AACR Journal Articles Recognized by Faculty of 1000
More than 200 articles from AACR journals have been ranked as "Recommended," "Must Read," or "Exceptional" by the Faculty of 1000 literature rating site. Two of the most highly rated articles are highlighted below:
A Selective PRL Phosphatase Inhibitor Suppresses Tumor Cell Anchorage-Independent Growth by a Novel Mechanism Involving p130Cas Cleavage
Sherif Daouti et al. Cancer Res 2008;68:1162-1169
F1000 Rating: Exceptional
The regulation of phosphorylation through kinases and phosphatases is an important mode of signal transduction. The phosphatase of regenerating liver (PRL) family of phosphatases has three members, PRL-1, PRL-2, and PRL-3, and can be classified as a subgroup of the VH1-like dual-specificity phosphatases. The expression pattern of each member varies in both normal and tumor tissues, suggesting that although the three PRLs are highly homologous, they have distinct cellular functions. PRLs have been shown to be involved in cell cycle control, proliferation, and transformation. Recent evidence also suggests a causative role in tumor metastasis.
In this article in Cancer Research, Daouti and colleagues identify a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which selectively inhibits all three PRL members but not other phosphatases in vitro. Inhibition of PRLs by thienopyridone results in the inhibition of tumor cell anchorage-independent growth and the induction of anoikis (a type of apoptosis) through the inhibition of p130Cas, a protein involved in cell survival, proliferation, and migration. Other anticancer agents such as etoposide and cisplatin are known to induce p130Cas cleavage and apoptosis through p53 pathway activation; however, unlike these agents, the effect of thienopyridone appears to be p53-independent. Furthermore, thienopyridone also inhibits mitogen-activated endothelial cell migration.
This is the first report of a potent selective PRL inhibitor that suppresses tumor cell growth by a novel mechanism involving p130Cas cleavage, revealing new insight into the role of PRL in tumor progression and validating PRL as a novel therapeutic target.
Polymeric Tubulysin-Peptide Nanoparticles with Potent Antitumor Activity
Thomas Schluep et al. Clin Cancer Res 2009;15:181-189
F1000 Rating: Must Read
Microtubules are dynamic structures involved in many critical cellular processes, including the organization of cell structure, cell division, and intracellular transport. Drugs interfering with microtubule function can be classified as microtubule destabilizers (e.g., vinca alkaloids, colchicines) or stabilizers such as taxanes. Agents interfering with microtubule structure and function have been successful in the clinic. However, toxicity and resistance remain important clinical problems. Tubulysin peptides are a novel class of tubulin-targeted agents isolated from strains of myxobacteria and act as antimitotic agents through microtubule depolymerization. Tubulysins have been shown to have high potency against a variety of tumor cell types, including cells with a multidrug resistant phenotype. Unfortunately, high toxicity and low solubility limit their clinical use.
The use of macromolecular carriers and nanoparticles is based on their ability to change the pharmacokinetics and pharmacodynamics of chemotherapeutics. Schluep and colleagues describe a strategy for conjugating tubulysin A to a polymeric derivative of beta-cyclodextrin (CDP-TubA) that increases the solubility and biodistribution of the parent drug. A disulfide linker was chosen due to its high plasma stability and selective release characteristics. They report that the maximum tolerated dose of CDP-TubA was 100-fold higher than the parent TubA and had equal or superior efficacy compared with vinblastine and paclitaxel in human colorectal and non-small cell lung carcinoma mouse xenograft models.
This article describes a novel nanoparticle delivery system that shows promise for improving the therapeutic index of tubulysins and promotes the continued development of other novel drug delivery systems to improve the safety and efficacy of anticancer agents.