Blood cancer drug's secret solved

Scientists from the Walter and Eliza Hall Institute of Medical Research have solved a mystery about how a promising new class of anticancer drugs works. Their study has been published in the journal Cell Reports.

So-called nutlins, which are in early clinical trials for treating blood cancers, have sparked interest worldwide for their ability to stop cancer growth by activating the body’s natural cancer-suppressing mechanism — a gene called p53 — while at the same time avoiding some of the damaging effects of chemotherapy. Until now, it was unknown whether nutlins were killing the cancerous cells or just suppressing them temporarily.

The researchers confirmed that nutlins cause cancer cells to self-destruct, not just go to sleep. They found that nutlins activate p53 to trigger programmed cell death (apoptosis) of blood cancer cells, as identified through the presence of a protein called PUMA.

Corresponding author Professor Andreas Strasser explained that p53 acts like a natural ‘guardian’ of healthy cells in the body and is a major barrier to developing cancer. When functioning properly, he said, the gene is activated in response to early cancerous changes in the cell — it acts by “either halting the cell while repairs are made, or by forcing the cell to die if it cannot be repaired”.

“Without the help of p53, a damaged cell can be allowed to multiply, leading to cancer development,” Professor Strasser continued. “p53 lies dormant in many types of cancer — that do not have mutations in p53 — and the nutlins work through reawakening its activity.”

Professor Strasser said knowing more information about what nutlins are capable of, by identifying how they were activating p53 to trigger cell death in cancers, was a critical step towards developing more sophisticated treatments for cancer.

“By understanding how nutlins are killing cancer cells, we can begin to formulate their best possible use, including choosing the best partner drugs to combine the nutlins with,” he said.

Co-author Dr Brandon Aubrey, who is also a clinical haematologist at The Royal Melbourne Hospital, said the team’s discovery not only reinforces that nutlins are a promising new treatment for blood cancer, but it also provides invaluable information for a more tailored approach to patient care.

“Our findings will help identify which patients are most likely to benefit from nutlins and which types of cancers are most likely to respond to nutlins as a treatment,” Dr Aubrey said.

“Understanding in detail how the drugs work will help in the design of better clinical trials and bring the world closer to more precise and personalised medical treatments for cancer.”

Image caption: Dr Brandon Aubrey. Image credit: The Walter and Eliza Hall Institute of Medical Research.