Triple-negative breast cancer (TNBC) is notoriously aggressive and is difficult to treat because its cells lack the targetable receptors found in other forms of breast cancer. Only about 30% of TNBC patients achieve a pathologic complete response, or a complete eradication of active cancer cells, following chemotherapy. Those who do frequently relapse shortly afterward.
‘Triple-negative breast cancer cells ramp up production of a key component of DNA in response to chemotherapy. Targeting this pathway could undermine their resistance to such therapies.’
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A team of researchers led by Alex Toker of the Ludwig Center at
Harvard has discovered a metabolic weakness in triple-negative breast
cancer (TNBC) cells that may be exploited to quell their resistance to
chemotherapy."Trying to understand the mechanisms that contribute to cancer's resistance to therapy is a major mission here at the Ludwig Center at Harvard," said Alex Toker.
In the new study, published online in the journal Cancer Discovery, Toker, an investigator at the Ludwig Center at Harvard Medical School, and his team including lead author Kristin Brown, formerly of the Ludwig Center at Harvard and now at Peter MacCallum Cancer Center in Melbourne, Australia, outline a newly discovered chink in the armor of TNBC cells. This "metabolic vulnerability" can be used to circumvent chemotherapy resistance.
The scientists demonstrated that chemotherapy effectively reprograms TNBC cells to ramp up production of the pyrimidine nucloetides, key building blocks of DNA. This heightens the cells' DNA repair abilities and ultimately results in greater resistance to chemotherapies that work by damaging the DNA of rapidly dividing cells.
"This actually makes sense if you think about it, because if a tumor cell is going to repair DNA and therefore evade the death-inducing effects of chemotherapy, the only way they can really do that is by rebuilding DNA, and the only way to rebuild DNA is to make more nucleotides," Toker said.
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"One of the major reasons we chose leflunomide is because we wanted a rapid path to clinical impact, and leflunomide is already FDA-approved and widely used to treat autoimmune diseases such as rheumatoid arthritis," Toker said.
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The scientists then repeated the experiment in mice that had been transplanted with human TNBC cells. "We found that treating the mice with doxorubicin or leflunomide alone only slowed tumor growth, but that a combination therapy involving both drugs resulted in significant tumor regression," Toker said.
Importantly, the combination therapy in mice did not cause any weight loss or gain in the animals - an indication that the drug regimen might be reasonably well-tolerated in humans.
"One of the things we would like to do is develop clinical trials in patients with this combination strategy, whether it be with leflunomide or some other drugs that are coming online that might have better pharmacological properties in patients," Toker said.
In the meantime, Toker said his group is moving forward with plans to investigate the molecular basis of increased pyrimidine biosynthesis in TNBC cells.
"There is something about this pathway in triple negative breast cancer that is especially important," Toker said. "We don't know what the genetic basis underlying it is, but it's something we would really like to find out."
Source-Eurekalert