studies, combining mTOR inhibitors with chemotherapy was far more effective against
T-cell acute lymphoblastic leukemia (T-ALL) than stand-alone treatment,
according to new research posted online by the Nature journal
Current treatments for
T-ALL achieve about a 90 percent initial remission rate. But scientists are
searching for improved therapy because relapses often occur, resulting in an
overall survival rate between 60 and 70 percent.
“The disease comes
back because of drug resistance that leads to relapse. Our study uncovers a way
to enhance the effectiveness of chemotherapy,” said Fukun Guo, PhD, study first author and a
researcher in the Division of Experimental Hematology and Cancer Biology
at Cincinnati Children’s.
The new study involved
laboratory cell lines of human leukemia and mouse models of the disease. A key
breakthrough came when the research team discovered that a molecular mechanism
in the Fanconi anemia DNA repair pathway also appears to make T-ALL resistant
to chemotherapy. This same pathway has been linked to drug resistance in other types
of cancer, Guo says.
To block the FA
repair pathway in leukemic cells, researchers tested three mTOR inhibitors currently
under development -- pp242, AZD8055 and INK128 -- in combination with three chemotherapies
-- AraC, Etoposide and Cisplatin.
In one example
highlighted by the researchers, mice treated only with pp242 or AraC died from
their leukemia within 80 days. However, 75 percent of mice receiving
combination treatment survived more than 100 days and 50 percent survived about
results involving cell lines and mice do not necessarily translate to human
treatment, the researchers say their findings suggest a new treatment strategy
for T-ALL. Inhibition the FA pathway coupled with chemotherapy may also be
useful against other types of cancer.
Guo and his
collaborators are continuing their studies by developing “humanized” mice,
which have been transplanted with patient cells of relapsed and refractory disease,
to further test mTOR inhibitors in combination with AraG, another chemotherapy
agent used clinically to treat T-ALL.