Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia.

Most cancer cells have high need for nicotinamide adenine dinucleotide (NAD) to sustain their survival. This led to the development of inhibitors of nicotinamide (NAM) phosphoribosyltransferase (NAMPT), the rate-limiting NAD biosynthesis enzyme from NAM. Such inhibitors kill cancer cells in preclinical studies but failed in clinical ones.

Reactive oxygen/nitrogen species contribute substantially to the antileukemia effect of APO866, a NAD lowering agent.

APO866 is a small molecule drug that specifically inhibits nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis from the natural precursor nicotinamide. Although, the antitumor activity of APO866 on various types of cancer models has been reported, information regarding mechanisms by which APO866 exerts its cytotoxic effects is not well defined. Here we show that APO866 induces a strong, time-dependent increase in highly reactive ROS, nitric oxide, cytosolic/mitochondrial superoxide anions and hydrogen peroxide.

MEK Inhibition Induces Therapeutic Iodine Uptake in a Murine Model of Anaplastic Thyroid Cancer.

Anaplastic thyroid carcinoma (ATC) is refractory to radioiodine therapy in part because of impaired iodine metabolism. We targeted the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3'K) pathways with the intent to induce radioiodine uptake for radioiodine treatment of ATC. Human ATC cells were used to evaluate the ability of pharmacologic inhibition of the mitogen-activated protein kinase and PI3'K pathways to induce radioiodine uptake.

PIK3CA-induced paradoxical ERK activation results in resistance to BRAF specific inhibitors in BRAF PIK3CA double mutant thyroid tumors.

Thyroid carcinomas are the most prevalent endocrine cancers. The BRAF mutation is found in 40% of the papillary type and 25% of the anaplastic type. BRAF inhibitors have shown great success in melanoma but, they have been, to date, less successful in thyroid cancer.

Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo.

Anaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3'-kinase inhibitor in pre-clinical models.