Often deadly "triple-negative" breast cancers
might be effectively treated in many cases with a drug that targets a
previously unknown vulnerability in the tumors, according to a UC San
Francisco researcher who described her discovery in a study published
online in the journal Cancer Cell.
UCSF researcher Luika Timmerman, PhD, an investigator in the UCSF Helen
Diller Family Comprehensive Cancer Center, found that many cell lines
obtained from triple-negative breast cancer are especially dependent on
cystine, one of the 20 amino acids that are the building blocks of
proteins that all cells need. Timmerman used an FDA-approved drug to
inhibit activity of a transporter protein that ferries cystine into
triple-negative breast cancer cells, and found that it significantly
inhibited their growth in culture and when the cancer cells were transplanted into mice.
Roughly one in six women with breast cancer have triple-negative breast
cancer, and only about three out of four with this type survive five
years or more. These tumors sometimes grow aggressively, advancing from
being undetectable to becoming difficult-to-treat between regular
screening mammography exams, for instance.
Drugs now are available that effectively target the estrogen and HER2
receptor proteins, which are found in many breast tumors, and these
drugs spare most normal cells in the body. However, triple-negative
breast cancers are difficult to treat effectively because they do not
make either of these receptors. To treat patients with triple-negative
breast cancer, physicians instead use older chemotherapies that produce
side effects in normal tissues, thus limiting the doses that patients
can receive.
Timmerman found that she could significantly slow growth of
triple-negative tumors using an FDA-approved anti-inflammatory drug
called sulfasalazine to block a specific cystine transporter called xCT.
While sulfasalazine itself would not be appropriate for treating
cancer, Timmerman said, it could serve as a "lead compound" that could
be used to develop drugs that specifically target xCT on tumor cells.
"This study of human tumors in mice and of breast cancer cell lines
demonstrates the potential of targeting not only this cystine
transporter, but also other metabolic abnormalities in cancer,"
Timmerman said.
Timmerman has spent several years studying the abnormal metabolic
behavior of cancer cells, which can differ substantially from the
metabolism of normal cells. "Different cancers seem to acquire different
metabolic abnormalities that might in some cases give them a growth or
survival advantage," she said.
"One of the strengths of this study was the large number of different
cell lines I was able to test. When I saw similar results in many
samples, I felt I was looking at a fundamental metabolic behavior that
we could exploit to specifically target triple-negative tumors that
overexpress the xCT cystine transporter, a significant group of
previously untargettable tumors."
Timmerman initially focused on investigating the metabolism of the amino
acid glutamine among different breast cancer-derived cell lines because
glutamine metabolism was long known to be perturbed in cancer. She
matched genetic "microarray" data that tracks gene activity to
functional differences among tumors and tumor cell lines in culture.
But she also measured amino acids and other molecules in cell culture to
detect metabolic changes. When she did so, she noticed that cystine and
glutamate levels are frequently correlated in triple-negative cancers. A
series of experiments led to the discovery that the cystine transporter
xCT was abundant and active on many triple-negative tumors and tumor
cell lines. Timmerman then tested sulfasalazine on tumors grown in mice
and in tumor cell lines and found that blocking xCT activity strongly
retarded the growth of triple-negative tumors.
"We have identified a compelling therapeutic target commonly expressed
by breast tumors of poorest prognosis, and a lead compound for rapid,
effective drug development," Timmerman said.
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