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Expert opinion on therapeutic targets [journal]
- Comment on: EGFR mutational status in Brazilian patients with penile carcinoma. [JOURNAL ARTICLE]
- Expert Opin Ther Targets 2013 May 23.
The authors describe the results on EGFR molecular alterations of 29 Brazilian patients with penile carcinoma (PC). DNA extracted from frozen tumor tissue of all patients was submitted to direct sequencing of the four exons (18 - 21) responsible for the EGFR tyrosine-kinase activity. Corroborating the data by Di Lorenzo et al. published in Expert Opin Ther Targets, none of the sequenced tumor samples showed relevant alterations in the four studied exons of the EGFR gene.
- Non-glycemic effects of pioglitazone and incretin-based therapies. [JOURNAL ARTICLE]
- Expert Opin Ther Targets 2013 May 22.
Atherosclerosis and cardiovascular events are highly prevalent and represent the major cause of mortality in patients with type 2 diabetes. Therefore, there is significant interest in the non-glycemic properties of anti-diabetic agents, particularly on those that are effective on cardiovascular risk factors. Thiazolidinediones and incretin-based therapies (IBTs) represent some of the most recent treatment options approved for the management of type 2 diabetes; these agents have shown important glycemic effects, as well as a number of non-glycemic effects. The latter include those on body weight, inflammation, hypertension and dyslipidemia, thus impacting the different components of the metabolic syndrome. Pioglitazone has been shown to significantly reduce cardiovascular adverse outcomes, while preliminary data on IBTs are very encouraging as well. Although highlighting the non-glycemic effects of pioglitazone and incretin-based therapies is of potential significance, clinical practice and patient care must be based largely on evidence-based medicine. Therefore, definitive opinions will await additional data from ongoing studies evaluating the effects of both GLP-1 agonists and DPP-4 inhibitors on cardiovascular morbidity and mortality.
- Related articles. [Journal Article]
- Expert Opin Ther Targets 2013 Jun; 17(6):i.
- Targeting TGF-β signaling in cancer. [JOURNAL ARTICLE]
- Expert Opin Ther Targets 2013 May 7.
Introduction: The transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β pathway are crucial in developing TGF-β-based therapeutics for cancer. Areas covered: This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given. Expert opinion: Targeting the TGF-β pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-β and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-β in each specific tumor. Future studies are needed in order to find safer and more effective TGF-β-based drugs.
- Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma. [JOURNAL ARTICLE]
- Expert Opin Ther Targets 2013 May 7.
Introduction: Cyclic AMP (cAMP) promotes growth arrest and/or apoptosis of various types of lymphoma, in particular chronic lymphocytic leukemia (CLL). These responses have spurred the interest in developing agents that increase cAMP to treat such malignancies and to identify mechanisms of the responses. Areas covered: The murine T-lymphoma cell line S49, has provided an important, pioneering model to define mechanisms of cAMP-mediated lymphoid cell death. Studies with S49 cells demonstrated that cAMP, acting via protein kinase A (PKA), is pro-apoptotic through a mitochondria-dependent pathway and identified cAMP/PKA-regulated targets involved in apoptosis. Akin to such findings, cAMP promotes apoptosis via PKA of cells from patients with CLL. Analysis of mediators of cAMP accumulation and cAMP-promoted apoptosis in CLL cells has revealed approaches to increase cAMP and engage its pro-apoptotic action. Expert opinion: This 'pathway approach' targeted to cAMP has identified GPCR agonists/antagonists, AC activators (e.g., AC7), PDE inhibitors (e.g., PDE7B) and/or activators or inhibitors of downstream mediators (PKA and Epac, respectively), which might be utilized therapeutically in CLL. Therapy directed at such targets may prove to be clinically useful and may also provide a proof-of-principle of the utility of targeting cAMP signaling in other types of cancer.
- Adenosine signaling pathways as potential therapeutic targets in respiratory disease. [JOURNAL ARTICLE]
- Expert Opin Ther Targets 2013 May 4.
Introduction: Adenosine receptors (ARs) and their differential pattern of expression modulate a series of pleiotropic activities that are known to contribute to the control of inflammation, remodeling, and tissue repair. Consequently, pharmacological manipulation of adenosine signaling pathway is of great interest and is currently exploited as a therapeutic target for a number of respiratory diseases with several molecules with agonist and antagonist activities against known ARs being developed for the treatment of different conditions of the respiratory system. Areas covered: Herein, we will review the rational basis leading to the development of novel therapies for asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cystic fibrosis. Their most recent clinical development will be also discussed. Expert opinion: Advances in our understanding of the pathogenetic role of adenosine in respiratory diseases may be soon translated into effective treatment options. In consideration of the complex interplay driven by the different pattern of receptor distribution and/or affinity of the four known AR subtypes in specific cell types at different stages of the disease, it is likely that combination of selective antagonist/agonists for different AR subtypes will be required to obtain reasonable clinical efficacy. Alternatively, controlling the factors involved in driving adenosine concentrations in the tissue may be also of great significance.
- Conference report from the 2012 AHA scientific sessions in Los Angeles. [Journal Article]
- Expert Opin Ther Targets 2013 Jun; 17(6):733-7.
The 2012 Scientific Sessions of the American Heart Association was held on November 3 - 7 in Los Angels, California. It covered up-to-date research on both basic- and clinical-cardiovascular science. We describe the highlights of the meeting focusing on basic science and clinical cardiology. More specifically we will discuss new insights on arrhythmias, cardiac cell death/survival and clinical studies involving novel and unique treatment paradigms.
- Author's reply. [Comment, Letter]
- Expert Opin Ther Targets 2013 Apr; 17(4):474-5.
- Targeting testis-specific proteins to inhibit spermatogenesis: lesson from endocrine disrupting chemicals. [JOURNAL ARTICLE]
- Expert Opin Ther Targets 2013 Apr 22.
Introduction: Exposure to endocrine disrupting chemicals (EDCs) has recently been linked to declining fertility in men in both developed and developing countries. Since many EDCs possess intrinsic estrogenic or androgenic activities, thus, the gonad is one of the major targets of EDCs. Areas covered: For the past 2 decades, studies found in the literature regarding the disruptive effects of these EDCs on reproductive function in human males and also rodents were mostly focused on oxidative stress-induced germ cell apoptosis, disruption of steroidogenesis, abnormal sperm production and disruption of spermatogenesis in particular cell adhesion function and the blood-testis-barrier (BTB) function. Herein, we highlight recent findings in the field illustrating testis-specific proteins are also targets of EDCs. Expert opinion: This information should be helpful in developing better therapeutic approach to manage ECD-induced reproductive toxicity. This information is also helpful to identify potential targets for male contraceptive development.
- Novel therapeutic targets for nonalcoholic fatty liver disease. [JOURNAL ARTICLE]
- Expert Opin Ther Targets 2013 Apr 22.
Introduction: Nonalcoholic fatty liver disease (NAFLD) is a serious public health problem. It is now estimated to affect 30% of adults and about 10% of children in the U.S. Hispanics are disproportionably affected with not only higher rates of NAFLD but also more severe disease. Treatment options are currently limited. Areas covered: In this review, we will focus on a series of novel findings related to the pathobiology of liver damage in nonalcoholic steatohepatitis (NASH) that are attractive targets for development of novel therapeutic strategies for human NASH. In particular, we will discuss four different areas due to their novelty and growing importance including microparticles, the inflammasomes, gut-liver axis and dietary lipids. Expert opinion: There is an urgent need to develop novel safe and effective therapies for the growing NAFLD epidemic. The data discussed in this article provide strong rational to think out of the box when considering novel therapeutic targets for patients with NAFLD.