Paclitaxel, O Taxol, is a well-known drug in the oncology field: only about half of breast cancer patients treated with the drug see their tumors shrink or disappear and doctors and researchers have no way of knowing which patients will benefit.
However, this problem could finally be solved thanks to the research led by the professor of cellular and regenerative biology of theUniversity of Wisconsin-Madison, Beth Weaver. In fact, the scientist, together with her team, carried out an analysis of the patients and discovered the key to breast cancers that makes them vulnerable or resistant to treatment with paclitaxel.
It studio was published in the scientific journal Science Translational Medicine
Paclitaxel: here’s how to properly exploit it
“It’s a huge problem“, Said Weaver, member of theYOUR Carbone Cancer Center: “Almost half of the patients who are given Paclitaxel may be subject to some rather important side effects without any therapeutic benefit ”.
The key to discovery is called chromosomal instability, found in about half of breast cancers and caused by errors that occur when cells divide improperly.
Almost all cells in the body divide. This is how organisms grow and adapt. During that process, called mitosis, the genetic material of the original cell, in the form of chromosomes, is equally distributed or “segregated” between two identical daughter cells. When this does not go well, the distribution of chromosomes becomes unbalanced or “disrupted” and each daughter cell contains an incorrect amount of genetic material. This is a hallmark of cancer.
Low rates of mis-segregation, called chromosomal instability, can encourage cells to start dividing out of control and causing tumors. However, if this mis-segregation is extreme, it results in cell death.
The researchers found that patients with tumors showing high levels of chromosomal instability were more sensitive to paclitaxel and had better tumor suppression, which means it could be the elusive predictor of paclitaxel’s success.
“It would be significant“Explained Weaver. “You could measure chromosomal instability on residual tissue from a diagnostic biopsy, which patients must have anyway, and potentially use that tissue for a biomarker test. “
Weaver, expert in cell division and chromosomal segregation, he has been studying paclitaxel in the laboratory since graduate school, but has gradually shifted his focus to examine how commonly used chemotherapy works in the cells of breast cancer patients.
Researchers once believed that paclitaxel worked by preventing cancer cells from dividing. But in a previous study of patients on a standard high-dose paclitaxel regimen, Weaver, his colleague from Carbone Mark Burkard and their research teams found that the model didn’t hold up. Instead, they found that the drug amplified mis-segregation in dividing cancer cells.
“This suggested to us that the way we thought Taxol had been working for the past 30 years was wrong, and this was a big question mark and concern “, specified Weaver. The research led her and her team tohypothesis that paclitaxel may exert its anticancer effects by causing or exploiting chromosomal instability.
In the latest study, the research team was able to study hard-to-obtain breast cancer samples they have captured a very specific time in the cell life cycle of breast cancer patients treated with a typical low-dose paclitaxel regimen. Then they looked at what was happening during cell division.
During normal cell division, the cell forms structures called spindles, which attach to chromosomes in the center of the cell and then, like small cords, separate the genetic material as the cell begins to divide in two. This helps ensure that the correct number of chromosomes remain in the original cell and are added to the new daughter.
These mandrels are anchored to a single position at the two ends of the cell or to two poles. However, in paclitaxel-treated patient samples, the spindles formed more poles in the cells. These cells faced one of two fates: the abnormal spindles were retained during cell division, or the spindles were finally “concentrated” in traditional bipolar spindles.
When the abnormal multiple spindles were maintained, the cells died and the tumors regressed. When the spindles were refocused into bipolar spindles, the cells generally became more resistant to paclitaxel.
“Understanding that this focus is an important resistance mechanism opens the door to the identification of new drug targets and therefore to the development of drugs that will sensitize to paclitaxel “, explains Weaver.
Taken together, the findings may represent a major step forward in the cancer community’s understanding of paclitaxel. And although many non-chemotherapy therapies, such as targeted therapies and immunotherapies, are being developed to treat breast cancer, Weaver says there’s a huge benefit in trying to teach this old drug some new tricks.
“What we are really trying to do is turn this conventional chemotherapy into personalized medicine“Said Weaver. “It would be the best of all worlds because Paclitaxel is widely used, it is inexpensive, and doctors have a lot of experience with it. If we could only refer it to the right patients, it would be a huge improvement in the care of the cancro”he concluded the expert.