Big news for drug discovery: chemotherapy treatments don't work as we thought

Surprising news that leading chemotherapy treatments don’t work as we have thought for decades could eventually help researchers to design more effective cancer treatments. Scientists in the US have found that antimicrotubule drugs like paclitaxel are effective because of the chromosomal instability they cause in cancer cells - and not, as previously accepted, by preventing mitosis.

Chemotherapy researchers have been “barking up the wrong tree” by focusing on stopping cancer cells from dividing, according to a new study.

A team from the University of Wisconsin–Madison has discovered that the leading chemotherapy drug paclitaxel does not – as previously thought - work by halting mitosis of cancer cells.

The “mind blowing” findings overturn commonly-accepted theories about how paclitaxel and other microtubule poison drugs act at a cellular level.

It may also explain why many novel compounds that target cancer by focusing on mitosis have been clinically unsuccessful – and allow scientists to refocus their efforts, ultimately helping the search for better chemotherapy treatments.

Writing in the journal PLOS Biology, the Wisconsin-Madison team demonstrate that paclitaxel does not stop tumour cells dividing -  but makes them do so in an abnormal fashion that causes many to die.

They also show that this abnormal division occurs because the drug interferes with chromosomal segregation by prompting chromosomal instability (CIN). In particular, CIN makes breast cancer cells form extra microtubule-based spindle poles that ultimately scramble the cancerous genome.

“In two clinical trials of primary breast cancers treated with both standard-of-care doses of paclitaxel, we directly sampled tumors after treatment,” the group wrote.

“(We) discovered that paclitaxel does not accumulate to the high concentrations necessary to cause mitotic arrest. Rather, the low concentrations achieved in patient tumors induce abnormal, multipolar mitotic spindles in every... tumor examined.”

A number of other antimicrotubule drugs – including docetaxel, ixabepilone, epothilone B,  vinblastine, vinorelbine, and eribulin – also achieved similar results when tested by the group on triple negative cancer cell lines. And with breast cancer biopsies, vinorelbine, eribulin, and nab-paclitaxel increased the incidence of multipolar spindles after about 20 hours.

The group also developed a new histone H2B fluorescence in timelapse spectroscopy method that allowed them to measure the amount of CIN and its effect on cancer cell DNA - finding that “Loss of ≥20% of DNA is typically lethal, (and) “on average, cells formed from successful multipolar divisions have lost approximately 1/3.”

The group said that - given that recent drug candidates that concentrate on inducing mitotic arrest have been clinically unsuccessful, and the limited efficacy of even the successful microtubule poison therapies like paclitaxel – future drug discovery “should not focus on agents that induce mitotic arrest but instead on CIN-inducing drugs”. They added that another advantage of CIN-focused compounds was that these could be successful “as single agents as well as in combination with microtubule therapy.”

Study leader Professor Beth Weaver said it was “sort of mind-blowing” that the scientific consensus about how paclitaxel and other microtubule poisons work had been overturned by her team’s research.

“For decades, we all thought that the way paclitaxel works in patient tumors is by arresting them in mitosis,” she said.

“This is what I was taught as a graduate student. We all ‘knew’ this. In cells in a dish, labs all over the world have shown this.

"(But) we've been barking up the wrong tree. We need to refocus our efforts on screwing up mitosis - on making chromosomal segregation worse."

For more about the science and history behind paclitaxel and docetaxel, check out this article from LGC Standards’ Pharmaceutical Roots series.