Healthcare Professionals

  • Combination therapy shows early promise against stubborn leukemia

    In early-stage 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 Leukemia.

    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 175 days.

    Although laboratory 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.

 
  • Fukon Guo, PhD.



    Fukon Guo, PhD.