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- Volume 5, Issue 3, 2010
Current Clinical Pharmacology - Volume 5, Issue 3, 2010
Volume 5, Issue 3, 2010
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Editorial [Hot topic: Selected New Developments in Oncology (Guest Editors: Jos H. Beijnen and Jan H.M. Schellens)]
Authors: Jos H. Beijnen and Jan H.M. SchellensIn several Western countries cancer has passed cardiovascular diseases of the top-3 causes of death and now heads the charts. Better treatment options and preventive measures in cardiovascular medicine have resulted in its sharp decrease of death rate. Part of the explanation, however, is that cancer incidence is still rising every year. This is primarily due to the proportional increase of the ageing population, with cancer being especially an old people's disease. On the other hand, the cancer death rate, fortunately, gradually declines. Better diagnostic tools with early recognition of malignancies, as well as better treatment outcomes have contributed to this. The cancer problem, however, is and remains immense in the coming years with a huge impact on people's life and society. It has been estimated that worldwide, more than 28 million people live with cancer nowadays. Progress and improvements in cancer treatment are difficult to forecast. Sometimes, big steps are made such as the introduction of cisplatin for the treatment of testicular cancer [1] or adjuvant chemotherapy in breast cancer [2] that can bring about the difference between death and cure. Major advances have also been made in the treatment of several hematological childhood cancers [3]. But, usually, small steps are made in oncology. Positive clinical trials yield mostly one or two months improvement in overall survival. Nevertheless, when many of these steps are taken consecutively, they may all together contribute to substantial changes in patient's perspectives. The chemotherapeutic treatment of colorectal, lung and ovary cancer has evolved in this manner. In the years to come, real breakthroughs in cancer treatments are most likely to be expected from the combination of basic understanding of the molecular processes underlying cancer development and the identification of the drivers that can serve as target for therapy. This approach was also followed in the search for effective therapies against human immunodeficiency virus (HIV) infection. Basic research revealed all the intricate steps in the life-cycle of the virus and bared the targets for drug therapy [4]. Nowadays, cocktails of antiretroviral drugs are used acting at different levels of the virus infection, from entry into and exit from host cells. This pharmacotherapy has turned, in less than 30 years, the HIV infection from a death sentence into a chronic disease with acceptable quality of life. Evidently, HIV infection and cancer are not synonymous. Above all, the infection is caused by a foreign virus and cancer arises from genetic aberrations in normal cells. Nonetheless, the same line of thinking in therapy design has come into sight [5]. This special Oncology issue of Current Clinical Pharmacology touches on a selection of new developments in cancer treatment. It is hoped that it will inspire its readers to participate in cancer research and treatment in the coming years and to witness all the new challenges to come.
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Personalized Medicine in Oncology: A Personal View with Myths and Facts
Authors: Jos H. Beijnen and Jan H.M. SchellensPersonalized treatments with molecularly targeted agents are considered new and heading towards a bright future in medical oncology. The development of imatinib was a landmark and its clinical and commercial success revolutionized many new developments in this area. Molecular targeted therapies require strict patient selection to identify those who may benefit. Novel targeted (personalized) therapies with antibodies such as trastuzumab have proven, undoubtedly, their added value in the clinic for large patient populations. Targeted therapies with “small molecules” are most successful, however, in “single defect”, rare cancers such as Philadelphia chromosome positive chronic myeloid leukemia. Resistance and side effects are limitations in their clinical application. Cancer is, in most cases, a multifactorial disease and multi-targeted agents or combinations may be required to obtain cancer cures finally. We present our personal view on the current developments in this field.
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Monoclonal Antibody Therapy in Haematological Malignancies
More LessThis review focuses on the development of monoclonal antibodies that have been or are being introduced in the treatment of both lymphoid and myeloid haematological malignancies in adults. After a general introduction on the principles of antibody selection for therapy, this review summarizes the results of the clinical trials that led to the approval of antibodies by the FDA (Food and Drug Administration, USA) and/or the EMEA (European Medicines Agency), e.g. different anti-CD20, anti-CD52 and anti-CD33 antibodies. Furthermore, several antibodies that seem promising in phase I/II studies (like anti-CD22, anti-CD23, anti-CD4, anti-CD30, anti-CD80, anti-VEGF, anti HLA-DR and anti-TNF) are highlighted. The application of monoclonal antibodies has nowadays become indispensable in the treatment of lymphoma and leukaemia's and the number of new indications is still growing. Therefore, also some interesting phase III studies that are recruiting patients at this moment, and some new technical developments are discussed.
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Monoclonal Antibodies in Solid Tumours
Authors: Ben Markman and Josep TaberneroMonoclonal antibodies (mAbs) have become an integral part of therapeutic strategies used to treat solid tumours. Directed against membrane-bound receptors or extracellular ligands with high specificity, they target elements upstream in the signal transduction pathways that contribute to malignant growth, proliferation, survival, angiogenesis and spread. Several mAbs have now received regulatory approval - trastuzumab, cetuximab, panitumumab, bevacizumab and catumaxomab- across multiple solid tumour types, including breast, colorectal, and non-small cell lung cancers, amongst others. Despite these successes there have been ample disappointments, which in turn is stimulating ongoing research and development efforts. Nevertheless, greater initiative and vision in this development process is needed, from intelligent compound design to enrichment of patient populations during clinical development, biomarker discovery and ultimately tailored, individualised treatment decisions. In this commentary we review those mAbs now in routine use for solid tumours, interesting aspects of their use and future directions.
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Molecular Targeted Therapy in Prevalent Tumors: Learning from the Past and Future Perspectives
Authors: Otto Metzger-Filho, Camilo Moulin and Ahmad AwadaImportant advances have been achieved with molecular targeted agents in clinical oncology. Breast, colon, and lung cancer, are now commonly treated with a combination of chemotherapy and targeted agents. In this article the authors discuss the limitations of targeted therapy development, failures of previous studies, and possible strategies for an intelligent drug development. Initial attempts to block mTOR in breast cancer, the magnitude of benefit obtained with anti-EGFR therapy in lung cancer, and the narrowing use of anti-EGFR therapy in colon cancer based on K-RAS status are discussed.
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Vascular Disrupting Agents (VDAs) in Anticancer Therapy
Authors: Laura G.M. Daenen, Jeanine M.L. Roodhart, Yuval Shaked and Emile E. VoestVascular disrupting agents (VDAs) represent a novel class of drugs targeting the tumor's blood supply. Conceptually and operationally different from currently used antiangiogenic agents, VDAs have a high specificity for the established but abnormal tumor vasculature. Upon administration, rapid changes in the microtubule cytoskeleton of tumor endothelial cells are induced, resulting in a cascade of events ultimately leading to blood flow stasis and vascular collapse. Subsequently, the cells in the core of the tumor become necrotic and die. However, tumor repopulation occurs from a rim of viable tumor tissue on the edges of the tumor, stimulating the search for appropriate combination strategies designed to interfere with the regrowth from the viable rim. Such combinations include chemotherapy, irradiation, and antiangiogenic drugs. In recent years, understanding of the molecular and cellular mechanisms taking place in response to VDA therapy has improved substantially. Multiple drug combinations have been designed and tested in preclinical models, some of which have shown encouraging results. Clinical benefits are currently under investigation in a number of ongoing clinical trials, including randomized phase III trials.
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Abrogation of the G2 Checkpoint by Inhibition of Wee-1 Kinase Results in Sensitization of p53-Deficient Tumor Cells to DNA-Damaging Agents
Authors: Suzanne Leijen, Jos H. Beijnen and Jan H.M. SchellensInducing DNA damage is a well known strategy for attacking cancer, already being used for many years by the application of a variety of anti cancer drugs. Tumor cells and other rapidly dividing cells are more sensitive to DNA damage caused by DNA damaging agents compared to normal cells. While normal cells can rely on various mechanisms for DNA repair in order to protect the integrity of the genome and to promote cell survival, most tumor cells, due to genetic changes, are more challenged when it comes to repair of DNA damage. Wee1 is a tyrosine kinase that phosphorylates CDC2 at Tyr 15 and as such plays a pivotal role in the G2 DNA damage checkpoint. The strategy of inhibition of Wee1 by a tyrosine kinase inhibitor is exploiting the impaired options for DNA damage repair especially in cells with deregulated p53, which results in malfunction of the G1 checkpoint. Tumor cells that are unable to rely on the G1 checkpoint are more sensitive to G2 checkpoint abrogation. Administration of DNA damaging chemotherapy in combination with a Wee1 inhibitor may therefore selectively sensitize p53 deficient cells, while normal cells are spared from toxicity. PD-166285 has been described as a novel G2 abrogator and Wee1 inhibitor, but has also been characterized as a broad-spectrum receptor tyrosine kinase inhibitor. MK-1775 is a specific and potent inhibitor of Wee-1 and is currently under investigation in a multi-center phase I study in combination with either gemcitabine, carboplatin or cisplatin in patients with advanced solid tumors. Preliminary results show good tolerability and promising anti-cancer activity.
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Inducing Synthetic Lethality using PARP Inhibitors
Authors: David S. Boss, Jos H. Beijnen and Jan H.M. SchellensThe enzyme poly(ADP)-ribose polymerase-1 (PARP-1) plays an important role in the repair of DNA damage via a mechanism called base excision repair (BER). Initially, inhibition of PARP-1 showed to be a promising anti-tumor strategy in preclinical models using BRCA1 and BRCA2 deficient tumor cell lines. More recently, several small molecules targeting PARP-1 entered the clinic and demonstrated compelling anti-tumor activity in patients with BRCA deficient breast and ovarian cancers, and in patients with triple-negative breast cancer. In this review we aim to summarize the most recent advances in the development of PARP inhibitors, with a focus on the clinical data.
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Role of Histone Deacetylases and Their Inhibitors in Cancer Biology and Treatment
Authors: Jan H. Beumer and Hussein TawbiHistone deacetylase (HDAC) inhibitors constitute a new group of epigenetic agents that has gained much attention in cancer drug development. Research in the field of epigenetics is furthering our understanding of malignant behavior and providing novel targets to improve the outcomes of cancer therapy. In this review we present an overview of the complex landscape of HDAC inhibitor development starting from a discussion of the various HDAC isotypes and their roles in cancer biology, to mechanisms of action of HDAC inhibitors and their current state of development. The large gamut of HDACs are classified into 3 classes of “classical HDACs” and the “sirtuins” but in general lack specificity of deacetylation targets as they deacetylate both histone and non-histone targets. This non-specificity underlies the pleiotropic effects of HDAC inhibitors that does not stop at alteration of gene expression but extends into a wide array of cellular (nuclear and/or cytoplasmic) processes. The potential of HDAC inhibitors for cancer therapy has been explored in preclinical models and has reached the clinic as some agents are FDA-approved in hematologic malignancies where they function as differentiation agents. In solid tumors, HDAC inhibitors are used in combination with chemotherapy, which raises issues of mechanisms of potentiation and optimal administration (schedule and dose). Lastly, we discuss the need for biomarker development which will facilitate and guide the rational development of HDAC inhibitors as anticancer therapy.
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Pharmacogenetics of Irinotecan Disposition and Toxicity: A Review
Authors: Ken-ichi Fujita and Alex SparreboomIrinotecan (CPT-11) is a widely used anticancer drug, especially for the treatment of colorectal cancer. Irinotecan is considered an inactive prodrug that requires activation to the active metabolite SN-38. Patients treated with irinotecan occasionally experience severe neutropenia and delayed diarrhea, and the occurrence of these adverse reactions is unpredictable and still largely unexplained. Various studies have demonstrated a relationship between SN-38 pharmacokinetics and the experienced toxicity. In recent years, genetic polymorphisms in UDP-glucuronosyltransferase (UGT) 1A1, an enzyme involved in SN-38 glucuronidation, has been linked to interindividual pharmacokinetic variability and irinotecan toxicity. In addition, variants in other genes encoding drug-metabolizing enzymes or transporters that are involved in the disposition of irinotecan may play a crucial role in the pharmacokinetic and pharmacodynamic profile of irinotecan. In this review, we provide an update on the pharmacogenetics of irinotecan.
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DNA Vaccination in Oncology: Current Status, Opportunities and Perspectives
After almost 20 years of research, DNA vaccination is still a relatively young technique in the vaccine-toolbox. DNA vaccines can easily be modified by conventional cloning techniques, are relatively easy to produce and might be particularly useful for therapeutic vaccination against intracellular pathogens and cancer. After the early pre-clinical successes, DNA vaccination moved into the clinic and numerous trials have been performed thus far. In the oncology field, these trials aimed for the induction of cellular immunity directed against tumor specific antigens. Although DNA vaccines proved to be well tolerated, and elicited some immune activation in patients, robust immune activation followed by clinical responses has not been observed yet. Nevertheless, several promising strategies are currently under development to increase the performance of the current generation DNA vaccines. Future research has to demonstrate whether these strategies are able to give DNA vaccination a defined position in cancer treatment.
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Scheduling of Taxanes: A Review
Authors: Emma J. Woodward and Chris TwelvesThe taxanes are widely used in the cytotoxic treatment of many solid tumours. Their optimal scheduling, however, remains unconfirmed. Here we review the development of both paclitaxel and docetaxel to identify evidence influencing the choice of schedule. Early work with paclitaxel identified that it exhibits non-linear pharmacokinetics which has important clinical implications. Paclitaxel has been administered with a wide range of infusion times, especially 3-weekly and recently weekly schedules. Clinical activity of a weekly schedule appears at least non-inferior, and, in certain circumstances superior, to the 3-weekly schedule, with improved tolerability. Similarly, docetaxel has been investigated for 3-weekly versus weekly schedule, reporting equivalent efficacy and improved side effect profile for weekly dosing with regards myelosuppression. Both paclitaxel and docetaxel are often used with the monoclonal antibodies trastuzumab and bevacizumab. It would appear that in this setting, activity may be again improved by administering the taxane weekly, especially in combination with trastuzumab.A further recent development is the use of nab-paclitaxel, nanoparticle albumin-bound paclitaxel; this Cremaphor EC-free preparation allows shorter infusion times without premedication. Benefits of a weekly schedule with this newer drug are also emerging from the limited randomised data. Whether the possibly greater efficacy of weekly paclitaxel in particular reflects a biological effect of more frequent exposure of cancer cells to the cytotoxic is less clear as this schedule also allows a higher dose intensity to be delivered. Nevertheless, after more than 20 years, weekly administration has emerged as the optimal schedule, especially for paclitaxel. In practice, the choice of schedule is a balance between the better tolerability (and possibly efficacy) of weekly treatment balanced against the inconvenience for both the patient and clinic of more frequent visits for chemotherapy.
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