Research 2007 Research Projects 2007 Research Yosef Yarden | 2007 Research Yosef Yarden |
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Rational design of ErbB-3 based therapeutics for the treatment of prostate cancer
Prof Yarden's team at the Weizmann Institute of Science The majority of prostate cancer patients, treated by the mainstay androgen ablation therapy, will eventually fail this therapy and develop androgen-independent prostate cancer (AIPC), to which no effective treatment exists. Finding novel targets for therapeutic intervention is thus a need of an utmost importance.
Current paradigms for treatment of hyper-proliferative diseases, combining chemotherapy and state of the art specific inhibitors to target cell-membrane-anchored receptors, have proven to be fruitful. The most studied receptors in this respect are the ErbB/HER family of receptors, comprised of four members, namely EGFR/ErbB-1, HER2/ErbB-2, ErbB-3 and ErbB-4. The number of ErbB-targeting cancer therapeutics is second to none, with several drugs commercially available world wide. Hence, ErbB-intercepting drugs are considered a hallmark example of the bench-to-clinic pathway of drug development and approval.
How can this be extrapolated for the benefit of those suffering from prostate cancer? Our current knowledge indicates that in cancer, ErbB-2 and ErbB-3 are associated with drug resistance and decreased patient survival. More specifically, expression of ErbB-2 in prostate cancer has been associated with progression to AIPC and with shortened survival, and it is considered to be an important factor for disease progression. However, since prostate cancer is not characterized by elevated levels of ErbB-2, it is refractory to current anti-ErbB-2 agents (e.g., Trastuzumab/Herceptin™) aimed to target tumours cells with considerable elevation of ErbB-2 levels.
Lessons from breast cancer cells, however, indicate that ErbB-3 functions as an indispensable partner of ErbB-2, and that these cells do not proliferate once ErbB-3 is blocked. Can ErbB-3 serve as the long-sought target to treat prostate cancer? Considering the fact that the vast majority of prostate cancer specimens show ErbB-3 expression indicates that it may indeed serve as a novel platform for the discovery and development of new and effective drugs.
It is noteworthy that to date, in contrast to the ever-growing arsenal of ErbB-1 and ErbB-2 targeting agents, no ErbB-3-based therapeutics exist, and only now it’s potential as a target is being explored with promising preliminary results.
We envision that blocking ErbB-3, the indispensable partner of ErbB-2, should confer clinical benefits in AIPC. Accordingly, we will study the role of ErbB-3 in prostate cancer and develop molecular tools to intercept it, as well as interfere with its association with ErbB-2. This may confer clinical benefits, either directly or by enhancing the activity of chemotherapeutic agents, an effect which has already been associated with other anti-ErbB drugs.
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