Highlights of This Issue

Abstract

Deregulation of the transcription factor c-Myb has been implicated in the development of leukemia and several other types of cancer, including breast and colon cancer, adenoid cystic carcinoma, and certain types of glioma. By searching for compounds that disrupt the interaction of Myb with the coactivator p300, Uttarkar and colleagues have identified Naphthol AS-E phosphate as the first small molecule inhibitor of c-Myb. This work highlights a strategy for the generation of therapeutic Myb inhibitors, which may have potential for the treatment of leukemia and possibly other tumors driven by deregulated Myb.The helix-loop-helix transcription factor c-Myc is a powerful oncoprotein widely expressed in human cancer and has long been considered “undruggable.” The best available small molecule inhibitors inhibit dimerization with c-Myc's binding partner Max, but suffer from poor bioavailability that limits their use in vivo. Here, Soodgupta, Pan, and colleagues demonstrate that a lipid-conjugated prodrug based on a small molecule Myc inhibitor is effective and can be incorporated into nanoparticles targeted to integrin surface proteins expressed on multiple myeloma cells. Anti-Myc nanoparticles prolong the survival of mice with disseminated myeloma, suggesting that this approach may be clinically applicable.Focal adhesion kinase (FAK) overexpression portends a poor prognosis and decreased overall survival in many malignancies. PTEN, frequently mutated in uterine cancer, dephosphorylates FAK. Here, Thanapprapasr, Previs, and colleagues demonstrated that PTEN-mutated cells were more sensitive to FAK inhibition and combination chemotherapy than wild-type PTEN cells in vitro and in vivo. In a cohort of patients, FAK and pFAKY397 expression was correlated with poor overall survival, and PTEN levels were inversely related to pFAKY397 expression. These findings demonstrate that PTEN-mutated uterine cancers are more sensitive to FAK inhibition, and PTEN represents a potential biomarker for further clinical development.Quiescent cancer cells, residing in hypoxic and nutrient-deprived parenchyma of solid tumors, pose a major obstacle for successful drug treatment. In order to identify compounds targeting this cell population, Senkowski and colleagues performed a high-throughput screening for drugs selectively toxic to quiescent cancer spheroids. Out of 1,600 compounds, the five most 3D selective were all inhibitors of mitochondrial respiration. Of these, a FDA-approved anthelmintic drug, nitazoxanide, produced strong in vivo tumor growth inhibition when combined with the standard chemotherapeutic agent irinotecan. This study identified nitazoxanide, a drug with minor side effects and good oral bioavailability, as a promising candidate for drug repurposing against colorectal cancer.