Target: Challenges and Opportunities by Bhupinder Kumar, Vivek Prakash Gupta, Vinod Kumar (87-97).
The monoamine oxidase (MAO) enzyme is responsible for the deamination of monoamine neurotransmitters and regulates their concentration in the central and peripheral nervous systems. Imbalance in the concentration of neurotransmitters in the brain and central nervous system is linked with the biochemical pathology of various neurogenic disorders. Irreversible MAO inhibitors were the first line drugs developed for the management of severe depression but most of these were withdrawn from the clinical practice due to their fatal side effects including food-drug interactions. New generations of MAO inhibitors were developed which were reversible and selective for one of the enzyme isoform and showed improved pharmacological profile. The discovery of crystal structure of MAO-A & MAO-B isoforms helped in understanding the drug-receptor interactions at the molecular level and designing of ligands with selectivity for either of the isoforms. The current article provides an overview on the MAO enzyme as potential drug target for different disease states. The article describes catalytic mechanism of MAO enzyme, crystal structures of the two MAO isoforms, traditional MAO inhibitors and various problems associated with their use, new developments in the MAO inhibitors and their potential as therapeutic agents especially in neurological disorders.
Targeting MET Receptor in Rhabdomyosarcoma: Rationale and Progress by Barbara Szewczyk, Klaudia Skrzypek, Marcin Majka (98-107).
MET is a tyrosine kinase receptor, which binds hepatocyte growth factor (HGF). It regulates many physiological processes and participates in the regulation of proliferation, differentiation and motility of various cells. It plays an important role in embryogenesis as well as in adult life. Aberrations within the regulatory pathways activated by MET can be one of the causes of tumor development. Recently novel important functions of MET signaling in tumor development have been described, such as maintenance of cancer stem cells or importance of endosomal localization of MET. Moreover, MET is considered as one of the important factors responsible for development of rhabdomyosarcoma (RMS), a soft tissue sarcoma related to myogenic lineage. Its origin remains debatable but it is suggested that it derives from defect in differentiation of the satellite cells or of the mesenchymal stem cells. In RMS MET downregulation induces differentiation of tumor cells and in consequence, metastatic potential of RMS cells is diminished. Therefore, blocking of MET may be clinically useful in novel differentiationbased therapies of RMS in future.
Nanosponge Carriers- An Archetype Swing in Cancer Therapy: A Comprehensive Review by Riyaz Ali M. Osmani, Umme Hani, Rohit R. Bhosale, Parthasarathi K. Kulkarni, Seetharaman Shanmuganathan (108-118).
Nanotechnology and nanomedicines are emerging research meadows; which chiefly focuses on creating and manipulating materials at a nanometer level for the betterment in imaging, diagnosis and treatment of a range of diseases together with cancer. Cyclodextrin-based nanosponges, anticipated as a new-fangled nanosized delivery system, are ground-breaking hyper-crosslinked cyclodextrin polymers nanostructured within a three-dimensional network. Nanosponges based systems hold the potential of elevating the solubility, absorption, penetration, bioavailability, in vivo stability, targeted as well as sustained delivery, and therapeutic efficiency of numerous anticancer agents. The extension of nanosponges based drug delivery systems is an exhilarating and demanding research pasture, predominantly to overcome aforementioned problems allied to existing anticancer formulations and for the further progressions in cancer therapies. Nanosponges in cancer therapy, particularly cyclodextrin based nanosponges are brought up in this review. By quoting diverse attempts made in pertinent direction, efforts have been made to exemplify the characteristics, suitability and versatility of cyclodextrin based nanosponges for their promising applications in cancer treatment.
Transcriptional Regulation of mPGES1 in Cancer: An Alternative Approach to Drug Discovery? by Meera Ramanan, Mukesh Doble (119-131).
Prostaglandins serve as the connecting link between inflammation and cancer. mPGES1, the downstream enzyme in the prostaglandin pathway is considered a better target than COX-2 against the progression of cancer due to the cardiovascular and other complications associated with the inhibition of the latter. Despite the discovery of several compounds that inhibit mPGES1 none could enter the market as drugs because of the problems concerning specificity and unacceptable pharmacokinetic properties. Expression of mPGES1 is inducible in conditions of inflammation and hypoxia and its expression is regulated by a number of transcriptional factors. Targeting these transcription factors could be an alternative approach in the drug discovery process. In this review, the characteristics of the transcription factors, their ability to bind to the promoter of mPGES1 gene and the inhibitors against them have been discussed. The Structure Activity Relationship of the reported inhibitors is highlighted. Finally, practical challenges to further the drug development and future research directions are discussed. These novel compounds that are inhibitors of the major transcription factors are promising candidates for further development as inhibitors of mPGES1.