A vulnerability in triple-negative breast cancer could improve treatment outcomes
Ludwig Institute for Cancer Research News Mar 11, 2017
Ludwig researchers have shown that triple–negative breast cancer cells ramp up production of a key component of DNA in response to chemotherapy and that targeting this pathway could undermine their resistance to such therapies.
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.
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 percent 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.
ÂTrying to understand the mechanisms that contribute to cancerÂs 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 Âmetabolic 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.
ÂThis 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.
Toker and his team reasoned that blocking the pyrimidine synthesis pathway in TNBC cells would hinder their DNA repair abilities and make them more susceptible to the DNA–damaging effects of chemotherapy. To test this hypothesis, the team exposed TNBC cells in the lab to a drug combination of doxorubicin, a commonly used chemotherapy agent, and leflunomide, a known inhibitor of dihydroorotate dehydrogenase (DHODH), a crucial enzyme in the biochemical reactions that generate pyrimidines.
ÂOne 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.
TokerÂs group found that leflunomide blocked the increase of pyrimidine nucleotides in TNBC cells, thus impairing their ability to repair the DNA damage dealt by doxorubicin, and resulting in increased cancer cell death.
The scientists then repeated the experiment in mice that had been transplanted with human TNBC cells. ÂWe 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.
In the meantime, Toker said his group is moving forward with plans to investigate the molecular basis of increased pyrimidine biosynthesis in TNBC cells.
Go to Original
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.
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 percent 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.
ÂTrying to understand the mechanisms that contribute to cancerÂs 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 Âmetabolic 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.
ÂThis 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.
Toker and his team reasoned that blocking the pyrimidine synthesis pathway in TNBC cells would hinder their DNA repair abilities and make them more susceptible to the DNA–damaging effects of chemotherapy. To test this hypothesis, the team exposed TNBC cells in the lab to a drug combination of doxorubicin, a commonly used chemotherapy agent, and leflunomide, a known inhibitor of dihydroorotate dehydrogenase (DHODH), a crucial enzyme in the biochemical reactions that generate pyrimidines.
ÂOne 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.
TokerÂs group found that leflunomide blocked the increase of pyrimidine nucleotides in TNBC cells, thus impairing their ability to repair the DNA damage dealt by doxorubicin, and resulting in increased cancer cell death.
The scientists then repeated the experiment in mice that had been transplanted with human TNBC cells. ÂWe 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.
In the meantime, Toker said his group is moving forward with plans to investigate the molecular basis of increased pyrimidine biosynthesis in TNBC cells.
Only Doctors with an M3 India account can read this article. Sign up for free or login with your existing account.
4 reasons why Doctors love M3 India
-
Exclusive Write-ups & Webinars by KOLs
-
Daily Quiz by specialty
-
Paid Market Research Surveys
-
Case discussions, News & Journals' summaries