Block DNA repair to fight therapy-resistant leukemia

New research suggests blocking part of a DNA repair complex that helps some types of leukemia resist treatment can increase the effectiveness of chemotherapy and enhance survival. An experimental combination treatment strategy that uses a small molecular inhibitor along with chemotherapy was particularly effective at stopping T-cell acute lymphoblastic leukemia (T-ALL). This study used laboratory cell lines of human leukemia and mouse models of the disease.

While initial remission rates for T-ALL with current treatments are about 90%, the overall survival is between 60% and 70%.

"Although initial remission rates are high with available treatments, the disease comes back because of drug resistance that leads to relapse. There is an urgent need to develop new therapeutic strategies to combat refractory T-ALL, and our study uncovers a way to enhance the effectiveness of chemotherapy," said first author Fukun Guo, PhD, of Cincinnati Children's Hospital Medical Center in Ohio. The study was published in Leukemia (2013; doi:10.1038/leu.2013.215).

A key breakthrough in the research came when the scientists discovered something that was previously unknown – a molecular mechanism in the Fanconi anemia DNA repair pathway apparently makes T-ALL resistant to chemotherapy. This same pathway has been linked to drug resistance in other types of cancer, Guo said.

Fanconi anemia (FA) is a genomic instability syndrome caused by mutations inside a cluster of proteins normally responsible for DNA repair in cells. Mutation or silencing of FA genes is also associated with increased sensitivity to DNA-damaging drugs. Guo and his fellow researchers worked under the premise that inhibiting the FA pathway and combining this with DNA-damaging chemotherapy drugs might be a promising strategy for cancer therapy.

To block the FA repair pathway in leukemic cells, researchers tested the inhibition of a protein called mTOR (mammalian target of rapamycin). The protein plays a critical role in the growth and survival of mammalian cells – although disruptions in the mTOR molecular pathway are linked to tumor growth, chemotherapy resistance, and poor prognoses in malignancies such as leukemia.

Initial testing of mTOR inhibition was achieved by direct deletion of the mTOR gene in mice. The scientists then tested three new mTOR inhibitors currently under development (pp242, AZD8055 and INK128) in combination with the chemotherapies cytarabine, etoposide, and cisplatin to see how they affected laboratory lines of leukemia cells and mouse models of the disease. They compared the effectiveness of the combination treatments with treating the leukemia by just chemotherapy or inhibitors alone. Tests showed that combining mTOR inhibitors with chemotherapy was far more effective at treating leukemia than when the inhibitors or chemotherapy were used as stand-alone treatments.

Although the researchers emphasized that laboratory results involving cell lines and mice do not necessarily translate to human treatment, they say their findings show that new mTOR inhibitors combined with chemotherapy could become a new treatment strategy for T-ALL. They also report that inhibition of the FA pathway coupled with chemotherapy may be useful for treating other types of cancer.
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