Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less
The Kelch‐like ECH‐associated protein 1/nuclear factor erythroid‐derived 2‐like 2 (KEAP1‐NRF2) system is a pivotal defense mechanism against oxidative and electrophilic stress. Although transient NRF2 Show more
The Kelch‐like ECH‐associated protein 1/nuclear factor erythroid‐derived 2‐like 2 (KEAP1‐NRF2) system is a pivotal defense mechanism against oxidative and electrophilic stress. Although transient NRF2 activation in response to stress is beneficial for health, persistent NRF2 activation in cancer cells has deleterious effects on cancer‐bearing hosts by conferring therapeutic resistance and aggressive tumorigenic activity on cancer cells. Because NRF2 increases the antioxidant and detoxification capability of cancer cells, persistently high levels of NRF2 activity enhance therapeutic resistance of cancer cells. NRF2 also drives metabolic reprogramming to establish cellular metabolic processes that are advantageous for cell proliferation in cooperation with other oncogenic pathways. As a result of these advantages, cancer cells with persistent activation of NRF2 often develop “NRF2 addiction” and show malignant phenotypes leading to poor prognoses in cancer patients. Inhibition of NRF2 is a promising therapeutic approach for NRF2‐addicted cancers and NRF2 inhibitors are being actively developed. However, giving systemic NRF2 inhibitors might have undesirable effects on cancer‐bearing hosts, considering the central roles of NRF2 in cytoprotection. To avoid these side‐effects, new therapeutic targets besides NRF2 for NRF2‐addicted cancers have been actively explored. This review introduces recent studies describing the development and characterization of NRF2‐addicted cancers, as well as their potential therapeutic targets. Expected advances in diagnostic and therapeutic interventions for NRF2‐addicted cancers are also discussed. Show less