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New advances in models and strategies for developing anti-obesity drugs.

ABSTRACT: Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events.The authors review the strategies for designing new anti-obesity drugs by describing those currently in development. They describe their target, mechanism of action and developmental or regulatory status. Furthermore, they discuss the problem of weight regain following weight loss, and its relevance to the long-term success of anti-obesity pharmacotherapy.For weight management drugs to achieve the safety and efficacy required to be impactful, current studies are uncovering and characterizing new targets, including new signaling circuits and hormones regulating appetite and metabolism, and re-evaluating the role of pharmacotherapy in weight management. To avoid the safety failures of many past weight-loss drugs, the models and strategies covered in this article incorporate recent advances in knowledge and technology. We discuss the emergence of cGMP signaling as a potentially transformative target in weight management. Modulating cGMP signaling may represent an ideal goal for an anti-obesity pharmacotherapy, reflecting some of the major themes described in the present review: targeting pathways that are newly realized as relevant for weight management; promoting safety by re-purposing drugs that are safe, proven, and approved for clinical use; and having a synergistic effect on multiple, reinforcing pathways.

SUBMITTER: Kim GW

PROVIDER: S-EPMC4103795 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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New advances in models and strategies for developing anti-obesity drugs.

Kim Gilbert W GW Lin Jieru E JE Blomain Erik S ES Waldman Scott A SA

Expert opinion on drug discovery 20130429 6

<h4>Introduction</h4>Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events.<h4>Areas covered</h4>The ...[more]

PMID: 23621300

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Project description:BackgroundGastric cancer is the second most common cause of cancer-related deaths worldwide. There are large geographic variations in the incidence of these tumors, with 60% occurring in East Asia. For patients with resectable disease, surgery and perioperative treatment can be effective. For patients with advanced gastric cancer, chemotherapy regimens result in a median survival of 9-11 months. In general, the prognosis for advanced disease is poor and 5-year overall survival rates are around 15%. Combination therapies yield better survival rates, albeit with increased toxicity. Therefore, more effective and less toxic treatment regimens are needed.SummaryThe molecular aberrations that characterize the different subgroups of gastric cancer have been used as therapeutic targets. However, the heterogeneity and complexity of gastric cancers is a major challenge for the development of effective targeted therapies. This review examines the main molecular targets in the treatment of gastric cancer, namely the vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), hepatocyte growth factor (HGF)/c-Met, epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K)/Akt pathways.Key messageThe molecular aberrations characteristic of gastric cancer are being explored for the development of targeted therapies, including the VEGF, HER2, HGF/c-Met, EGFR and PI3K/Akt signaling pathways.Practical implicationsTrastuzumab, an antibody which targets HER2, is the first approved targeted therapy for the treatment of gastric cancer. However, trastuzumab is only effective in HER2-positive tumors (about 10-20% of all gastric cancers). Ramucirumab, which targets the VEGF receptor 2, has yielded benefits with respect to overall survival in a phase III trial and is an effective treatment for advanced gastric cancer with approval in second-line treatment. Apatinib and rilotumumab are another two promising new agents currently under development.

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New advances in models and strategies for developing anti-obesity drugs.

Publications

New advances in models and strategies for developing anti-obesity drugs.

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