Recent research has provided new insights into the action of taxanes on androgen-receptor trafficking, helping to explain the clinical activity of these agents in the treatment of prostate cancer and shedding more light on why a patient may not respond to such therapy.
Taxane chemotherapy (paclitaxel, docetaxel, and cabazitaxel), which is used against a range of tumors, is widely believed to have just one function: stopping a cancer cell from dividing, according to information from New York–Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College, in New York, New York, where Paraskevi Giannakakou and her colleagues carried out the new study. Giannakakou’s team found, however, that taxanes act much more powerfully and broadly, particularly against prostate cancer, as they reported in Cancer Research (2012;72:4611-4615).
Taxane chemotherapy works by binding tubulin, a protein that makes up microtubules. These rope-like channels provide a skeletal structure to cells while also serving as “highways” along which proteins, RNA complexes, vesicles, and other molecules can travel from one part of a cell to another and interact with one another.
Giannakakou’s group demonstrated that the androgen receptor, which is a driving force in the growth and metastasis of prostate cancer, is transported to the nucleus of a cell by moving along microtubules. When a taxane binds microtubules, the androgen receptor can no longer travel. “Microtubules are the highly dynamic network of wires within cells, and when taxanes are used, the network stops moving,” summarized Giannakakou in the New York–Presbyterian/Weill Cornell statement.
In the laboratory, prostate cancer cells double every 30 to 48 hours; taxane stops that process. “This leads everyone to think that this is exclusively how taxanes work—they stop cells from dividing,” commented Giannakakou.
However, she and her fellow investigators pointed out in their new study that in actual patients, prostate cancer cells divide only every 33 to 577 days, indicating that the therapeutic benefit of taxanes on microtubules depends on more than just stopping cell division.
“In the 20 years since Taxol [paclitaxel] was approved, hundreds of labs worldwide are trying to understand how taxanes work to stop cell division in cancer,” said Giannakakou. “However, we think they need to now take a fresh approach and look at what these drugs do during the normal life cycle of a cancer cell and target the newly revealed underlying mechanisms and modes of movement with novel therapies, in combination with taxane therapy, to provide lifesaving therapy for patients who don’t benefit from taxanes.”
For example, cancers that are insensitive to taxanes or have become resistant to these drugs may switch to alternate forms of “transportation” to shuttle proteins within cells in a way that does not depend on the cell’s skeletal structure, which is the target of taxane therapy.