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Children's Hospital Boston Researchers ID Protein That May Explain Paclitaxel Resistance

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This story originally ran on Feb. 1.

By Tony Fong

Researchers from Children's Hospital Boston have used a proteomics approach to identify a protein that may play a key role in determining why some patients fail to respond to one of the most successful cancer treatments in history.

Described in a study published Jan. 25 in the online edition of the Proceedings of the National Academy of Sciences, the findings could lead to new strategies in treating patients who show an initial resistance to the drug, paclitaxel, or eventually develop a resistance to it.

The researchers are also working to develop the protein, prohibitin1, as a biomarker for paclitaxel resistance for clinical use.

Paclitaxel belongs to a group of drugs called taxanes and is the generic name for Taxol, sold by Bristol-Myers Squibb. Though sales of the Taxol peaked at $1.6 billion a decade ago and have declined since going off patent, it and its generic version remain one of the world's most successful cancer drugs.

And, according to the authors of the study, paclitaxel and other taxanes are being used at an increasing rate to treat patients with cancers that have progressed beyond the initial tumor stage.

A mitotic inhibitor, paclitaxel is used primarily for the treatment of lung, ovarian, breast, and head and neck cancers. It also is used to treat advanced forms of Kaposi's sarcoma and to prevent restenosis.

In their study, when the researchers silenced prohibitin1 in drug-resistance tumors, they observed improved sensitivity to paclitaxel, suggesting that the protein is "a mediator of paclitaxel resistance" which may be a "potential target for therapeutic strategies for the treatment of drug-resistant tumors," they wrote in the paper.

Moreover, the researchers observed that rather than an overall increase in the total level of prohibitin1, it was an overexpression of the protein on the cell surface that resulted in paclitaxel resistance, suggesting that the "intracellular distribution" of prohibitin1 may "be more relevant to the resistant phenotype" than absolute levels of the protein in the cell.

To be sure, the results from the study are preliminary, and it remains unclear how prohibitin1 may contribute to paclitaxel resistance. In an interview, Bruce Zetter, the corresponding author on the study and a professor of cancer biology at Harvard Medical School, acknowledged that it also has not been unequivocally determined that an upregulation in prohibitin1 is the actual cause of paclitaxel resistance, and not the byproduct of resistance.

Prohibitins are highly conserved proteins found in a wide array of organisms, from yeast to humans. Prohibitin1 is "ubiquitously expressed in all tissues tested to date and has been shown to have significant effects on cell senescence, development, and tumor suppression," the authors wrote.

While it is well known that prohibitin1 moves around different cellular compartments, including the mitochondria, nucleus and cytoplasm, a correlation between paclitaxel resistance and site specificity had not been previously reported.

The scientists came across their findings based on a "blind proteomics" study begun in 2003 using 2D gel electrophoresis coupled with mass spectrometry to discover and identify proteins whose expression levels correlated with paclitaxel resistance, Zetter told ProteoMonitor.

Initially, they came up with a list of more than 50 proteins, but honed in on prohibitin1 for further research because it consistently was overexpressed in the microsomal fractions of the two paclitaxel-resistant cell lines the researchers studied.

Because Zetter and his colleagues were unable to see all the proteins from the cell on a single gel, they decided to use membrane cell fractions. They observed that prohibitin1 was upregulated in the cell fractions and "assumed … that that just meant that it was upregulated all over the cell," Zetter said.

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But when they looked at the whole-cell levels of prohibitin1, that turned out not to be the case. "So what we actually found was that the correlation with taxane resistance in prohibitin was not an increase in the amount of prohibitin but a shuttling of prohibitin from one part of the cell to the other," he said.

"The one thing that this study highlights is the importance of looking at cellular localization and being aware that when you're using cell fractions that you might be seeing things that are unique to those fractions and not just representative of what's going on in the whole cell," he added.

Exactly why prohibitin1 overexpression on the cell surface would lead to drug resistance is unclear, but other studies have shown that the protein plays an important role in regulating several cell functions, including increasing evidence that prohibitin1 may have an apoptotic function within the cell.

Zetter and his colleagues surmise that this may explain how the protein causes a cell to become drug resistant.

In the PNAS article, the authors wrote that prohibitin1 expression correlates with the "initial events of apoptosis, and that transient or stable overexpression of prohibitin1 can protect cells from apoptosis." Zetter said that getting at the mechanisms behind prohibitin1's ability to render a cell resistant to paclitaxel will be the subject of future studies by his group.

If the overexpression of prohibitin1 on the cell surface is, indeed, the cause of paclitaxel resistance, it could lead to new therapeutic strategies, such as targeting drugs to the tumor cells, "so localization of the tumor cells can be done both to bring drugs [to the cancer cells] and for imaging and detection," Zetter said.

Researchers at the MD Anderson Cancer Center have identified CKGGRAKDC, a peptide that binds to prohibitin1 and has been previously used to target non-tumor cells that express prohibitin1, and "we think we could use that peptide to target drugs to taxane-resistant tumor cells," Zetter said.

He and his colleagues emphasize, however, that prohibitin1 by itself does not completely explain paclitaxel resistance, and other proteins such as GSTπ, a protein whose role in "multi-drug resistance" is well established, probably need to be repressed, as well.

"We do not propose that prohibitin1 is the only modulator of taxane sensitivity in human cancers as other mediators have been reported including increased levels of GSTπ, tubulin mutations, and alterations in the [multidrug resistance] pathway," Zetter and his co-authors wrote.

In addition to studying the mechanism behind prohibitin1 and paclitaxel resistance, they plan on researching the effect of silencing prohibitin1 and GSTπ concurrently on reducing paclitaxel resistance, as well as drugs that may target prohibitin1, Zetter said.

The researchers are also in the beginning stages of a prospective study using tissue and blood samples from two groups of patients — those who respond to paclitaxel and those who are resistant to the drug — to investigate differences in their prohibitin levels.

If differences are detected, it would further suggest prohibitin1 could be a biomarker for paclitaxel resistance.

"What we're going to see is whether people who are inherently resistant to taxane at the time that they're diagnosed with metastatic cancer are expressing cell-surface prohibitin," Zetter said. "Or [whether] people who later develop taxane resistance after being treated with it … are, during the course of their treatment, expressing more cell-surface prohibitin."

The research, he added, has received interest from a number of drug companies, though he did not name them.

Their findings, Zetter and his colleagues said, may also have implications beyond taxanes. The translocation of prohibitin1 to the cell surface appears to lead to resistance to other oncology drugs such as docetaxel, doxorubicin, and etoposide, they said, and silencing the protein resulted in greater sensitivity of drug-resistance cell lines to those therapies.

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