Triple-negative breast cancer accounts for nearly 20% of
breast cancer cases and is defined by its cells' lack of receptors for
three well-known drivers of other forms of the disease - estrogen,
progesterone and human epidermal growth factor (HER2). Without receptors
for this trio of hormones, TNBC is impervious to the therapies used to
combat other breast cancer subtypes.
Physicians currently have no targeted treatment options
available for women diagnosed with an aggressive form of breast cancer
known as triple-negative breast cancer (TNBC), leaving standard-of-care
chemotherapies as a first line of defense against the disease.
‘Triple-negative breast cancer can be controlled by blocking pyrimidine biosynthetic pathway using an existing inhibitor in combination with chemotherapy.’
most women with TNBC do not respond to these broadly-targeted
chemotherapies, and those who do often develop resistance to the drugs.
Investigators at the Cancer Center at Beth Israel Deaconess Medical
Center (BIDMC) have discovered a vulnerability that offers a new
strategy to combat TNBC. Their findings are published online today in
the journal Cancer Discovery
"Given the complete lack of any targeted therapies specific to
triple-negative breast cancer, we started thinking about how we could
find other vulnerabilities in tumor cells," said corresponding author
Alex Toker, chief of the Division of Signal Transduction in the
Department of Medicine and Pathology and the Cancer Center at BIDMC. "If
we could find such vulnerabilities, we could develop strategies to
exploit them, perhaps with already FDA-approved drugs that could be used
in combination with existing cancer drugs."
TNBC treatment is limited to
standard-of-care chemotherapies that work by damaging cancer cells' DNA,
to which it often develops resistance. Moreover, these non-specific
standard-of-care, first line therapies are blunt instruments that may
also kill normal cells and are responsible for the side effects
associated with cancer treatment such as nausea and hair loss.
Researchers still don't know what initiates or drives the development
of TNBC tumors. However, Toker and his colleagues demonstrated that the
cancer cells increase production of nucleotides called pyrimidines when
exposed to standard chemotherapy. Because pyrimidines are a crucial
ingredient in DNA, the researchers reasoned that its increased
production - or, biosynthesis - is an adaptive response that promotes
resistance to DNA-damaging chemotherapies.
"What chemotherapy does in triple-negative breast cancer - for
reasons we don't yet fully understand - is reprogram this
pyrimidine-biosynthetic pathway to really crank up production of these
nucleotides," said Toker, who is also an investigator at the Ludwig
Center at Harvard. "If we could inhibit this increase, then we might be
able to restore the chemotherapeutic benefit of standard-of-care drugs."
To test that notion, Toker and colleagues, including lead author
Kristin K. Brown, PhD, formerly of BIDMC and now at Peter MacCallum
Cancer Center in Melbourne, Australia, treated TNBC cells with a
cancer-killing drug called doxorubicin. As expected, the cancer cells
increased production of pyrimidine nucleotides. The scientists
reproduced these results both in vitro - in cancer cells grown on
plastic - and in vivo, in mice implanted with human TNBC cells.
Next, the researchers treated TNBC cells with a combination of a
standard-of-care chemotherapy called doxorubicin and leflunomide, a drug
known to block the pyrimidine biosynthetic pathway that is already an
FDA-approved treatment for rheumatoid arthritis. Again, TNBC cells
responded as Toker and colleagues expected. In mice, the scientists saw
significant tumor regression with the combination therapy. Other
experiments revealed that either drug alone had minimal impact on TNBC
cells, while the combination therapy had no impact on the other breast
cancer subtypes driven by estrogen, progesterone or HER2.
Based on these findings, Toker intends to initiate clinical trials in
partnership with clinical oncologists. He will also focus on testing
both FDA-approved as well as newer drugs that may exploit this new-found
Achilles' heel in TNBC and other cancers that depend on similar
metabolic pathways to develop chemotherapy resistance. The goal is to
speed new potential therapies to patients.
"We focused our attention on the pyrimidine-biosynthetic pathway
because we wanted to develop a combination therapy strategy without
having to develop new drugs," said Toker, who plans to start a company
to test existing drugs. "Indeed there is already one drug in use that
inhibits one of the key enzymes in this pathway. Repositioning that drug
should provide a much more rapid path to clinical impact and clinical