Special Issue "Targeted Therapy"

Guest Editor
Prof. Dr. Maurizio Recanatini
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
Website: http://www.scfarm.unibo.it/
E-Mail:
Interests: computational medicinal chemistry; structure-based ligand design & discovery; modeling of targets and ligand-target complexes of therapeutic interest (cancer, Alzheimer's disease, hERG-related drug toxicity); chemical biology

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

Submission

All manuscripts should be submitted to pharmaceuticals@mdpi.org with a copy to the Guest Editor. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access monthly journal published by MDPI.

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

Manuscript ID: Pharmaceuticals-targthrap-20090831-Waller-us
Type of Paper: Review
Title: The Use of Ipilimumab (Anti-CTLA-4 Antibody) in Oncology
Authors: Mojtaba Akhtari, Mohammad S. Hossain and Edmund K. Waller
Affiliation: Department of Hematology and Medical oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA; E-mail: makhtar@emory.edu
Abstract: Ipilimumab, a gully human monoclonal anti-body to cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), is a novel anti-cancer treatment which targets the immune system rather than the tumor directly. It has been used in the treatment of malignant melanoma, renal cell carcinoma, prostate cancer, ovarian carcinoma and hematological malignancies relapsed following hematopoietic stem cell transplantation. The mechanism for its anti-tumor effect is blocking the activity of CTLA-4, a surface molecule that inhibits the activation of T-cells and regulates immune responses, thereby increasing the numbers and activity of long-lived effector T-cells, including T-cell clones with anti-tumor immunity. The clinical use of ipilimumab has been complicated by the development of a variety of auto-immune conditions which their management could be challenging. The use of ipilimumab may, thus augment latent anti-tumor immune responses that can be further potentiated by cytotoxic chemotherapy which depletes regulatory T-cells and by tumor vaccines which enhance the numbers of tumor-specific T-cell effectors. A number of recent clinical studies support the safety and efficacy of ipilimumab as monotherapy or used in combination with other drugs to treat metastatic melanoma and other types of cancer. In this review, we summarize current clinical output of anti-CTLA-4 antibody as cancer immunotherapy, dose related toxicities, pharmacokinetics and pharmacodynamic. The immunomodulatory effects of ipilimumab on different types of immune populations are addressed as well as unanswered questions and challenges that are currently limiting the therapeutic potential of ipilimumab and related compounds as anti-cancer drugs. A more complete understanding of the effects of ipilimumab on the immune system, and the interaction between its immune-modulating activities and the effects of traditional cytotoxics and other immune approaches will greatly facilitate the rational design of clinical trials utilizing ipilimumab as treatment for a multitude of cancers.

Manuscript ID: Pharmaceuticals-targthrap-20091009-Arcangeli-it
Type of Paper: Review
Title: New Trends in Cancer Therapy: Targeting Ion Channels
Authors: Annarosa Arcangeli and Andrea Becchetti
Affiliations: Department of Experimental Pathology and Oncology, University of Florence, Italy; Department of Biotechnology and Biosciences, University of Milan, Italy; E-Mail: annarosa.arcangeli@unifi.it
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. This opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. -For instance, hERG1 channels are aberrantly expressed in several human cancers, where they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth both in vitro and in vivo. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which leads to life-threatening ventricular arrhythmias. Less harmful compounds can be developed which bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which is crucial for neoplastic progression.-Overall, 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 expressed in tumors; 3) using specific ligands to convey traceble or cytotoxic compounds; 4) developing channel blocking antibodies; 5) designing new molecular tools to decrease channel expression in selected cancer types.

Manuscript ID: Pharmaceuticals-targthrap-20091017-Khong-us
Type of Paper: Review
Title: Demethylating Agents in the Treatment of Cancer
Author: Hung T. Khong
Affiliation: USA Mitchell Cancer Institute, 1660 Spring Hill Ave., Mobile AL 36604, USA; E-Mail: hkhong@usouthal.edu
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 reexpression in malignancies. Two demethylating agents, azacitadine and decitabine, are approved for the treatment of myeodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitadine 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 azacitadine and decitabine in cancer therapy.