Pseudoprogression of Melanoma Brain Metastases.

PURPOSE OF REVIEW: Immune checkpoint inhibitors are increasingly being used to treat melanoma brain metastases. One potential complication of immune checkpoint inhibitors is a phenomenon called pseudoprogression, in which a tumor transiently increases in size due to lymphocyte infiltration. This article reviews the characteristics of pseudoprogression and their clinical implications. RECENT FINDINGS: Pseudoprogression can be challenging to differentiate from true progression noted clinically or radiographically, thereby complicating management decisions and potentially confusing patients and their families. The transient tumor enlargement can also cause symptoms that mimic true tumor progression. Because the use of immunotherapy on melanoma brain metastases is a relatively new treatment paradigm, there is limited evidence to guide clinical decision-making and prognostication related to pseudoprogression.

Screening for Recurrence and Secondary Cancers.

The population of adult cancer survivors is increasing over time and they are at risk of developing recurrent and secondary cancers, even years after completion of treatment. Post-treatment care of survivors is increasingly the responsibility of primary care providers. Surveillance for recurrence and screening for secondary malignancies related to treatment depend largely on the primary malignancy, treatment regimen, and presence of a hereditary cancer syndrome, such as a BRCA mutation. This article presents surveillance strategies for the most common malignancies.

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.

Discovery and in vivo evaluation of dual PI3Kß/δ inhibitors.

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.