Obesity is a growing pandemic and related health and economic costs are staggering. Pharmacotherapy partnered with lifestyle modifications form the core of current strategies to reduce the burden of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing anti-obesity therapies, including targets, mechanisms, and developmental status are highlighted. Progress in this field is underscored by Belviq® (lorcaserin) and Qsymia® (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic management weight in obese patients. On the horizon, novel insights in metabolism and energy homeostasis reveal cGMP signaling circuits as emerging targets for anti-obesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off-the-shelf approaches leveraging existing approved drugs that modulate cGMP levels for the management of obesity.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remain unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.

Obesity is a world-wide pandemic and its incidence is on the rise along with associated comorbidities. Currently, there are few effective therapies to combat obesity. The use of lifestyle modification therapy, namely, improvements in diet and exercise, is preferable over bariatric surgery or pharmacotherapy due to surgical risks and issues with drug efficacy and safety. Although they are initially successful in producing weight loss, such lifestyle intervention strategies are generally unsuccessful in achieving long-term weight maintenance, with the vast majority of obese patients regaining their lost weight during followup. Recently, various compensatory mechanisms have been elucidated by which the body may oppose new weight loss, and this compensation may result in weight regain back to the obese baseline. The present review summarizes the available evidence on these compensatory mechanisms, with a focus on weight loss-induced changes in energy expenditure, neuroendocrine pathways, nutrient metabolism, and gut physiology. These findings have added a major focus to the field of antiobesity research. In addition to investigating pathways that induce weight loss, the present work also focuses on pathways that may instead prevent weight regain. Such strategies will be necessary for improving long-term weight loss maintenance and outcomes for patients who struggle with obesity.

SUMMARY The RAF inhibitor vemurafenib achieves remarkable clinical responses in mutant BRAF melanoma patients. However, vemurafenib is burdened by acquired drug resistance and by the side effects associated with its paradoxical activation of the ERK1/2 pathway in wild-type BRAF cells. This paradoxical effect has driven the development of a new class of RAF inhibitors. Here, we tested one of these selective, non-paradox-inducing RAF inhibitors termed paradox-breaker-04 (PB04) or PLX7904. Consistent with its design, PB04 is able to efficiently inhibit activation of ERK1/2 in mutant BRAF melanoma cells but does not hyperactivate ERK1/2 in mutant RAS-expressing cells. Importantly, PB04 inhibited ERK1/2 phosphorylation in mutant BRAF melanoma cells with acquired resistance to vemurafenib/PLX4720 that is mediated by a secondary mutation in NRAS. Consistent with ERK1/2 re-activation driving the re-acquisition of malignant properties, PB04 promoted apoptosis and inhibited entry into S phase and anchorage-independent growth in mutant N-RAS mediated vemurafenib-resistant cells. These data indicate that paradox-breaker RAF inhibitors may be clinically effective as a second line option in a cohort of acquired vemurafenib-resistant patients.