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
Simple Summary The gene-regulatory factors ATF5, CEBPB and CEBPD promote survival, growth, metastasis and treatment resistance of a range of cancer cell types. Presently, no drugs target all three at Show more
Simple Summary The gene-regulatory factors ATF5, CEBPB and CEBPD promote survival, growth, metastasis and treatment resistance of a range of cancer cell types. Presently, no drugs target all three at once. Here, with the aim of treating cancers, we designed novel cell-penetrating peptides that interact with and inactivate all three. The peptides Bpep and Dpep kill a range of cancer cell types in culture and in animals. In animals with tumors, they also significantly increase survival time. In contrast, they do not affect survival of non-cancer cells and have no apparent side effects in animals. The peptides work in combination with other anti-cancer treatments. Mechanism studies of how the peptides kill cancer cells indicate a decrease in survival proteins and increase in death proteins. These studies support the potential of Bpep and Dpep as novel, safe agents for the treatment of a variety of cancer types, both as mono- and combination therapies. Abstract Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we characterized the in vitro and in vivo anti-cancer efficacy of novel synthetic cell-penetrating peptides (Bpep and Dpep) designed to interfere with the formation of active leucine-zipper-based dimers by CEBPB and CEBPD, transcription factors implicated in multiple malignancies. Both peptides similarly promoted apoptosis of multiple tumor lines of varying origins, without such effects on non-transformed cells. Combined with other treatments (radiation, Taxol, chloroquine, doxorubicin), the peptides acted additively to synergistically and were fully active on Taxol-resistant cells. The peptides suppressed expression of known direct CEBPB/CEBPD targets IL6 , IL8 and asparagine synthetase ( ASNS ), supporting their inhibition of transcriptional activation. Mechanisms by which the peptides trigger apoptosis included depletion of pro-survival survivin and a required elevation of pro-apoptotic BMF. Bpep and Dpep significantly slowed tumor growth in mouse models without evident side effects. Dpep significantly prolonged survival in xenograft models. These findings indicate the efficacy and potential of Bpep and Dpep as novel agents to treat a variety of cancers as mono- or combination therapies. Show less
BACKGROUND: Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic ac Show more
BACKGROUND: Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic acidurias. In the past decade, the same tricarboxylic acid cycle metabolites have been implicated and studied in cancer. The accumulation of these metabolites in certain cancers not only serves as a biomarker but also directly contributes to cellular transformation, therefore earning them the designation of oncometabolites.
CONTENT: D-2-hydroxyglutarate, L-2-hydroxyglutarate, succinate, and fumarate are the currently recognized oncometabolites. They are structurally similar and share metabolic proximity in the tricarboxylic acid cycle. As a result, they promote tumorigenesis in cancer cells through similar mechanisms. This review summarizes the currently understood common and distinct biological features of these compounds. In addition, we will review the current laboratory methodologies that can be used to quantify these metabolites and their downstream targets.
SUMMARY: Oncometabolites play an important role in cancer biology. The metabolic pathways that lead to the production of oncometabolites and the downstream signaling pathways that are activated by oncometabolites represent potential therapeutic targets. Clinical laboratories have a critical role to play in the management of oncometabolite-associated cancers through development and validation of sensitive and specific assays that measure oncometabolites and their downstream effectors. These assays can be used as screening tools and for follow-up to measure response to treatment, as well as to detect minimal residual disease and recurrence. Show less