Methods to predict, prevent and revert resistance to taxoid compounds
Inventors: Bruce Zetter, Sabarni Chatterjee
Categories: Diagnostic/Prognostic, Therapeutics
Taxoid compounds such as paclitaxel (Taxol®) and docetaxel (Taxotere®) are widely used treatments for aggressive malignancies of the breast, lung, prostate and ovaries. 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 with such agents as etoposide, doxyrubicin, and cisplatin.
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).
• Prohibitin as a new therapeutic target to delay and reverse resistance to taxoids and as a biomarker for taxane resistance.
• Prohibitin's involvement in drug resistance opens up a new avenue to modulate chemotherapeutic drug response and sensitize cancer cells to drug treatment
• 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
• The presence of prohibitin on the cell surface of taxane-resistant cancer cells could be used as a means to specifically target and deliver alternative, non-taxane based chemotherapeutic agents
• Collaboration and licensing opportunities available
Key Publications: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2503-8. Epub 2010 Jan 25.