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Special Issue "Targeted Therapy"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (28 February 2010)

Special Issue Editor

Guest Editor
Prof. Dr. Maurizio Recanatini (Website)

Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
Fax: +39 051 20 99734
Interests: computational medicinal chemistry; structure-based ligand design & discovery; modeling and simulation of targets and ligand-target complexes of therapeutic interest; chemical biology

Special Issue Information

Dear Colleagues,

In the last decade, the increased knowledge of the molecular determinants of cancer has boosted the search for the so-called “targeted drugs”, some of which are now clinically available, whereas many more are in clinical trials. Within this definition, we include both small organic molecules and monoclonal antibodies that, differently from the traditional chemotherapeutic agents, are able to recognize and bind specific protein targets in the diseased cells, such to impair their functioning and leading the cells to death. Great advantages in terms of improved efficacy and reduced toxicity can thus be achieved, as imatinib and bevacizumab have shown in the treatment of leukemias and solid tumors. However, the great expectations raised by the introduction of these innovative drugs are not fully satisfied, and, actually, the success rate is slower than predicted. Reasons for this are being presently explored, and one of them might reside just in the definition of the approach: in fact, defining the “target” against which to direct a chemical agent is crucial in determining the success or the failure of the intervention. There is a consensus nowadays on the idea that targeting a single protein is not enough to impair the myriad of interconnected events at the basis of the cellular life and development. Rather, it seems mandatory to identify and target one or more network of intracellular interactions to achieve a lethal interference with vital processes of the cancer cells. Accordingly, the present efforts towards the discovery of novel anticancer agents are firmly based on the acquired molecular knowledge of the biology of cancer, but aim at interrupting at multiple levels cellular pathways deemed as important and specific for the cells. Target identification and validation, molecular design, and advanced organic synthesis are key activities for the discovery of new clinical candidates, while the identification of biomarkers and the design of innovative clinical trials are fundamental for properly and quickly assessing the clinical efficacy of the new agents. The present Special Issue of “Pharmaceuticals” aims at collecting contributes reporting on the discovery and/or development of “targeted agents”, as well as on methods and approaches followed to meet this aim.

Prof. Dr.
Maurizio Recanatini
Guest Editor

Keywords

  • receptor kinases
  • intracellular signaling
  • cell cycle regulation
  • protein dynamics
  • kinase inhibitors
  • epigenetic modulators
  • proapoptotic agents

Published Papers (7 papers)

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Research

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Open AccessArticle Molecular Therapies in Thyroid Cancer
Pharmaceuticals 2011, 4(1), 91-100; doi:10.3390/ph4010091
Received: 2 November 2010 / Revised: 9 December 2010 / Accepted: 22 December 2010 / Published: 24 December 2010
Cited by 1 | PDF Full-text (53 KB) | HTML Full-text | XML Full-text
Abstract
Thyroid cancer is a common diagnosis with greater than 34,000 cases per year in the United States. Early stage thyroid cancer is often managed with surgical intervention and radioactive iodine; however, for recurrent or metastatic disease, the treatment options, historically, have been [...] Read more.
Thyroid cancer is a common diagnosis with greater than 34,000 cases per year in the United States. Early stage thyroid cancer is often managed with surgical intervention and radioactive iodine; however, for recurrent or metastatic disease, the treatment options, historically, have been limited to chemotherapy. Chemotherapy for metastatic thyroid cancer has been of limited efficacy. Encouragingly, molecular therapeutics have played a greater role in managing patients with advanced disease. These agents work primarily through disruption of tyrosine kinase pathways. This review will discuss the expanding role of molecular targets in managing patients with advanced thyroid cancer. Full article
(This article belongs to the Special Issue Targeted Therapy)

Review

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Open AccessReview EGFR Targeting in Hormone-Refractory Prostate Cancer: Current Appraisal and Prospects for Treatment
Pharmaceuticals 2010, 3(7), 2238-2247; doi:10.3390/ph3072238
Received: 25 May 2010 / Revised: 6 July 2010 / Accepted: 14 July 2010 / Published: 19 July 2010
Cited by 6 | PDF Full-text (88 KB) | HTML Full-text | XML Full-text
Abstract
The incidence of prostate cancer increases with age and because of its high prevalence this disease has become a major public health concern. Despite advances in our understanding of the biological mechanisms responsible for the development of this cancer, the transition to [...] Read more.
The incidence of prostate cancer increases with age and because of its high prevalence this disease has become a major public health concern. Despite advances in our understanding of the biological mechanisms responsible for the development of this cancer, the transition to the hormone refractory stage (HRPC) and metastatic progression pose real problems of clinical management. Currently, docetaxel chemotherapy has been shown to have a slight but significant impact on survival, though the gain in median survival is still less than three months. Research is therefore continuing to improve treatment outcomes. The progression of prostate cancer is accompanied by the overexpression of EGFR (epidermal growth factor receptor) in a very large majority of cases, suggesting that this may play a mechanistic role. Unfortunately, although preclinical findings seem to be promising for therapies targeting the EGFR in HRPC, current clinical results are disappointing. These results should however encourage us to look for different ways of using anti-EGFR agents or combining them with other targeted therapies. Full article
(This article belongs to the Special Issue Targeted Therapy)
Open AccessReview Demethylating Agents in the Treatment of Cancer
Pharmaceuticals 2010, 3(7), 2022-2044; doi:10.3390/ph3072022
Received: 4 May 2010 / Revised: 22 June 2010 / Accepted: 29 June 2010 / Published: 2 July 2010
Cited by 7 | PDF Full-text (157 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the [...] Read more.
Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We also summarize findings from clinical trials that used these two demethylating agents in the treatment of solid tumors. Lastly, we discuss some limitations in the use of azacitidine and decitabine in cancer therapy. Full article
(This article belongs to the Special Issue Targeted Therapy)
Open AccessReview Aptamers for Targeted Drug Delivery
Pharmaceuticals 2010, 3(6), 1761-1778; doi:10.3390/ph3061761
Received: 5 March 2010 / Revised: 19 May 2010 / Accepted: 26 May 2010 / Published: 27 May 2010
Cited by 42 | PDF Full-text (262 KB) | HTML Full-text | XML Full-text
Abstract
Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential [...] Read more.
Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX). SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery. Full article
(This article belongs to the Special Issue Targeted Therapy)
Figures

Open AccessReview Targeted Therapy of Cancer Using Photodynamic Therapy in Combination with Multi-faceted Anti-Tumor Modalities
Pharmaceuticals 2010, 3(5), 1507-1529; doi:10.3390/ph3051507
Received: 3 March 2010 / Revised: 28 April 2010 / Accepted: 11 May 2010 / Published: 14 May 2010
Cited by 44 | PDF Full-text (375 KB) | HTML Full-text | XML Full-text
Abstract
Photodynamic therapy (PDT) has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS), which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS), that [...] Read more.
Photodynamic therapy (PDT) has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS), which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS), that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine. Full article
(This article belongs to the Special Issue Targeted Therapy)
Open AccessReview New Trends in Cancer Therapy: Targeting Ion Channels and Transporters
Pharmaceuticals 2010, 3(4), 1202-1224; doi:10.3390/ph3041202
Received: 16 February 2010 / Revised: 25 March 2010 / Accepted: 29 March 2010 / Published: 20 April 2010
Cited by 16 | PDF Full-text (312 KB) | HTML Full-text | XML Full-text
Abstract
The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. [...] Read more.
The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. For instance, Kv11.1 (hERG1) channels are aberrantly expressed in several human cancers, in which they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which can lead to life-threatening ventricular arrhythmias. Several possibilities exist to produce less harmful compounds, such as developing specific drugs that bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which appears to be crucial in certain stages of neoplastic progression. The potential approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1) targeting specific conformational channel states; (2) finding ever more specific inhibitors, including peptide toxins, for channel subtypes mainly expressed in well-identified tumors; (3) using specific ligands to convey traceable or cytotoxic compounds; (4) developing channel blocking antibodies; (5) designing new molecular tools to decrease channel expression in selected cancer types. Similar concepts apply to ion transporters such as the Na+/K+ pump and the Na+/H+ exchanger. Pharmacological targeting of these transporters is also currently being considered in anti-neoplastic therapy. Full article
(This article belongs to the Special Issue Targeted Therapy)
Open AccessReview Hybridoma-Derived Idiotype Vaccine for Lymphoma: Approval Must Wait
Pharmaceuticals 2010, 3(3), 667-678; doi:10.3390/ph3030667
Received: 5 February 2010 / Revised: 3 March 2010 / Accepted: 8 March 2010 / Published: 15 March 2010
PDF Full-text (95 KB) | HTML Full-text | XML Full-text
Abstract
Hybridoma-derived idiotype vaccines have been used for the experimental treatment of human lymphoma over the last twenty years, providing evidence of biological efficacy, clinical efficacy and clinical benefit. However, the product that has come closer to regulatory approval is unlikely to clear [...] Read more.
Hybridoma-derived idiotype vaccines have been used for the experimental treatment of human lymphoma over the last twenty years, providing evidence of biological efficacy, clinical efficacy and clinical benefit. However, the product that has come closer to regulatory approval is unlikely to clear that hurdle due to the insufficiently robust data obtained in a recently closed clinical trial. This review aims at discussing the reasons for hybridoma-derived idiotype vaccines, more difficult to produce but also more successful than recombinant idiotype vaccines so far, are unlikely to gain regulatory approval. In particular, it is necessary to examine the many peculiar features of this therapeutic approach in a broader context, with special attention to concepts like customized active immunotherapy and randomization. Most published trials based on hybridoma-derived idiotype vaccines are being analyzed, together with the yet non-peer reviewed data from the only randomized study conducted so far with this product, and with the main trials on recombinant idiotype vaccines for thorough comparison. All in all, the sole randomized trial ever conducted on hybridoma-derived idiotype vaccines failed to achieve its primary clinical end point because of an insufficient accrual and because the statistical significance achieved was not as stringent as required for regulatory approval. Full article
(This article belongs to the Special Issue Targeted Therapy)

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