Fla. — Clinicians testing the drug dasatinib, approved for
several blood cancers, had hoped it would slow the aggressive
growth of the deadly brain cancer glioblastoma. While clinical
trials to date have not found any benefit, researchers at Mayo
Clinic, who conducted one of those clinical trials, believe
they know why dasatinib failed — and what to do about it.
online issue of Molecular Oncology, investigators report
finding that dasatinib inhibits proteins that promote cancer
growth as expected but also suppresses proteins that protect
findings suggest that pretesting patient glioblastoma biopsies
will help identify who may respond well to dasatinib and who
should avoid using the drug, says the study’s senior author,
Panos Z. Anastasiadis, Ph.D., chair of the Department of
Cancer Biology at Mayo Clinic in Florida.
is a general Src-family kinase (SFK) inhibitor. It shuts down
all members of the Src family of protein kinases, which are
believed to activate proteins that essentially give tumors
"legs" upon which to crawl through tissue to seek
study, the investigators teased apart dasatinib’s effect on
individual Src family members — Src, Fyn, Yes and Lyn —
using laboratory glioblastoma cell lines and mouse models of
the brain cancer.
cell lines, inhibiting Src, Fyn and Yes generally reduced
growth and migration. So did Lyn, but to a lesser degree.
there were significant differences in mice, depending on which
Src family member was experimentally inhibited. Mice with
glioblastoma tumors lacking functioning Src or Fyn showed no
difference in survival, compared to untreated mice. In
contrast, inhibiting Yes in mice increased survival, while
inhibiting Lyn resulted in shorter survival and accelerated
findings were very surprising to us for two reasons," Dr.
Anastasiadis says. "One is the difference between lab and
animal findings. The other is that, together with the bad,
dasatinib inhibited the good, as well."
promotes cancer growth, so it should be inhibited," he
says. "Unexpectedly though, Lyn protects against cancer
growth, and so it should not be deactivated by use of
found that not all human tumors express all members of the Src
family, and that expression of Yes and Lyn differed among
research team is examining tumor biopsies from the patients
who participated in Mayo Clinic’s clinical trial testing the
use of dasatinib combined with bevacizumab (Avastin), an agent
that restricts blood flow to tumors. They will match
expression of Lyn and Yes with clinical outcomes.
hope these results will affirm our conclusion that patients
with high levels of Lyn should not be treated with dasatinib,"
says Dr. Anastasiadis. "Instead, dasatinib may prove to
work well in select patients whose tumors express Yes, but not
last thing we want to do is target both the good and the bad
with dasatinib," says Dr. Anastasiadis. "In the long
run, developing a drug that targets Yes, but has no effect on
Lyn could prove a much more effective therapy for gliomas."