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Tumor-targeting compound points the way to new personalized cancer treatments
Date:12/1/2011

"fish out" entire networks of abnormal proteins in tumor cells in an unbiased fashion, which has not been possible up until now. Importantly, many or even most of the genes encoding proteins that maintain tumor cell survival are not mutated in tumors. Hence genetic screening would not be able to detect these networks, Dr. Melnick says. "The value of this method is that it's the first time you can go and probe the functional proteome, or the whole set of proteins that are important to maintaining the tumor." This strategy opens up new avenues for understanding in greater detail the molecular basis of cancer and identifying novel drug targets.

For example, in chronic myeloid leukemia cells, the PU-H71 drug preferentially binds to the Hsp90 complex containing Bcr-Abl, an abnormal protein that is overactive in these cells, rather than to Hsp90 associated with the normal protein Abl. Similar findings were observed in other tumor types, with PU-H71-Hsp90 complexes protecting only the tumor-associated proteins.

The researchers then used PU-H71 and proteomic analyses to identify all of the abnormal proteins bound to Hsp90 in chronic myeloid leukemia cells and built networks of these proteins using bioinformatics analyses. They found that these proteins are part of signaling pathways involved in cell death, growth and division. Bcr-Abl is known to use many of these pathways to propagate abnormal signaling in this type of cancer cell. The researchers experimentally confirmed that proteins from these pathways are crucial for cancer cell growth, division and survival, suggesting that their approach can be used to accurately identify Bcr-Abl-related protein networks. Moreover, the same experiments identified many proteins not previously known to drive chronic myeloid leukemia cells. One example of such a protein was CARM1, a regulator of gene expression, which the investigators showed maintains survival of these tumor cells.

Importantly, this PU-H71
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Contact: John Rodgers
jdr2001@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
Source:Eurekalert

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