Molecularly targeted therapies in adult soft tissue sarcomas: present approach and future directions

Background: Sarcomas are rare neoplasms. Given the overwhelming chemotherapy resistance of the disease, patients with progressive and metastatic soft tissue sarcomas are ideal candidates for trials of investigational new drugs. Objective: The authors review the molecular mechanisms underlying soft tissue sarcomas and discuss molecularly targeted therapies developed to improve the poor outcome of these uncommon tumors. Methods: A Medline and American Society of Clinical Oncology abstract search was conducted using the keyword ‘soft tissue sarcoma’. Articles and abstracts were reviewed and eligible for inclusion if they used targeted therapies for the treatment of patients with soft tissue sarcomas. Results/conclusion: Phase II clinical trials for patients with soft tissue sarcomas using novel targets and present recognized targets are ongoing and planned.     

Molecularly targeted therapies in adult soft tissue sarcomas: present approach and future directions

BACKGROUND: Sarcomas are rare neoplasms. Given the overwhelming chemotherapy resistance of the disease, patients with progressive and metastatic soft tissue sarcomas are ideal candidates for trials of investigational new drugs. OBJECTIVE: The authors review the molecular mechanisms underlying soft tissue sarcomas and discuss molecularly targeted therapies developed to improve the poor outcome of these uncommon tumors. METHODS: A Medline and American Society of Clinical Oncology abstract search was conducted using the keyword 'soft tissue sarcoma'. Articles and abstracts were reviewed and eligible for inclusion if they used targeted therapies for the treatment of patients with soft tissue sarcomas. Results/conclusion: Phase II clinical trials for patients with soft tissue sarcomas using novel targets and present recognized targets are ongoing and planned.     

Targeted therapy in acute myeloid leukaemia: current status and future directions

Background: The limit of acceptable toxicity for standard chemotherapeutic drugs used in acute myeloid leukaemia (AML) therapy has been reached. New therapeutic strategies are therefore needed. Objective: This review summarizes development in new strategies, and gives an overview of the clinical status on new drugs for non-promyelocytic AML in adults. Methods: Information was principally gathered from the databases ClinicalTrials.gov and PubMed.gov. Results/conclusion: The major improvements in AML treatment during the last two decades has not been the introduction of new therapeutic agents, but rather the more optimal use of well-known drugs (e.g., high-dose cytarabine therapy, the use of ATRA in maintenance therapy of acute promyelocytic leukaemia) and improvement in the diagnosis and treatment of potentially life-threatening complications in patients treated with allogeneic stem cell transplantation. However, further investigations based on specific targeted therapy and stratification of patients according to knowledge of the individual disease and health status will probably be necessary in future studies of new targeted therapy.     

Targeted anti-IL-13 therapies in asthma: current data and future perspectives

Introduction: The identification of patients with severe asthma who will benefit from a personalized management approach remains an unmet need. Interleukin-13 (IL-13) is a cytokine possessing a significant role in asthma pathogenesis and progression of disease. Humanised monoclonal antibodies against IL-13 and IL-13 and IL-4 receptors are mainly proposed as add-on therapy in patients with T_H2-high inflammation with uncontrolled asthma despite maximum therapy.

Areas covered: The role of IL-13 in airway inflammation in severe asthma, the targeted anti-IL-13 therapies and biomarkers that predict response to anti-IL-13 treatment are discussed.

Expert opinion: New effective individualized therapies in severe asthma are urgently needed to block specific inflammatory pathways using monoclonal antibodies. Studies on anti-IL-13 therapies showed that asthmatic patients could benefit from this novel targeted therapy as far as lung function and exacerbation rate are concerned. T_H2-high and especially periostin-high groups of asthmatics with moderate-to-severe uncontrolled asthma seem to compose the group that could benefit from anti-IL-13 therapy. Targeting IL-13 alone may not be sufficient to achieve asthma control. Inhibition of IL-13 and IL-4 with mabs may be more encouraging and patients will probably have additional benefits from these therapeutic interventions because of IL-13/IL-4 overlapping actions in asthma pathophysiology.     

Targeted therapies for gastric cancer: current status

Gastric cancer represents one of the most common cancers internationally. Unfortunately the majority of patients still present at an advanced stage, and despite advances in diagnostic and treatment strategies, outcomes still remain poor with high mortality rates despite a decline in incidence. Whilst the utility of classical chemotherapy agents has been explored thoroughly (and continues to be investigated, alone or in various combinations), advances have been slow and the efficacy of these agents has reached a plateau. As such, the focus of recent study has shifted toward developing a greater understanding of the molecular biology of carcinogenesis and the cancer cell phenotype, and, in turn, the development of rationally designed drugs that target molecular aberrancies in signal transduction pathways specific to gastric cancer. These targets include circulating growth and angiogenic factors, cell surface receptors, and other molecules that comprise downstream intracellular signalling pathways, including receptor tyrosine kinases. Therapeutic advances in this area significantly lag behind other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted therapies in gastric cancer, including rationale and mechanism of action, current and emerging data, as single-agent therapy or in combination regimens. A recently published randomized phaseIII trial supporting the use of trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2)/neu monoclonal antibody, in a selected population of patients is discussed. Therapies that have been evaluated in phase II trials are also reviewed, as well as promising new therapies currently being investigated in preclinical or phase I studies. There is optimism that targeted therapies, whether as single-agent therapy or in combination with traditional therapies, including chemotherapy, radiotherapy and surgery, may yet have an impact on improvement of the overall prognosis of gastric cancer.     

Nanotechnology in ocular delivery: current and future directions

Our knowledge in the field of ocular drug delivery is rapidly expanding. An increase in the understanding of ocular drug absorption and disposition vis-à-vis developments in nanotechnology has led to the emergence of many of the nanotechnology-based ocular drug delivery systems including nanoparticles, microemulsions, liposomes, solid lipid nanoparticles, light-sensitive nanocarrier systems, etc. The need to develop effective treatments for posterior eye segment diseases is more important than surface delivery. Treatment of blinding diseases of the eye, such as proliferative retinopathy or macular degeneration, requires effective and safe delivery of drugs to posterior eye segment tissues, and recent advances in nanotechnology have demonstrated successful outcomes. Nanoscientists should focus their efforts on nano-ophthalmology. This review describes the current status and progress made so far, and the course that needs to be pursued in the future.     

Biologic therapies in rheumatology: lessons learned, future directions

During the past decade biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the management of rheumatic disease. By targeting key cytokines and immune cells biologics have provided more specific therapeutic interventions with less immunosuppression. Clinical use, however, has revealed that their theoretical simplicity hides a more complex reality. Efficacy, toxicity and even pharmacodynamic effects can deviate from those predicted, as poignantly illustrated by the catastrophic effects witnessed during the first-into-human administration of TGN1412. This review summarizes lessons gleaned from practical experience and discusses how these can inform future discovery and development of new biologic therapies for rheumatology.     

Haemophilia B: current pharmacotherapy and future directions

Introduction: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality.

Areas covered: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients.

Expert opinion: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.     

Psoriatic arthritis: current therapy and future directions

Introduction: Psoriatic arthritis (PsA) once regarded as an auto-inflammatory arthritis that involves the skin is proving to be more complex with a different driver of disease process compared to rheumatoid arthritis. As growing differences emerge between PsA and rheumatoid arthritis so have the experiences and responses to therapeutics used in both disease processes.

Areas covered: This review highlights articles of interest in the past 10 years in the OVID and PubMed database and focuses on major concepts regarding current disease-modifying anti-rheumatic drugs in PsA as well as newer target agents.

Expert opinion: Presently, it is agreed upon that use of tumor necrosis factor inhibitors (TNFi) has greatly changed our ability to manage varying aspects of disease in PsA. However, there remain many unanswered questions in which research in PsA is mirroring RA work, these include: i) the need for outcome measures that are more specific to PsA, ii) the concept of early and treat to target, iii) the role of highly sensitive imaging, and iv) efficacy of combination therapy and further targets in those unable to tolerate or fail TNFi.     

Haemophilia B: current pharmacotherapy and future directions

Introduction: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality. Areas covered: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients. Expert opinion: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.     

Polycythemia vera: current pharmacotherapy and future directions

Introduction: In the past, management of polycythemia vera (PV) was built upon a cornerstone of control over erythrocytosis, through therapeutic phlebotomy, as well as the use of low-dose aspirin. Historically, selected patients were managed with additional cytoreductive therapies to decrease the risk of vascular events, with the recognition that these therapies likely did not impede progression.

Areas covered: Recent clinical trials have demonstrated, in a randomized fashion, that optimal control of the hematocrit to target levels < 45% are important for decreasing the risk of vascular events. We are identifying that our historical set of cytoreductive agents, such as hydroxyurea, may be replaced in the future. The first candidate is pegylated interferon alpha-2a, which is demonstrating the ability to control vascular events and control extended hematopoiesis, while potentially having impact on fibrotic progression and Janus kinase 2 (JAK2) V1617F mutant allele burden. Ruxolitinib, as well as other JAK2 inhibitors in development, are demonstrating that this class of agents is making a very meaningful impact on the risk of vascular events in PV, controlling expanded hematopoiesis, as well as helping with symptomatic burden.

Expert opinion: Future goals include attaining a better understanding of the specific roles of JAK inhibitor therapy and whether their use in combination with standard therapies offers greater efficacy than single agents alone.     

Reproductive toxicology: current and future directions.

During the 20th century, there has been an increased risk from environmental by-products that may be harmful to reproductive function in humans. Therefore, as the 21st century begins, it is appropriate to evaluate future directions within the field of reproductive toxicology. This commentary identifies several approaches and developing technologies that would help research continue in a meaningful direction. Four areas for development are suggested, and selected examples of research involved in those areas are discussed: (1) Translational applications: workplace exposures thought to cause infertility in men (1,2-dibromo-3-chloropropane, DBCP) and menstrual disturbances in women (2-bromopropane, 2BP) are given as examples of human effects that have prompted animal studies. (2) Exposure paradigms: extrapolating dosing in animals to exposures in humans becomes complex. Two examples of surprising findings using lower doses are cited: ovotoxicity caused by polycyclic aromatic hydrocarbons (PAHs), and disrupted sexual differentiation caused by the fungicide vinclozolin. (3) Gender differences: predicting variable risk between women and men requires investigation of the effects of reproductive toxicants in both genders. The phthalates provide a good example for this comparison. Whereas di-(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant working by similar mechanisms in males and females, di-n-butyl phthalate (DBP) produces developmental effects in males and reproductive tract effects in females. (4) Endocrine disruptors: recent research has identified environmental chemicals that disrupt reproductive processes by altering the actions of endogenous steroid hormones. The endocrine disruptor issue is discussed in terms of evaluation of the actual risk these chemicals may pose in humans.     

Anticancer antifolates: current status and future directions

Antifolates are the oldest of the antimetabolite class of anticancer agents and were one of the first modern anticancer drugs. The first clinically useful antifolate, described in 1947, was 2,4-diamino-pteroylglutamate (4-amino-folic acid; aminopterin; AMT) which yielded the first-ever remissions in childhood leukemia. AMT was soon superseded by its 10-methyl congener, methotrexate (MTX), based on toxicity considerations; MTX remains, with one limited exception, the only antifolate anticancer agent in clinical use to this date. Because of the safety and utility of MTX, considerable effort has been invested in attempting to design more therapeutically selective antifolates or antifolates with a wider tumor spectrum. Initially, the design was based on the burgeoning knowledge of folate-dependent pathways and the determinants of the mechanism of action of MTX. These determinants include transport, the tight-binding inhibition of its target (the folate-dependent enzyme dihydrofolate reductase (DHFR)), and metabolism of MTX to poly-gamma-glutamate (Glu(n)) metabolites. These early studies led to the development of other antifolate DHFR inhibitors of two types: (1). "classical" analogs that use the same cellular transport systems as MTX and are also metabolized to Glu(n); and (2). "nonclassical" (i.e., lipophilic) analogs that do not require transport systems and that are not metabolized to Glu(n). Although several of these analogs have undergone clinical trial, none is proved superior to MTX. Detailed examination of the mechanisms of cytotoxicity and selectivity of MTX showed that inhibition of both dTMP synthesis and de novo purine synthesis, secondary to DHFR inhibition, led to DNA synthesis inhibition and subsequent cell death; inhibition of other folate-dependent pathways did not appear necessary for cell death. Further studies showed that the contribution of inhibition of dTMP or purine synthesis to cell death varied in different cell types. These data suggested that inhibition of one of these pathways individually might (at least in some cases) be therapeutically superior to the dual inhibition induced by MTX. Thus in rational design and in structure-based design studies, two new classes of antifolate enzyme inhibitors were elaborated-direct inhibitors of thymidylate synthase (TMPS) and direct inhibitors of one or both of the two folate-dependent enzymes of de novo purine synthesis. Members of each class included both classical and nonclassical types. After preclinical evaluation, several of these have moved into clinical trials. To date only one new TMPS inhibitor has successfully completed clinical trials and been approved for routine use; this drug, Tomudex (D1694, raltitrexed) is currently approved only in Europe and only for the treatment of colon cancer. This still represents a step forward for antifolates, however, since MTX is well-known to be ineffective in colon cancer; thus Tomudex extends the tumor range of antifolates. Antifolate development continues. Based on the immense body of knowledge now extant on antifolates, specific aspects of the mechanism of action have been the focus. Newer antifolates have been described that inhibit more than one pathway in folate metabolism, that have improved delivery, or that inhibit other targets in folate metabolism. These new analogs are in various stages of preclinical and clinical development.     

Angiogenesis inhibitors: current & future directions

The field of angiogenesis modulation is at a major crossroad. A tremendous advancement in basic science in this field is providing an excellent support for the concept, which is in contrast to a lack of strong clinical support to date. With regard to the large gap between experimental data and clinical data, the best model of human malignancy is in human cancer patients and the best model of human ocular angiogenesis-mediated disorders such as diabetic retinopathy (DR) and age related macular degeneration (AMD) is in human RD and AMD patients. Additionally, clinical outcomes should include benefit/risk ratios, hard end points (mortality and quality of life as opposed to increased microvascular density with pro-angiogenic agents or tumor size reduction with anti-angiogenesis agents) as well as cost effectiveness. Experimental models should be used to provide guidance, placebo effect, comparative data, and mechanistic understanding as opposed to being used for expected clinical efficacy. We also have to understand existing strategies and how angiogenesis modulation can add further value (i.e. not to replace existing strategy but rather improve efficacy/safety). Recent investigation defined numerous strategies in the modulation of angiogenesis. Those strategies are driven from haemostatic, fibrinolytic, cell adhesion molecules, extracellular matrix, growth factors, and other endogenous systems involved in the modulation of angiogenesis.     

Tocolysis: current controversies, future directions

The use of tocolytic agents for the treatment of preterm labor is not supported by the current evidence from placebo-controlled trials. Despite this, tocolytics continue to be widely used in clinical practice. Possible reasons for the lack of observed benefit include the hypothesis that suppression of labor may be harmful in some situations, along with a failure to appreciate the implications of the complex physiology of parturition. Importantly, however, it must be recognized that the quality of evidence addressing the question is poor, with studies significantly underpowered to detect changes in health outcomes. Where tocolysis is used, recent trends have favored agents with lower maternal side effect profiles, including calcium channel blockers and the oxytocin receptor antagonist atosiban. The use of cyclooxygenase-selective inhibitors of prostaglandin synthesis is currently being explored. Future directions in tocolytic research include the use of multiple agent therapies, along with the development of more selective treatments with low side effect profiles. Such agents include oxytocin receptor antagonists with more favorable pharmacological properties and prostaglandin F2alpha receptor antagonists. Future research into tocolytic therapies must focus on evaluating health outcomes from treatments rather than simply the ability to prolong pregnancy, and consequently the design of appropriate clinical studies needs careful consideration with respect to issues such as inclusion criteria, sample size and the selection of appropriate outcome measures.     

Antithrombotic therapies in primary angioplasty: rationale, results and future directions

Despite the improvement in outcome observed with primary angioplasty compared with thrombolysis, there is still room for improvement. Indeed, despite restoration of optimal epicardial flow in the vast majority of patients, suboptimal myocardial reperfusion is observed in a relatively large proportion. The aim of this article is to provide an up-to-date review of adjunctive antithrombotic therapy for primary angioplasty for ST-segment elevation myocardial infarction (STEMI).The HORIZONS trial has shown a significant reduction in mortality and major bleeding complications in patients treated with bivalirudin compared with those treated with glycoprotein (GP) IIb-IIIa inhibitors. Thus, bivalirudin may be considered as an alternative strategy to heparin plus GPIIb-IIIa inhibitors in primary angioplasty, especially in patients at high risk for bleeding complications. However, despite the negative results of the FINESSE trial, a large amount of evidence has been observed in favour of early administration of GPIIb-IIIa inhibitors, which should still be considered a reasonable strategy.Non-responsiveness to aspirin and clopidogrel is relatively common. However, future trials are needed to evaluate whether the routine assessment for non-responsiveness and a consequent change in therapy (to higher dosages of clopidogrel or a switch to another adenosine diphosphate [ADP]-receptor antagonist) may improve clinical outcome. Even though not yet demonstrated, it is conceivable that the greatest benefits of clopidogrel may come from early administration, and that this might be considered as part of a pharmacological facilitation strategy, together with early administration of GPIIb-IIIa inhibitors. As a result of better and faster inhibition of platelet aggregation, further benefits might be expected from the early administration of one of the new oral platelet ADP-receptor antagonists.As a consequence of the very low mortality currently achieved by primary angioplasty, additional endpoints, such as infarct size and myocardial perfusion, should be considered when exploring the potential benefits of adjunctive antithrombotic therapies in future randomized trials among patients undergoing mechanical revascularization for STEMI.