Current Drug Targets, Volume 6, No. 3, 2005
Contents
ErbB
Family and Downstream Signal Transduction Pathways as Targets for Anticancer
Therapy
Guest
Editor: F. Caponigro
Editorial Pp.241-242
F. Caponigro
The ErbB Receptors and their Ligands in
Cancer: An Overview Pp.243-257
N. Normanno, C.
Bianco, L. Strizzi, M. Mancino, M. R. Maiello, A. De Luca, F. Caponigro and D.
S. Salomon
Small Molecules with EGFR-TK Inhibitor
Activity Pp.259-274
Joan Albanell and Pere
Gascon
Monoclonal Antibodies Targeting the Epidermal
Growth Factor Receptor Pp.275-287
R. Bianco, G. Daniele,
F. Ciardiello and G. Tortora
Antitumor Therapeutic Strategies Based on the
Targeting of Epidermal Growth Factor-Induced Survival Pathways Pp.289-300
P. Tagliaferri, P.
Tassone, S. Blotta, C. Viscomi, F. Grillone, A. Budillon, M. Caraglia and S.
Venuta
Isoprenylation of Intracellular Proteins as a
New Target for the Therapy of Human Neoplasms: Preclinical and Clinical
Implications Pp.301-323
M. Caraglia, A.
Budillon, P. Tagliaferri, M. Marra, A. Abbruzzese and F. Caponigro
Drugging Cell Cycle Kinases in Cancer Therapy
Pp.325-335
S. Blagden and J. de
Bono
Multiple-Target Drugs: Inhibitors of Heat
Shock Protein 90 and of Histone Deacetylase Pp.337-351
A. Budillon, F.
Bruzzese, E. Di Gennaro and M. Caraglia
General Articles
Molecular Targets for Design of Novel
Inhibitors to Circumvent Aminoglycoside Resistance Pp.353-361
S. Jana and J.K. Deb
Colloidal Carriers for Ophthalmic Drug
Delivery Pp.363-371
Rubiana Mara
Mainardes, Maria Cristina Cocenza Urban, Priscila Oliveira Cinto, Najeh Maissar
Khalil, Marco Vinicius Chaud, Raul Cesar Evangelista and Maria Palmira Daflon
Gremiao
Abstracts
[Back
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F. Caponigro
ErbB family of receptors include 4 different receptors, each of which, with the exception of ErbB 2, has a number of ligands [1].
ErbB 1, also identified as epidermal growth factor receptor (EGFR), is the most important surface receptor of this family, and a lot of efforts have been put over last years to effectively interfere with EGFR-driven signal transduction with the idea that it was a crucial pathway. Small molecular weight tyrosine kinase inhibitors (TKIs), and monoclonal antibodies targeting EGFR represent the most effective ways to achieve this goal. EGFR TKIs are among the most exciting class of compounds in the era of molecular targeted therapy. These are drugs which apparently do not share many characteristics with conventional cytotoxic compounds: they are given orally, the toxicological pattern is different, they are suitable for long term administration and may in theory be used in different settings, such as maintenance therapy, minimal residual disease, adjuvant therapy [1]. Gefitinib has been the first of this class of compounds to be studied, and a lot of enthusiasm accompanied the phase III program of the drug in advanced non-small cell lung cancer (NSCLC). Unfortunately, these trials, which had not selected patients according to molecular characteristics, turned out to be negative, thus highlighting the need to have a better molecular selection of patients to be included in clinical trials (from bench to bedside and back to bench again) [2, 3]. Recently, a gain of function somatic mutation at exons 18-21 (TK domain) of the EGFR gene has been associated with sensitivity to gefitinib in NSCLC patients with well characterized clinical and epidemiological features [4, 5, 6]. In solid tumors up to now many potential targets have been identified, but a clear “molecular driver” as in Philadelphia+ chronic myeloid leukaemia does not seem to exist. There is evidence that specific molecular events, such as activating somatic mutations of the EGFR gene, can make a target “prioritaire”, thus working as a molecular driver. This concept is highlighted in the review provided by Tagliaferri et al. in this issue. Of potential clinical interest is target “prioritization” by the use of agents like interferon alpha, which is capable of activating EGFR-driven survival pathways. The clustering of mutations within specific regions of the EGFR tyrosine kinase domain makes possible the potential development of rapid and reliable diagnostic testing to guide the clinical use of gefitinib. Prospective validation of EGFR tyrosine kinase mutations as predictors of the responsiveness to gefitinib is warranted, and genotype-directed clinical trials of gefitinib in different settings should now be considered. Even if somatic mutations occur in only 8% of the entire population of patients with NSCLC, having the possibility to treat successfully a small fraction of patients with such a common disease points to a major breakthrough [7]. Erlotinib is another small molecular weight TK inhibitor, whose development has been parallel to gefitinib. However, unlike gefitinib, it has been shown able to increase survival of pretreated patients with advanced NSCLC in a placebo controlled randomized study. This last result is really encouraging, since it is the first trial in which a survival advantage has been obtained with a TK inhibitor [Shepherd et al., Proc ASCO 2004]. Cetuximab is a chimerized monoclonal antibody, which has gained the registration in advanced colorectal cancer. However, the most exciting clinical results have been reported in locally advanced head and neck cancer, where combined treatment of cetuximab + radiotherapy yielded better locoregional control and survival than standard treatment with radiotherapy alone [Bonner et al., Proc ASCO 2004].
DNA in chromatin is packaged into orderly repeating protein-DNA complexes known as nucleosomes, which consist of a core of histone proteins around which DNA wraps. Histone acetylation is a well understood posttranslational modification whose entity depends on two enzyme families, namely histone acetyltransferase, and histone deacetylase (HDAC). The mechanism of growth inhibition mediated by histone hyperacetylation include transcriptional activation of a pre-programmed set of genes, such as p21, p27, cyclin E, induction of markers of differentiation, cell cycle arrest, growth inhibition. As addressed in the review provided by Budillon et al . in this issue, HDAC inhibitors are an example of multitarget drugs and are able to block multiple proliferative as well as escape survival mechanisms activated by cancer cells. Very important preclinical studies show that a histone deacetylase inhibitor, such as suberoylanilide (SAHA), has synergistic antiproliferative and apoptotic effects with gefitinib in head and neck cancer cell lines; interestingly, this effect is evident also in cells partially resistant to gefitinib [Bruzzese et al., Proc. AACR 2004]. This is a nice example of combination of different molecular targeted therapies acting at different levels, and achieving a synergistic effect. Since cancer cells have several dysregulated and redundant pathways, the way forward in cancer therapy has necessarily to include this approach.
[Back
to top] The
ErbB Receptors and their Ligands in Cancer: An Overview
N. Normanno, C.
Bianco, L. Strizzi, M. Mancino, M. R. Maiello, A. De Luca, F. Caponigro and D.
S. Salomon
This review article provides an overview on the most recent advances on the role of ErbB receptors and growth factors of the epidermal growth factor (EGF)-family of peptides in cancer pathogenesis and progression. The ErbB tyrosine kinases and the EGF-like peptides form a complex system. In fact, the interactions occurring between receptors and ligands of these families affect the type and the duration of the intracellular signals that derive from receptor activation. Interestingly, activation of ErbB receptors is also driven by different classes of membrane receptor, suggesting that ErbB kinases can amplify growth promoting signals carried by different pathways. The importance of ErbB receptors and EGF-like peptides in development of organs and tissues has been demonstrated by using different mouse models. In vitro and in vivo studies have also shown that ErbB receptors and their ligands can act as transforming genes. However, evidence suggests that cooperation of different receptors and ligands is necessary to induce a fully transformed phenotype. Indeed, co-expression of different ErbB receptors and EGF-like growth factors is a common phenomenon in human primary carcinomas. This observation suggests that the growth and the survival of carcinoma cells is sustained by a network of receptors/ligands of the ErbB family. In this respect, the contemporary expression of different ErbB tyrosine kinases and/or EGF-like growth factors in human carcinomas might also affect tumor response to target based agents directed against the ErbB receptor/ligand system.
[Back
to top] Small Molecules with EGFR-TK Inhibitor Activity
Joan Albanell and Pere
Gascon
Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic .In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.
[Back
to top] Monoclonal
Antibodies Targeting the Epidermal Growth Factor Receptor
R. Bianco, G. Daniele,
F. Ciardiello and G. Tortora
The epidermal growth factor receptor (EGFR, HER1) autocrine pathway contributes to a number of highly relevant processes in cancer development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. The crucial role that EGFR plays in human cancers has led to an extensive search for selective inhibitors of its signaling pathway. The results of a large body of preclinical studies and clinical trials thus far conducted suggest that targeting the EGFR could bring a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR. The most promising strategies in clinical development include monoclonal antibodies, to prevent ligand binding, and small molecules inhibitors of the tyrosine kinase enzymatic activity, that inhibit autophosphorylation and downstream intracellular signaling. Several blocking monoclonal antibodies against the EGFR have been developed. Among these, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibody that has been the first anti-EGFR targeted therapy to enter clinical evaluation in cancer patients in Phase II and III studies, alone or in combination with conventional radiotherapy and chemotherapy. However, other antibodies against EGFR have demonstrated antitumor activity in several preclinical models of human cancer and are currently under investigation in the clinical setting, such as ICR62, ABX-EGF and EMD72000. This review will focus on all the preclinical data available on monoclonal antibodies engineered against the EGF receptor.
[Back
to top] Antitumor
Therapeutic Strategies Based on the Targeting of Epidermal Growth
Factor-Induced Survival Pathways
P. Tagliaferri, P.
Tassone, S. Blotta, C. Viscomi, F. Grillone, A. Budillon, M. Caraglia and S.
Venuta
Cellular receptors for the Epidermal Growth Factor are considered important targets for the experimental treatment of human cancer. Monoclonal antibodies as well as small tyrosine kinase inhibitors have been developed and have undergone extensive evaluation in preclinical and clinical studies. Most of these studies have been conceived on the general idea that epidermal growth factor receptor (EGFR) plays a critical role on the growth and survival of human tumors. This assumption has been derived by the successful development of BCR/ABL tyrosine kinase inhibitors in human chronic myeloid leukemia as well as on the activity of antiCD20 monoclonal antibodies in lymphoproliferative disease and of anti HER2 agents in breast tumors overexpressing the targeted antigens. It is now becoming clear that factors regulating sensitivity to kinase inhibitors may differ from monoclonal antibodies and that the molecules targeted by interferring drugs must be prioritaire for growth and survival of those specific tumors in order to achieve valuable results. Recent evidence of major responses to the EGFR inhibitor Gefitinib in tumors harboring activating mutations in the EGFR appears on line with this concept. In this article we will discuss the significance of targeting the EGFR driven survival pathways. Specifically, we will afford the point of EGFR survival signalling prioritization by means of pharmacological treatment. Finally, we will address the role of profiling technologies and of novel computational system biology-based approaches for identification of innovative strategies for effective targeting of EGFR driven survival pathways.
[Back
to top] Isoprenylation of
Intracellular Proteins as a New Target for the Therapy of Human Neoplasms: Preclinical
and Clinical Implications
M. Caraglia, A.
Budillon, P. Tagliaferri, M. Marra, A. Abbruzzese and F. Caponigro
Cell proliferation, differentiation, and survival are regulated by a number of extracellular hormones, growth factors, and cytokines in complex organisms. The transduction of the signals by these factors from the outside to the nucleus often requires the presence of small intracellular proteins (i.e. ras and other small G proteins) that are linked to the plasma membrane through a isoprenyl residue that functions as hydrophobic anchor. Isoprenylation is a complex process regulated by different enzymatic steps that could represent potential molecular targets for anti-cancer strategies. In the present paper the different transduction pathways regulated by some isoprenylated proteins such as ras and other small G proteins are described. Moreover, the molecular mechanisms of the isoprenylation process and the mode of action of the different isoprenylation inhibitors are discussed with attention to statins, farnesyltransferase inhibitors (FTI) and aminobisphosphonates. The role of different candidate targets in the determination of anti-tumour effects by FTIs is also described in order to define potential molecular markers predictor of clinical response. On the basis of several preclinical data, new strategies based on multi-step enzyme inhibition or on target prioritization are proposed in order to enhance the anti-tumour activity of agents inhibiting isoprenylation. Finally, a summary of the principal data on clinical trials based on the use of FTIs and statins is given. In conclusion, the inhibition of isoprenylation is an attractive, but still not completely investigated therapeutic alternative that requires optimization for the translation in the current treatment of neoplasms.
[Back
to top] Drugging Cell Cycle
Kinases in Cancer Therapy
S. Blagden and J. de
Bono
Cell cycle kinases are comprised of cyclin-dependent kinases (Cdks), non-Cdk kinases such as Plk-1 and Aurora and checkpoint proteins such as Chk1 and Chk2. Though ubiquitous to dividing cells, many cell cycle kinases are amplified or over-expressed in malignancy and are potential targets for anti-cancer therapies. Cdk inhibiting drugs (such as flavopiridol, UCN-01, E7070, R-Roscovitine and BMS-387032) have shown preclinical and clinical anticancer activity. However, many of these agents are promiscuous and undiscerning, targeting other non-cell cycle kinases and affecting normal cells, thereby causing significant toxicity. To overcome this, a new generation of Cdk inhibitors are in development with greater target specificity, as well as others that inhibit non-Cdk cell cycle kinases, both directly and indirectly. The outcome of early clinical trials involving these agents is awaited, but these certainly represent a promising new area of anticancer drug development.
[Back
to top] Multiple-Target
Drugs: Inhibitors of Heat Shock Protein 90 and of Histone Deacetylase
A. Budillon, F.
Bruzzese, E. Di Gennaro and M. Caraglia
In spite of the improvement of conventional medical therapy for cancer treatment, the impact on cancer related mortality in the last ten years has been modest especially for advanced disease in adults. On the other hand, understanding of molecular events underlining tumor development lead to the definition of new molecular targets for novel anti-tumor therapeutical approaches. On this regard, several biotechnology products selected by academic as well as industrial research are currently in clinical trials. Epigenetics as well as post-translational modifications of proteins are emerging as novel attractive targets for anticancer therapy. In addition, the heterogeneity of tumor cells within a selected neoplastic lesions as well as the redundancy of proliferative and survival pathways present in cancer cells favor the development of single drugs that are able to affect multiple pathways. Inhibitors of heat shock protein 90 and of histone deacetylase are two novel classes of multi-target agents that entered recently in clinical studies.
This review will focus on the most important issues in the development of both these classes of agents.
[Back
to top] Molecular Targets
for Design of Novel Inhibitors to Circumvent Aminoglycoside Resistance
S.
Jana and J.K. Deb
Aminoglycosides are a class of clinically important antibiotics used in the treatment of infections caused by Gram-positive and Gram-negative organisms. They are bactericidal, targeting the bacterial ribosome, where they bind to the A-site and disrupt protein synthesis. Antibiotic resistance is a growing problem for all classes of anti-infective agents. One of the first groups of antibiotics to encounter the challenge of resistance was the aminoglycoside –aminocyclitol family. Initially, the resistance that emerged in organisms such as Mycobacterium tuberculosis was restricted to modification of the antibiotic targets, which we now know to be the bacterial ribosomal rRNA and proteins. As new aminoglycosides came to the clinic, however, the prevalence of chemical modification mechanisms of resistance became dominant. Enzymatic modification of aminoglycosides through kinases (O-phosphotransferases, APHs), O-adenyltransferases (ANTs) and N-acetyltransferases (AACs) has emerged in virtually all clinically relevant bacteria of both Gram-positive and Gram-negative origin. Although their clinical use has been extensive, their toxicity and the prevalence of resistance in clinical strains have prompted the pharmaceutical industry to look for alternatives. Whereas the search for novel targets for antibiotics from the genomic information is ongoing, no antibacterial agent based on these efforts has so far entered clinical trials. Meanwhile, structural knowledge of the ribosome, the target for aminoglycosides, has invigorated the field of antibiotic development. It is expected that knowledge of the binding interactions of aminoglycosides and the ribosome would lead to concepts in drug design that would take us away from the parental structures of aminoglycosides in the direction of different structural classes that bind to the same ribosomal target sites as aminoglycosides. The challenge to ensure the continued use of these highly potent antibacterial agents will require the effective management of resistance at several levels. One potential mechanism of circumventing resistance is the development of inhibitors of modification enzymes, a methodology that is now well established in the b-lactam field. This approach requires knowledge of resistance at the molecular and atomic levels for the rational design of inhibitory molecules. The understanding of the molecular basis for aminoglycoside resistance modification has been greatly enhanced by the recent availability of representative 3D-structures from the three classes of modifying enzymes: kinases, acetyltransferases and adenyltransferases. The challenge is now to firmly establish the mechanisms of enzyme action and to use this information to prepare effective and potent inhibitors that will reverse antibiotic resistance. In this review, we discuss the molecular mechanisms of resistance of aminoglycosides specifically on aminoglycoside-modifying enzymes and newly developed strategies to circumvent resistance including antisense technology, which is an example of new strategy to deal with antibiotic resistance.
[Back
to top] Colloidal Carriers
for Ophthalmic Drug Delivery
Rubiana Mara
Mainardes, Maria Cristina Cocenza Urban, Priscila Oliveira Cinto, Najeh Maissar
Khalil, Marco Vinicius Chaud, Raul Cesar Evangelista and Maria Palmira Daflon
Gremiao
To achieve effective drug concentration at the intended site for a sufficient period of time is a requisite desired for many drug formulations. For drugs intended to ocular delivery, its poor bioavailability is due to pre-corneal factors. Most ocular diseases are treated by topical drug application in the form of solution, suspension and ointment. However, such dosage forms are no longer sufficient to combat some ocular diseases. Intravitreal drug injection is the current therapy for disorders in posterior segment. The procedure is associated with a high risk of complications, particularly when frequent, repeated injections are required. Thus, sustained-release technologies are being proposed, and the benefits of using colloidal carriers in intravitreal injections are currently under investigation for posterior drug delivery. This review will discuss recent progress and specific development issues relating to colloidal drug delivery systems, such as liposomes, niosomes, nanoparticles, and microemulsions in ocular drug delivery.