Methods to predict, prevent and revert resistance to taxoid compounds
Inventors: Bruce Zetter, Sabarni Chatterjee
Categories: Diagnostic/Prognostic, Therapeutics
Relative improvement of paclitaxel sensitivity in vivo after repression of PHB1 or GST.
Nude mice were inoculated s.c. with 4 X 106 A549TR cells stably expressing (A) control, (B) PHB1. The animals were divided randomly into groups consisting of at least eight mice per group. Once the average tumor volume within each groupwas at least 120 mm 3, vehicle-control and paclitaxel (12 mg/kg) were administered for the times indicated.
Taxoid compounds such as paclitaxel (Taxol ®) and docetaxel (Taxotere ®) are widely used treatments for aggressive malignancies of the breast, lung, prostate and ovary. As with other traditional chemotherapeutic agents, resistance to taxoids is common and limits treatment success. Using a proteomics approach, Drs. Zetter and Chatterjee have found elevated levels of prohibitin, a mitochondrial chaperone protein known to regulate cell survival and growth, on the surface of paclitaxel-resistant lung cancer cells and uterine sarcoma cells versus parental cells. Moreover, knockdown of prohibitin in these paclitaxel-resistant cells sensitized them to drug treatment.
The discovery by Drs. Zetter and Chatterjee indicates that prohibitin could be used both as a new therapeutic target to delay and reverse resistance to taxoids, and as a biomarker for taxane resistance. Paclitaxel has been used extensively to treat lung, prostate, ovarian and breast cancers but drug resistance limits the clinical usefulness of this drug. For example, no objective response with taxane-based regiments is observed in 40-80% of women with metastatic breast cancer (primary resistance); all taxane responders eventually relapse after 6-12 months (secondary resistance).
Currently, patients who are or who become resistant to taxanes have limited treatment options and have a short life expectancy. As drug resistance poses a major limitation to the efficacy of taxanes, the discovery by Drs. Zetter and Chatterjee of prohibitin’s connection to drug resistance opens up a new avenue to modulate chemotherapeutic drug response and sensitize cancer cells to drug treatment. It is also possible that prohibitin could be used as a biomarker for selecting patients likely to respond to taxane therapy. In addition, proteins that inhibit prohibitin or mimic its action may be an effective strategy for modulating the response to paclitaxel or docetaxel.
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Key Publications: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2503-8. Epub 2010 Jan 25.