Based on their familiarity with the programmed cell death mechanism, and on their knowledge of which existing drugs target which components of the mechanism, the researchers were able to take two existing drugs "off-the-shelf" in a rational way and show that they worked extraordinarily well, when combined, for treating "Akt-positive" lymphomas (Lymphomas in which the hyperactivity of a protein called Akt inactivates the programmed cell death mechanism).
Genetic lesions that aberrantly activate the Akt protein or other components of the Akt-mediated growth control pathway (e.g. mTOR or another protein called PI3 kinase) are common in leukemia, lymphoma, and in a variety of solid tumors. Therefore, the combination therapy outlined by the new study is a promising general strategy for treating many cancers that are refractory to current therapies.
The drug chosen to restore the programmed cell death mechanism was the antibiotic rapamycin. Rapamycin treatment blocks the action of an Akt "effector" protein called mTOR and thereby restores the programmed cell death mechanism in Akt-positive lymphomas.
The drug chosen to trigger the programmed cell death mechanism was a different antibiotic called doxorubicin. Like many traditional chemotherapy drugs, doxorubicin triggers programmed cell death by damaging DNA.
With the programmed cell death mechanism restored by rapamycin treatment, triggering the mechanism by doxorubicin treatment delivered the decisive, knockout blow to Akt-positive lymphomas. The researchers observed massive death of lymphoma cells when the animals were treated with both rapamcyin and doxorubicin. The animals rapidly became tumor-free, and their period of tumor-free survival was greatly extended compared to that of mice bearing genetically different, non-responsive "Bcl2-positive" lymphomas, and when compared to mice bearing Akt-positive lymphomas that were either untreated or treated with rapamycin or doxorubicin al
Contact: Jeff Picarello
Cold Spring Harbor Laboratory