HIGHLIGHTS

PROGNOSIS Wouldn’t we all like the power to pre- good-prognosis groups. The progno- dict the future? For breast cancer sis signature assigned 115 tumours to patients, the accuracy with which the the good-prognosis category and 180 progress of their disease can be to the poor-prognosis category. There Prediction power mapped can make the difference was a strong correlation between the between whether they are overtreated probability of remaining free of or undertreated and can also affect metastases and of surviving, and the predictions of their survival. Current good-prognosis signature. criteria used for prognosis in breast Interestingly, the prognostic profile cancer include age, the size of the was independent of lymph-node sta- tumour, axillary-node status, histo- tus, but was also highly predictive of logical type, pathological grade and the risk of distant metastases in the hormone-receptor status. van de lymph-node-positive subgroup. This Vijver and colleagues now add a could be useful for identifying patients -expression profile to the list of with lymph-node-positive disease useful prognostic indicators, as they who have an unexpectedly good prog- report in the 19 December issue of nosis and indicates that lymph-node New England Journal of Medicine. metastases develop independently of The authors used a 70-gene prog- distant metastases. nosis profile that was first described The gene-expression profile was by the same research team earlier in also predictive of overall survival — 2002 to classify 295 patients with pri- 94.5% of patients in the good-prog- mary breast cancer — which nosis group survived for 10 years included 61 of the 78 patients, all compared with 54.6% in the poor- lymph-node negative, from the first prognosis group. The hazard ratio study — into poor-prognosis and for distant metastases in the poor-

THERAPEUTICS Mass destruction

The pathway is involved in So, how toxic are these toxins? When just the size of the tumours by more than 85%, physiological and pathological tissue 2 µg of the native toxin, PrAg, was and completely eradicated all remodelling processes, including cancer given to mice with FB59, extreme toxicity was fibrosarcomas in 67% of mice after only invasion and metastasis. Both urokinase observed — widespread organ damage and one treatment. No increase in apoptosis (uPA) and its death occurred within a few hours. By was seen, indicating that the toxin triggered receptor (uPAR) are overexpressed in contrast, up to 30 µg of the modified toxin, necrotic cell death. nearly all human cancers, but are only PrAg-U2, resulted in no toxicity. Next, the The engineered toxin suppressed tumour expressed at very low levels in normal authors used mice with complete deficiencies growth and destroyed established tumours tissues, except as a rapid response to tissue in key components of the urokinase pathway with no toxicity to normal tissues. Because injury. Bugge, Leppla and colleagues have — including plasminogen (Plg), which is uPA is overexpressed on epithelial, exploited this tumour-associated uPA activated by urokinase — to show that the mesenchymal and haematopoietic tumours, system to activate a targeted immunotoxin, uPA system is crucial in activation of PrAg- this strategy has promise as a broad-acting based on anthrax, which causes potent U2. Whereas wild-type mice died when given antitumour therapy. The authors suggest destruction of tumours. 40−200 µg PrAg-U2 plus FP59, uPA–/–, that modifications could be made to is secreted by bacteria as uPAR–/– and Plg–/– mice remained healthy, increase specificity or to use other three antigens and is activated when the and mice null for uPA inhibitor were toxin instead of anthrax. The protective antigen (PrAg) binds to a hypersensitive to the toxin. This shows that therapeutic index of immunotoxins already ubiquitously expressed cell-surface receptor the components of the uPA pathway are in clinical use might also be improved by (tumour endothelium marker 8), is cleaved crucial to the activation of PrAg-U2 in vivo. adapting this strategy. by furin and forms a complex The authors now knew that PrAg-U2 was Ezzie Hutchinson with the two other antigens. Binding of the specifically activated by the tumour- active part of the complex with fusion associated urokinase system, so they next References and links ORIGINAL RESEARCH PAPER Liu, S. et al. Potent 59 (FP59) kills the cell by inhibiting tested the tumoricidal activity of the toxin antitumour activity of a urokinase-activated engineered translation elongation factor 2. The authors in mice bearing established fibrosarcomas, anthrax toxin. Proc. Natl Acad. Sci. 13 Jan 2003 modified PrAg so that it is cleaved by uPA melano-mas and lung carcinomas — (doi:10.1073/pnas.0236849100) WEB SITE and not by furin, so that only cancer cells tumours that have a poor response to Thomas Bugge’s lab: would be targeted. conventional treatment. PrAg-U2 reduced http://wwwdir.nidcr.nih.gov/dirweb/opcb/ptru.asp

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