Current Medicinal Chemistry (v.21, #8)
Editorial (Thematic Issue: Targeted Therapies in Upper Gastrointestinal Malignancies) by Amalia Azzariti, Nicola Silvestris (947-947).
Target Therapies in Pancreatic Carcinoma by Nicola Silvestris, Antonio Gnoni, Anna Elisabetta Brunetti, Leonardo Vincenti, Daniele Santini, Giuseppe Tonini, Francesca Merchionne, Evaristo Maiello, Vito Lorusso, Patrizia Nardulli, Amalia Azzariti, Michele Reni (948-965).
Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early locoregional spread anddistant metastases at diagnosis, leading to dismal prognosis and limited treatment options. Traditional cytotoxic chemotherapyprovides only modest benefit to patients with PDAC. Identification of different molecular pathways, overexpressedin pancreatic cancer cells, has provided the opportunity to develop targeted therapies (monoclonal antibodies andsmall-molecule inhibitors) and peculiar new class of taxanes with a crucial therapeutic role in this cancer setting. A phaseIII trial has shown that erlotinib in combination with gemcitabine was clinically irrelevant and skin toxicity can be a positiveprognostic factor. Moreover, the combination of cetuximab or erlotinib with radiotherapy in advanced pancreatic cancerhas shown to be synergistic and a reversal of radio-resistance has been suggested by inhibition of VEGF/EGFR pathway.To overcome EGFR-inhibition therapy resistance several alternative pathways targets are under investigation (IGF-1R, MMPs, Hedgehog proteins, m-TOR, MEK, COX-2) and provide the rationale for clinical use in phase II/III studies.Also nab-paclitaxel, a new taxanes class, uses high pancreatic albumin-binding protein SPARC levels to act in cancercells with a less toxic and more effective dose with respect to classic taxanes. Understanding of molecular pathogenesis ofpancreatic adenocarcinoma continues to expand. However, many promising data in preclinic and phase I/II trials did notyield promise in phase III trials, suggesting that identification of predictive biomarkers for these new agents is mandatory.The knowledge of biologic and molecular aspects of pancreatic cancer can be the basis for future therapeutic developments.
Targeted Therapies in Hepatocellular Carcinoma by F. Bronte, G. Bronte, S. Cusenza, E. Fiorentino, C. Rolfo, G. Cicero, E. Bronte, V. Di Marco, A. Firenze, G. Angarano, T. Fontana, A. Russo (966-974).
The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease,such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance forearly diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possibleand systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has beenthe best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the properpatient setting to treat is not well defined, since the results in Child-Pugh B patients are conflicting. To date various newtarget drugs are under developed and other biological treatments normally indicated in other malignancies are under investigationalso for HCC. These strategies aim to target the different biological pathways implicated in HCC developmentand progression. The target drugs studied in HCC include anti-VEGF and anti-EGFR monoclonal antibodies, tyrosinekinase inhibitors and mTOR inhibitors. The most important challenge is represented by the best integration of these drugswith standard treatments to achieve improvement in overall survival and quality of life.
MET As a Potential Target for the Treatment of Upper Gastrointestinal Cancers: Characterization of Novel c-Met Inhibitors from Bench to Bedside by A. Avan, M. Maftouh, N. Funel, M. Ghayour-Mobarhan, U. Boggi, G.J. Peters, E. Giovannetti (975-989).
The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) plays a pivotal role in regulationof cell proliferation and migration. Abnormal expression of c-Met has been associated with poor prognosis in several cancertypes, including upper gastrointestinal malignancies. Moreover, c-Met interaction with multiple signalling pathwaysinvolved in tumor growth and invasive/metastatic phenotype has gained substantial attention in the last few years, suggestingthe therapeutic potential of this target. This has led to the development and evaluation of a number of c-Met inhibitors.Here we describe the critical role of the HGF/c-Met pathway in cancer, as well as the preclinical and clinical investigationson c-Met inhibitors in solid tumors, with particular emphasis on recent findings with small-molecule inhibitorsin gastrointestinal cancers. Clinical trials with several of these novel inhibitors have been encouraging and one ofthem, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung cancers with ALK-rearrangement. Thereare accumulating evidences on the therapeutic potential of this and other c-Met inhibitors for the treatment of other malignancies,such as gastric and pancreatic cancers. These inhibitors might be used in combination with chemotherapy as wellas with other biological agents, in order to overcome different resistance mechanisms. However, further studies areneeded to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic and environmental alterationsaffecting c-Met and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivityof current and future anticancer strategies targeting c-Met.
Targeted Therapies in Combination with Radiotherapy in Oesophageal and Gastroesophageal Carcinoma by F. Cellini, V. Valentini (990-1004).
Oesophageal cancer is the sixth cause of cancer-related death worldwide. Nowadays radiochemotherapy(RTCT) plays a central role in the treatment settings of such disease. Evaluation of molecular targeted therapies is an attractiveopportunity for the management of oesophageal, GEJ and gastric cancers to improve outcomes as for other primarytumours. Clinical trials focused on the potential of many molecular targeted agents included in CT schedules, andalso on the possibility, efficacy and tolerance of their use combined with RT. This review will focus on the over 15 morepromising agents studied in combination with RT for esophagogastric tumour, describing the mechanism and target of action,evidences and potential future role on over 50 trials evaluated. Mechanisms of action, studies and evidences aboutHuman Epidermal Growth Factor type 2 Targeting Agents (one of the more promising), Epidermal Growth Factor's ReceptorInhibitors (nowadays showing a lower potential than expected), Vascular Endothelial Growth Factor Inhibitors,Mesenchymal Epithelial Transition Factor, Hepatocyte Growth Factor and other targeting agents are reviewed.
Targeted Strategies in the Treatment of Primary Gastric Lymphomas: From Rituximab to Recent Insights into Potential New Drugs by Francesca Merchionne, Pasquale Iacopino, Carla Minoia, Angela Iacobazzi, Antonio Rana, Simona Serrati, Giacoma De Tullio, Giacomo Loseto, Angela Lapietra, Annunziata Lucarelli, Attilio Guarini (1005-1016).
Primary gastric non-Hodgkin's lymphomas (PG-NHL) are the most common extranodal lymphomas, representingbetween 47% and 74% of all gastrointestinal lymphoma cases. In Western countries two histological types, diffuselarge B-cell (DLBC) NHL and mucosa-associated lymphoid tissue (MALT) NHL, are more frequently represented, accountingfor the majority of gastric tumors after adenocarcinoma. For several years treatment of these PG lymphomasconsisted of surgery, chemotherapy and radiotherapy, alone or in combination. In the last two decades however, advancesin our understanding of their pathogenesis and biology have changed the treatment strategy, at least as regards the earlystages of disease. In addition to making tumor regression possible through the eradication of Helicobacter pylori, which isconsidered the main pathogenic agent, this understanding has also provided a solid rationale to assess the efficacy of targetedtherapy, namely of drugs which interfere with specific molecules expressed by tumor cells or are involved in keygrowth pathways of these lymphomas. In particular, rituximab, a monoclonal anti-CD20 antibody, radioimmunotherapy,the first-generation proteasome inhibitor bortezomib and lenalidomide have been evaluated. Despite significant antitumoractivity in this subset of NHL and manageable toxicity, many questions still remain however about the optimal dose, thebest administration schedule and their combination with conventional chemotherapy. This review focuses on the pathogenesisof PG-MALT and DLBC lymphomas, and discusses the results of clinical trials on the impact of new agents onprognosis and survival in these patients, considering also potential new therapautic targets.
Molecular Targeted Therapy in Enteropancreatic Neuroendocrine Tumors: From Biology to Clinical Practice by N. Fazio, A. Scarpa, M. Falconi (1017-1025).
Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies,including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has beenmade in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy:somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, researchhas moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically bindingto the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several moleculartargeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. ThemTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA andEMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), onthe basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has beenstudied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological andclinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigationare addressed.
Targeted Therapy in Advanced Gastric Carcinoma: The Future is Beginning by G. Schinzari, A. Cassano, A. Orlandi, M. Basso, C. Barone (1026-1038).
Gastric cancer represents one of the most common cancer worldwide. Unfortunately, the majority of patientspresent in advanced stage and outcome still remains poor with high mortality rate despite decreasing incidence and newdiagnostic and therapeutic strategies. Although utility of classical chemotherapy agents has been widely explored, advanceshave been slow and the efficacy of these agents has reached a plateau of median overall survival not higher than 12months. Therefore, researchers focused their attention on better understanding molecular biology of carcinogenesis anddeeper knowledge of the cancer cell phenotype, as well on development of rationally designed drugs that would targetspecific molecular aberrancies in signal transduction pathways. These targets include cell surface receptors, circulatinggrowth and angiogenic factors and other molecules involved in downstream intracellular signaling pathways, includingreceptor tyrosine kinases. However, therapeutic advances in gastric cancer are not so encouraging when compared to othersolid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted agents in gastriccancer as single-agent therapy or in combination regimens, including their rational and emerging mechanism of action,current and emerging data. We focused our attention mainly on published phase III studies, therefore cornerstone clinicaltrials with trastuzumab and bevacizumab have been largely discussed. Phase III studies presented in important internationalmeetings are also reviewed as well phase II published studies and promising new therapies investigated in preclinicalor phase I studies. Today, in first-line treatment only trastuzumab has shown significantly increased survival in combinationwith chemotherapy, whereas ramucirumab as single agent resulted effective in progressing patients, but - despiteseveral disappointing results - these are the proof of principle that targeting the proper molecular aberration is the bestway for implementing outcome of therapy.
New Vascular Disrupting Agents in Upper Gastrointestinal Malignancies by A.E. Quatrale, L. Porcelli, A. Gnoni, G. Numico, A. Paradiso, A. Azzariti (1039-1049).
Antivascular approaches aim to cause rapid and catastrophic shutdown in the vascular function of the tumour,leading to extensive tumour cell death. Tumour vascular disrupting agents (VDAs) are a new class of cancer therapies thattarget the existing vasculature of tumours, taking advantage of the relative instability of tumour vasculature and its supportingstructures. Treatment with VDAs induces a rapid collapse and regression of tumour vessels, with a consequentdeprivation of blood and oxygen which leads to ischemic or hemorrhagic necrosis of the tumour. In this review, an overviewof the most recently developed vascular disrupting agents is reported, focusing on the biological effects exerted bythese compounds on endothelial cells and tumour vasculature, potentially effective in the treatment of several malignanciesincluding upper gastrointestinal tumours. In particular, we have focused on the antimitotic agent combretastatin andits numerous synthetic analogues such as combretastatin A-4-phosphate, OXI4503, and AVE8062, and on the colchicineanalogue ZD6126.
Stimulation of DDX3 Expression by Ginsenoside Rg3 through the Akt/p53 Pathway Activates the Innate Immune Response via TBK1/IKKε/IRF3 Signalling by Yeo-Jin Choi, Li-Jung Kang, Seong-Gene Lee (1050-1060).
DEAD-box RNA helicase DDX3 is a well-known host factor that inhibits hepatitis B viral proliferation andboosts innate immune responses via TANK-binding kinase 1 (TBK1)/IKKε -mediated and/or interferon (IFN)-β promoterstimulator-1 (IPS-1)-mediated IFN-β induction. Previously, we demonstrated the anti-hepatitis B activity of Rg3 viastimulation of TRAF6/TAK1 degradation and inhibition of JNK/AP-1 signaling. To determine the effects of Rg3 on innateimmunity, an IFN-β promoter assay was performed. Rg3 ameliorated IFN-β expression via upregulation of both theTBK1/IKK ε pathway and DDX3 expression. In addition, Rg3 induced the phosphorylation of IRF3 and its translocationinto nucleus, which is a key molecule to induction of IFN-β expression. To evaluate the molecular mechanism of Rg3 onDDX3 expression, the DDX3 promoter (-1406/+105) was subjected to luciferase assay and ChIP analysis. p53 phosphorylationresulted in upregulation of DDX3 expression, which enhanced DDX3 promoter transactivation activity. Transienttransfection with wild-type p53 increased DDX3 promoter activity in Hep3B cells which have null mutant of p53,whereas knockdown p53 by si-p53 reduced DDX3 promoter activity in HepG2.2.15 and HepG2 cells, respectively. Rg3-mediated phosphorylation of p53 resulted in inhibition of Akt phosphorylation, which in turn reduced MDM2-mediatedp53 degradation. An Akt inhibitor augmented DDX3 promoter activity and reduced the secretion of hepatitis B surface antigen.Our data indicate that Rg3 enhances innate immunity by inducing IFN-β expression through upregulation of DDX3promoter activity via p53-mediated transactivation and activation of the TBK1/IKKε /IRF3 pathway.
Effect of Resveratrol and Tiron on the Inactivation of Glyceraldehyde-3- phosphate Dehydrogenase Induced by Superoxide Anion Radical by A. Rodacka, J. Strumillo, E. Serafin, M. Puchala (1061-1069).
Protein damage mediated by oxidation has been associated with aging and age-related diseases, in particularneurodegenerative diseases. The protein that is known to be one of the major targets of oxidative stress is glyceraldehyde-3-phosphate dehydrogenase. GAPDH is believed to play a key role in certain neurodegenerative disorders, such as Alzheimer's,Parkinson's, and Huntington's diseases. Several recent studies have suggested that a wide range of variety ofpolyphenols including resveratrol may have neuroprotective effects. Here, we present data that clearly indicate theprooxidative properties of resveratrol and tiron in the inactivation of GAPDH induced by the superoxide anion generatedvia xanthine oxidase mediated oxidation of xanthine. Generated in the studied system tiron and resveratrol radicals aremuch more efficient in the inactivation of GAPDH than the superoxide anion alone. The analysis of CD spectra of proteinexposed to the tiron and resveratrol radicals revealed little effect on the secondary structure of GAPDH. In both cases reductionof α-helical structure was followed by the increase in β-sheet conformation. Thus, the most probable mechanismof inactivation of GAPDH in the studied system is oxidation of cysteine residues in the catalytic center of the enzyme. Finally,molecular modeling of the resveratrol - GAPDH and tiron - GAPDH complexes showed potential binding sites forthose antioxidants with binding affinity -45 kcal/mol and -48 kcal/mol respectively.