Current Pharmaceutical Design - Volume 20, Issue 42, 2014

Oncolytic viruses (OV) are promising anti-cancer agents, capable of selectively replicating in tumour cells and killing them. Chemotherapy, on the other hand, remains the backbone of current cancer treatment, although it is limited by a narrow therapeutic index, significant toxicity, and frequent acquired resistance. There is an increasing body of evidence on a variety of chemotherapeutic agents that have been shown to be synergic with OV and result in increased response rates in preclinical studies. Several possible mechanisms have been proposed to mediate the enhanced anti-tumour activity of such combination treatment. Moreover, it has been shown how prodrug- activating enzymes armed oncolytic viruses promote synergy with prodrugs. In the present review we summarise the current knowledge concerning the benefits of the combination of OV and cytotoxic drug treatment and discuss the translational opportunities such therapeutic synergies have in the fight against cancer.

As the number of novel drugs that have entered the market in oncology has slowed in recent years, there has been a dramatic shift towards new therapeutic approaches. The majority of cancer patients die from metastasis formation, which has prompted the pharmaceutical industry to begin to investigate a new class of agents: anti-metastatics. This review provides an overview of the targets, mechanisms of action, and drug substances currently in the pharma pipeline to inhibit tumor cell migration and metastasis formation.

Oxidative stress is often considered as a causative factor in carcinogenesis. In addition, current knowledge recognizes oxidative stress as a mechanism by which various cancer therapies act against cancer. To ameliorate the side effects of cancer therapy, many of the patients suffering from cancer are subject to adjuvant therapy, which often implies antioxidant supplementation. Yet, the benefits of such adjuvant treatments are still uncertain owing to the lack of appropriate integrative and personalized medical approach. In particular, reactive oxygen species formed during oxidative stress and products of lipid peroxidation are not only cytotoxic, but can modulate signal transduction in cells, which also behave similar to individuals under stress. Accordingly, pro-oxidants and antioxidants might be considered as modifiers of specific cellular redox signaling. Therefore, there is a need to evaluate the potential benefits of antioxidant supplements in healthy persons, and in particular in cancer patients during therapy. Our review will present a summary of the existing knowledge regarding the effects of various antioxidants in cancer therapies, focusing on cellular adaptation to oxidative stress interacting with redox signaling transduction pathways thereby influencing cell growth.

The onset of cancer is a complex process that is driven by the accumulation of multiple genetic mutations. However, the fact that inhibition of a single oncogene can impair the proliferation and survival of cancer cells due to their “oncogene addiction” provides implications for the so-called “molecular targeted therapy” in cancer treatment. The oncogenic transcription factor c-Myc is overexpressed in many types of cancers, and as a typical oncogene to which many cancers are addicted, c-Myc is necessary for the rapid proliferation of cancer cells. Strategies aimed at targeting c-Myc, including interfering with c-Myc synthesis, stability and transcriptional activity, have emerged as effective cancer treatments. We have recently shown that a natural agent, oridonin, promotes the Fbw7-mediated proteasomal degradation of c-Myc, leading to subsequent cell growth inhibition and apoptosis and demonstrating a new c-Myc-targeting strategy. Despite the effectiveness of molecular targeting in cancer treatment, failure to achieve long-lasting efficacy with a single agent is observed because cancer cells can recover from oncogene addiction as a result of their genomic instability and heterogeneity. Combined cancer therapies were therefore developed and showed better efficacies than single-agent therapy in cancer cell lines and mouse models. Combined therapy based on c-Myc targeting can be achieved through various strategies. Agents that also target c-Myc but use different mechanisms, or agents that act on other genes in the c-Myc pathway, can be selected for combination. In addition, the targeting of genes involved in different cellular processes in other pathways might also be a successful strategy. Regardless of the therapy adopted, it is important to first determine the molecular mechanisms underlying the agents to inform the therapy design. Among the various targets of therapeutic agents is a family of noncoding small RNAs, called microRNAs, that have been implicated in the anti-cancer activity of many therapeutic agents. c-Myc, as a transcription factor, regulates the expression of many microRNAs and is in turn regulated by microRNAs. Combining c-Myc-targeting agents with those that target microRNAs might provide a novel approach for cancer therapy.

Toll-like receptors (TLRs) are a group of transmembrane receptors that recognize molecular motifs of pathogen origin and activate immune response. Although TLRs were first identified in immune system cells, recent studies show they can also be expressed in tumor cells. TLR3 recognizes dsRNA or its synthetic ligand poly (I: C) and is responsible primarily for the defense against viral infections. Recent studies showed that TLR3 can trigger apoptosis in cancer cell. Furthermore, other dsRNA binding receptors (MDA5 and RIG-I), localized in cytoplasm, can also bind poly (I: C) and therefore contribute to this effect. With TLR3’s capacity to induce apoptosis and activate the immune system at the same time, TLR3 ligands are an attractive therapeutic option for treatment of cancer. Novel therapies include combining poly (I: C) with other components such as chemotherapeutics, apoptosis enhancers, other TLR ligands and peptides activating the immune system. Slightly modified TLR3 agonists (Ampligen®, Hiltonol®, poly IC-LC) are already being used in clinical studies for cancer therapy as single agents or in combination with other drugs. On the other hand, latest studies forewarn that TLR3 activation can also have tumor promoting role so it is crucial to identify the terms by which TLR3 has pro-tumor/anti-tumor effect in order to safely implement TLR3 ligand based therapy into clinical trials.

Cancer initiation and progression are governed by a complex multistep process in which successive alterations accumulate in multiple protein-coding and noncoding genes. MicroRNAs are an evolutionarily conserved class of endogenous 19- to 24-nucleotide noncoding RNAs that have been validated as key players in the balance of most cellular processes, including drug resistance. MicroRNAs change the output of protein-coding genes through posttranscriptional regulation by binding in a sequence-specific manner to the transcripts of their target genes. Resistance to therapy remains a major challenge in cancer treatment; clear solutions to this problem have yet to be found, in spite of intensive research in recent years. In this review, we explore the concept of cancer multitherapy using noncoding RNAs. We also address basic scientific questions that are related to personalized cancer treatment.

Aromatase inhibitors (AIs) have become one of the mainstays of treatment of postmenopausal women with hormone receptorpositive breast cancer. However, acquired resistance to treatment continues to be a significant clinical challenge. There is increasing evidence from preclinical studies that activation of growth factor signaling pathways, as well as cross-talk between these pathways and estrogen receptor-alpha signaling pathways are important mechanisms that contribute to AI resistance. These preclinical studies have been the foundation for multiple randomized clinical trials that have evaluated combination targeted therapy in patients with advanced breast cancer. While the clinical benefit observed in these trials has been variable, the preclinical studies were successful in predicting clinical outcomes. This review focuses on mechanisms of acquired AI resistance and describes preclinical studies that have evaluated combination targeted therapy to overcome AI resistance, as well as clinical trials that have translated this information to the clinical setting.

The term ribosome-inactivating protein (RIP) is used to denominate proteins mostly of plant origin, which have N-glycosidase enzymatic activity leading to a complete destruction of the ribosomal function. The discovery of the RIPs was almost a century ago, but their usage has seen transition only in the last four decades. With the advent of antibody therapy, the RIPs have been a subject of extensive research especially in targeted tumor therapies, which is the primary focus of this review. In the present work we enumerate 250 RIPs, which have been identified so far. An attempt has been made to identify all the RIPs that have been used for the construction of immunotoxins, which are conjugates or fusion proteins of an antibody or ligand with a toxin. The data from 1960 onwards is reviewed in this paper and an extensive list of more than 450 immunotoxins is reported. The clinical reach of tumor-targeted toxins has been identified and detailed in the work as well. While there is a lot of potential that RIPs embrace for targeted tumor therapies, the success in preclinical and clinical evaluations has been limited mainly because of their inability to escape the endo/lysosomal degradation. Various strategies that can increase the efficacy and lower the required dose for targeted toxins have been compiled in this article. It is plausible that with the advancements in platform technologies or improved endosomal escape the usage of tumor targeted RIPs would see the daylight of clinical success.

Although grouped under the same name, neuroendocrine tumors comprise a heterogeneous family of neoplasms with a wide range of clinical and biological behaviors and responses to different treatment options. Most of the tumors derived from enterochromaffin cells are indolent or at least not as aggressive as epithelial tumors. However, a small percentage of these tumors have a poor prognosis and highly aggressive histology that results in a very short overall survival and scarce treatment options compared with well and moderately differentiated tumors. Patients with poorly differentiated neuroendocrine carcinomas barely exceed 6-8 months of survival. This particular poor risk subgroup of neuroendocrine tumors remains an unmet medical need and becomes a challenge in the daily clinical practice. A deeper knowledge of the biology and novel targeted agents might allow for future clinical development of novel agents in this setting. In this review we summarize the current background behind the management of poorly differentiated neuroendocrine carcinomas in daily clinical practice.

Over the past, progress has always been achieved in therapy of various human diseases with the introduction of novel methodologies from basic to clinical research. Recent advances in techniques, especially DNA sequencing and methylation analyses, faster miniaturized proteomics and live cellular stainings, are opening a new era in cancer research. Perhaps the difference this time can be envisaged as the beginning of the long-sought individualization of forthcoming cancer therapies. Cancer has complex genetic susceptibility that is wider than previously thought. Apart from genes encoding six functional capabilities of cancer – independent growth, avoidance of apoptosis, immortalization, multi-drug resistance, neovascularization, and invasiveness - predisposition includes four more factors that promote genome instability, inflammation, deregulation of metabolism as well as evasion of destruction by the immune system. The underlying genetic events, i.e. base-pair DNA mutations, are not the sole factors in cancer development. Additional novel controls of gene expression have been found in the epigenetic machinery, which has been increasingly important in assessing cancer risk in recent years. The predisposing factors, including their regulatory elements, are bona fide potential new targets in prospective cancer pharmacotherapy.

Pancreatic cancer is the only human malignancy for which patients’ survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.

Proviral integration site for Moloney murine leukemia virus (Pim) kinases is a potential therapeutic target in both hematological and solid tumors, and is up-regulated in various cancer types. In certain cases, their expression levels are positively correlated with poor clinical outcome. A number of selective Pim kinase inhibitors are under development and a few are in clinical trials. Investigations of the mechanism of actions of these drugs have demonstrated that by inhibiting Pim kinases, processes such as transcription, translation, cell cycle progression, cell survival and drug resistance are affected. Pim kinases can be upregulated by multiple growth factors, cytokines, and chemokines, which also activate redundant pathways such as phosphatidylinositide 3-kinases/protein kinase B/mammalian targets of rapamycin, and mitogen-activated protein kinases. Interestingly, Pim kinases also share substrates with these parallel pathways. To overcome this challenge, Pim kinase inhibitors were tested in combination with other therapeutic agents based on their unique mechanism of actions. Based on existing literature, we identified studies where Pim kinase inhibitors were part of the combination strategies that used targeted agents or broad-spectrum chemotherapeutic drugs (including FDA-approved agents). The addition of Pim kinase inhibitors to these treatment strategies leads to additive to synergistic cytotoxic effect in cancer cells. Depending on the compound, combination results in sequential or complementary blockage or downregulation of oncogenic pathway. In summary, these studies provide evidence for developing mechanism-based combination therapies with Pim kinase inhibitors to treat cancers.

The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-ΚB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-ΚB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-ΚB activity and its inhibitory effect on NF-ΚB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-ΚB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-ΚB by selectively combining curcumin and various anticancer drugs.

Due to its extremely high mortality rates, strong efforts continue to be made to develop new therapies in the treatment of pancreatic adenocarcinoma. The use of combined modality chemoradiotherapy for the treatment of pancreatic adenocarcinoma remains an approach with both promise and controversy. This article reviews the conflicting data with regards to role of combined modality therapy in pancreatic adenocarcinoma and provides an update on current studies in the field.

The regulation of neurohypophyseal peptides secretion reflects the convergence of a large number of afferent neural pathways on vasopressinergic and oxytocinergic neurons of supraoptic (SON) and paraventricular nuclei (PVN). In addition to afferent input, vasopressin and oxytocin can also exert an autocrine regulation of neuronal activity. In fact, magnocellular neurons (MCNs) of SON and PVN are able to secrete these hormones not only at the endings of their terminal axons, but also from their dendrites and this local release, by activating a range of ion gated, ion channel and G protein coupled receptors, participate in pre- and post-synaptic modulation of neural activity of MCNs. In this review we analyzed the molecular mechanisms involved in the control of neurohypophyseal hormones secretion and related possible pharmacological targets.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is capable of selectively inducing apoptosis of cancer cells, is a potential targeted drug for cancer therapy. Many clinical trials have verified the safety, tolerability, and therapeutic efficacy of TRAIL or TRAIL agonists in patients. However, the resistance to TRAIL in multiple cancer cells resulted in limited treatment response and poor prognosis. In this review, the molecular mechanisms of TRAIL resistance in cancer cells are summarized. How TRAIL receptors, structure of the cellular membrane, the Protein Kinase B (Akt) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ΚB) pathways involve in regulating TRAIL resistance is described. A full understanding of the exact molecular mechanisms of TRAIL resistance in cancer cells could help to design more suitable strategies and new drugs to overcome TRAIL resistance and obtain better therapeutic outcomes.