According to researchers at Weill Cornell Medical College in the Sept. 15 issue of the journal Cancer Research, taxne-based chemotherapy drugs are not well understood as they may be more powerful than many have believed.
Generally, it is believed that taxane chemotherapy (paclitaxel, docetaxel and cabazitaxel) just stop a cancer cell from dividing — but researchers at Weill Cornell believe that the taxane chemotherapies act more broadly and powerfully, especially against advanced prostate cancer.
According to Dr. Paraskevi Giannakakou, an associate professor of pharmacology in medicine and pharmacology and director of laboratory research for the Division of Hematology and Medical Oncology at Weill Cornell, “Taxanes are one of the best class of chemotherapy drugs that we can use to treat our cancer patients, but while they are effective against a wide range of tumors, they don’t work in all of them, and often patients become resistant…..However, our new understanding of the precise action of taxanes in a cancer cell may help us overcome drug insensitivity or acquired resistance to the drugs and design therapies that can be used in combination with them to improve cancer control.”
In the study, the researchers stress that investigators must shift their attention away from taxane’s function during cell division to the drugs’ effects on halting the everyday movement of proteins and protein-to-protein communication within cancer cells — and to understanding how and why a cancer cell can still survive.
Researchers do believe that when cancers become insensitive, or non-responsive to taxane treatments they do so by switching to an alternate form of “transportation” to move the proteins within cells in a way that does not depend on the cell’s skeletal structure, which is the target of taxane therapy.
In their study, the researchers showed that the androgen receptor (AR) (the vehicle that allows androgens to enter into and “feed” the prostate cancer) “moves” along microtubules to be transported to the prostate cancer cell’s nucleus. When a taxane binds microtubules, it stops AR from traveling, thus inhibiting its activity.
Taxane chemotherapy drugs such as paclitaxel, docetaxel and cabazitaxel work by binding the protein tubulin. Microtubules are the rope-like channels that provide both a skeletal structure to cells as well as provide “highways” along which molecules, such as proteins, RNA complexes and vesicles, can travel from one part of the cell to another and interact with each other.
“Microtubules are the highly dynamic network of wires within cells, and when taxanes are used, the network stops moving,” says Dr. Giannakakou. This is best observed when cancer cells attempt to divide, she says. “It is easy to see in the laboratory, that prostate cancer cells double every 30-48 hours, and taxane stops them from doing that, which pushes these cells to die. This leads everyone to think that this is exclusively how taxanes work — they stop cells from dividing.”
But Dr. Giannakakou and her research team point out in their new study that patients have significantly lower rates of cell division in their tumors than do cancer cells growing in the lab. In fact, cancer cells in prostate cancer patients only divide every 33-577 days, she says. “Thus, the therapeutic benefit of taxanes on microtubules depends on more than just stopping cell division.”
This research provides an insight into the role of taxanes on AR trafficking. This would explain the clinical activity taxanes in the treatment of prostate cancer while at the same time can help researchers better understand why individual patients respond differently to taxane therapy. Understanding and being able to modify the intra-cellular transport of proteins could help us extend the utility of taxane therapy.
This study was published inScience Today (September 17, 2012) and funded by grants from the National Institutes of Health, the National Cancer Institute’s Physical Sciences-Oncology Center at Cornell University, the Weill Cornell Clinical and Translational Science Center, a Creativity Award from the Prostate Cancer Foundation, and support from the Genitourinary Oncology Research Fund.
Joel T Nowak, M.A., M.S.W.