Current Signal Transduction Therapy - Volume 8, Issue 1, 2013

Malignant gliomas are the most common primary central nervous system tumors, and the most aggressive and frequent form is the World Health Organization (WHO) grade IV astrocytoma, or glioblastoma. The standard treatment of glioblastoma consists of aggressive resection, radiation therapy, and concomitant and adjuvant treatment with the DNAalkylating agent temozolomide. Despite treatment, the prognosis is dismal for the vast majority of glioblastoma patients, with over 90% of patients succumbing to the disease within 5 years and a median survival of just over 1 year after diagnosis. There is clearly a great need for the development of therapeutic agents targeting pathways driving glioma malignancy, including cell proliferation, invasion, survival, as well as angiogenesis and pathways leading to resistance to cytotoxic therapies. Identification and validation of biomarkers predictive of response to therapy for patient stratification is an essential component of the development of targeted therapies. Comprehensive molecular characterization of tumor tissues is becoming prevalent, and developing approaches to integrate and bring this knowledge to the clinic will fuel the incorporation of targeted therapy in the management of malignant gliomas.

The prognosis for malignant gliomas remains poor despite multimodality therapy. An increased understanding of the molecular pathogenesis involved in glioma development and growth has resulted in development of agents that specifically target these molecular processes and pathways. Except for inhibitors of the vascular endothelial growth factor pathway, results from most single agent trials have been modest at best. Tailoring therapy to the individual patients is an attractive strategy although most studies have failed to determine predictive biomarkers. Numerous novel agents, multitargeted agents, and combination therapies are now in clinical trials for malignant glioma.

Bevacizumab is a humanised monoclonal antibody targeted to the vascular endothelial growth factor (VEGF). VEGF is the ligand for VEGF receptors (VEGFR), which are important for the development and maintenance of the angiogenic phenotype in high-grade solid tumors, including malignant gliomas. An overview of VEGF, VEGFR, and the pharmacology of bevacizumab will be presented. Bevacizumab is active in pre-clinical testing against glioma tissue cultures and xenograft models. In the clinical setting, in combination with irinotecan and other chemotherapy agents, it has shown significant activity in patients with glioblastoma multiforme (GBM) and other brain tumors. Objective responses on neuro-imaging have been noted in 30-60% of reported cases. Prolongation of progression-free survival and overall survival have also been suggested in many reports. Treatment of bevacizumab is associated with potential side effects, including thromboembolic disorders, fatigue, intracranial hemorrhage, proteinuria, hypertension, and bowel perforation.

A flurry of recent research has established that microRNAs have fundamental roles in the biology of the aggressive brain tumor, glioblastoma multiforme. MicroRNAs function in multiple hallmark biological characteristics of glioblastoma, including cell proliferation, invasion, glioma stem cell behavior, and angiogenesis as well as sensitivity to conventional therapies. Many of these microRNAs intersect with key pathways in glioblastoma, indicating their importance in the disease. MicroRNAs also have prognostic potential, may be useful biomarkers and can be used to define subclasses of glioblastoma. MicroRNAs have also shown therapeutic activity in preclinical cancer models.

Glioblastoma multiforme (GBM) is the most commonly diagnosed primary Central Nervous System tumors in adults, with approximately 10,000 new cases annually in the United States. GBMs rank among the deadliest of all human cancers with no curative options available; no meaningful therapeutic advances have been made in over 30 years. Recurrence is inevitable in the vast majority of cases, and a permanent cure for GBM remains elusive. Even those individuals who respond to first-line therapies subsequently exhibit a limited response to second-line therapies, which eventually leads to their demise. Therefore, there is an urgent need to develop novel therapeutic options that effectively target therapy-resistant GBM cells. GBM stem cells (GSCs) are a subpopulation of highly tumorigenic cells that contain stem cell characteristics. While our understanding of GSCs is evolving, studies support that GSCs drive GBM propagation and enable resistance to conventional therapies such as radiation. Identification of novel therapeutics designed to target the GSC population in GBM has emerged as a promising strategy to overcome this lethal disease. This review summarizes the latest understanding about translational research toward molecular characterization of GSCs and potential therapeutic application of the recent pre-clinical research discoveries to the clinic.

During development of the cerebellum, a large number of molecular factors interact to produce an intricate brain structure. Many of these developmentally significant genes are members of signaling cascades implicated in the formation and growth of the embryonal brain tumor medulloblastoma. Genes controlling critical developmental pathways such as Hedgehog, Notch, Wnt, and Myc are known to be overexpressed and/or genetically altered in subsets of medulloblastoma. These pathways are also linked by their ability to induce or maintain stem-cell phenotypes in normal development. Their over-activation in tumors can lead to proliferation, invasion, altered metabolism, and evasion of treatment-induced cell death. The importance of these signaling cascades in medulloblastoma cells makes them attractive targets for therapeutic intervention. The development of therapeutic agents targeting these pathways may lead to improvement in patient survival and a reduction in the intensity of highly morbid radiation and chemotherapy that patients currently receive. In this review, we discuss a number of approaches to targeting these pathways in medulloblastoma.

The family of type I cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, shares common transducing element the common cytokine receptor γc. The receptors containing γc exert prominent mitogenic effects and play an important role in several immunological functions and in supporting cell survival. The γc-dependent cytokine receptors use the Janus Kinase (JAK)/Signal transducer and activator of transcription (STAT) signaling pathway to mediate gene activation or repression. The Growth Hormone (GH) is a peptide of 191 amino acids and 22 kDa molecular weight, produced by the adenohypophysis, that regulates many important functions, as control of cellular metabolism, immune functions, fertility and somatic growth. Of note, the existence of a previously unappreciated functional interaction between γc and Growth Hormone receptor (GH-R) has been recently documented. The impairment of various GHinduced events in patients affected with severe combined immunodeficiencies due to γc defects suggests a potential functional interaction between GH-R pathways and γc, indicating a further link between endocrine and immune system with potential implication of the molecule in the cell cycle progression and control. GH-R pathways and γc interaction leads to the activation and intranuclear translocation of STAT5b protein. Moreover, evidence suggests that both GHinduced and spontaneous cell cycle progression and cell growth are strongly dependent on the amount of γc expression. To date, the regulation of cell survival and apoptosis can be considered a delicate teamwork and a proper functionality of γc-dependent cytokines on the whole seems to play prominent roles, as revealed by the profound impact that their abnormal function can have on the homeostasis of the immune system.

Neurotrophins (NTs) and their receptors, TrKs and p75NTR, have been shown to regulate proliferation and apoptosis of neoplastic cells. Pharmacological TrK blockade is considered a valuable target in cancer therapy, and several TrK inhibitors are under investigation. However, only a few of them have reached the stage of clinical development. Myosarcomas are aggressive cancers, which secrete NGF and respond poorly to available chemotherapies. Our previous work has shown that these cancers, characterized by autocrine activation of TrKA by NGF, which promotes cancer growth and survival, are highly susceptible to TrK blockade, both in vitro and in vivo. The same pattern has also been described in prostatic carcinoma. The present report characterizes for the first time the anti-proliferative and pro-apoptotic effects of the oxindole TrK inhibitor GW441756, in a panel of human myosarcomas and prostatic adenocarcinoma cell lines. Furthermore, we provide novel evidence that, in myosarcomas, characterized by a high-TrK/low-p75NTR phenotype, GW441756 upregulates p75NTR receptor expression, leading to apoptosis via caspase-3 activation. Altogether, our data expand the knowledge of the anti-neoplastic and pro-apoptotic mechanisms of GW441756, and of TrK inhibitors in general, lending further support to the therapeutic potential of TrK blockade in clinical oncology.

Triptolide is the major active ingredient of extracts derived from the traditional Chinese Medicine tripterygium wilfordii Hook F. As a complex natural extract, triptolide has a broad range of biological target points and exhibits a variety of pharmacological effects including anti-inflammatory, immunosuppressive, antioxidant, and anti-infertility. In addition, considerable evidences show that triptolide holds dramatic anti-tumor activities manifested by antiproliferative and proapoptotic activities at low nanomolar concentration. In clinical trial, some clinical departments in China have used triptolide to treat leukemia without toxicity of heart, liver, kidney as well as gastrointestinal tract at therapeutic dose. The present review delineates the molecular mechanism of the anti-tumor activities of triptolide in hematological malignancies. Our research shows the extensive biological effects of triptolide are mediated by means of perturbing multiple signal pathways and molecular cascades including regulation of tumor cell survival pathway (Bcl-2, Mcl-1, XIAP, caspases, nuclear factor-kappaB ), blocking the progression of cell cycle (CDKs, cyclin D1, P21wap1/cip1 and P27kip1), epigenetic modulation of target genes via interaction with histone methyltransferases and demethylases (EZH2, SUV39H1, NSD1, SMYD3, LSD1, JMJD2B, RIZ1), as well as regulation of angiogenesis pathway (VEGF, VEGFR) in hematological malignancies.

Since the initial identification of microRNAs (miRNA) in C. elegans, functional characterisation of these small non-coding RNAs has demonstrated their critical involvement in numerous biological processes. Typically 20-22 nucleotides in length, miRNAs act as negative gene regulators at the post-transcriptional level. A large body of evidence points to the role of miRNAs in haematopoiesis. miRNAs provide a network of signals important for haematopoietic cell maintenance, lineage differentiation and cell maturation. The mechanism by which they mediate their effects in haematopoiesis is complex, demonstrating cell-specific, tissue-specific and maturation-specific expression. Understanding haematopoietic expression and key targets of miRNAs is important to further elucidate the functional roles of miRNAs. Furthermore, an appreciation of their role in normal physiological processes sheds light on the possibility that aberrations of miRNA expression may perturb these processes and cause disease. Indeed, deregulation of miRNAs has been demonstrated in oncogenesis and in haematological malignancies in particular. This review focuses on miRNA expression in normal haematopoiesis and provides brief insight into how deregulation of these miRNA may contribute to cancer pathogenesis.