Slowing the growth of p53-mutant tumors
When the research team tested the Lonsurf–talazoparib combination in mice with colorectal tumors with normal
TP53, it had about the same effect on tumor growth and survival as either drug alone.
But in mice with TP53-mutant colorectal or pancreatic tumors, the combination substantially slowed tumor growth, whereas either drug alone had no effect or very limited effect. The combination also appeared to trigger much more DNA damage and cell death than either drug alone.
As a result, mice with
TP53-mutant tumors treated with the combination lived longer than those treated with either drug alone. And the combination didn’t appear to cause any significant side effects.
The team saw similar outcomes with the combination of Lonsurf and olaparib.
“Achieving synergy without also increasing toxicities is one of the holy grails of cancer treatment,” Dr. Fountzilas noted.
However, “both these compounds do interfere with DNA repair,” Dr. Johnson cautioned. “The [laboratory] studies show that the [normal] cells can deal with the damage, but there might be concerns as you move into [clinical trials].”
Separately, both Lonsurf and PARP inhibitors are known to damage blood cells, and in rare cases, PARP inhibitors can lead to certain kinds of blood cancer.
Although the researchers tested the drug combination only in mice with colorectal or pancreatic tumors, the approach could work for other types of cancers with
TP53 mutations, Dr. Johnson said.
A treatment that’s effective against a broad range of cancers with
TP53mutations “would be very powerful,” he said.
That could include people with
Li-Fraumeni syndrome, who are born with
TP53 mutations and have a higher risk of developing certain cancers, Dr. Bakin pointed out. “Our work brings hope to these [people] as well,” he said.