Submitted February 7, 2008
Accepted January 8, 2009
Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia
Roman Crazzolara, Adam Cisterne, Marilyn Thien, John Hewson, Rana Baraz, Kenneth F. Bradstock, and Linda J. Bendall*
Westmead Institute for Cancer Research, Westmead Millennium, University of Sydney, Westmead, NSW, Australia
Department of Haematology, Westmead Hospital, Westmead, NSW, Australia
* Corresponding author; email: linda_bendall{at}wmi.usyd.edu.au.
Despite advances in the treatment of acute lymphoblastic leukemia (ALL), the majority of children who relapse still die from ALL. Therefore the development of more potent but less toxic drugs for the treatment of ALL is imperative. We investigated the effects of the mammalian target of rapamycin (mTOR) inhibitor, RAD001 (Everolimus), in a NOD/SCID model of human childhood B cell progenitor ALL. RAD001 treatment of established disease increased the median survival of mice from 21.3 days to 42.3 days (p<0.02). RAD001 together with vincristine significantly increased survival compared to either treatment alone (p<0.02). RAD001 induced a cell cycle arrest in the G0/1 phase with associated dephosphorylation of the retinoblastoma protein, and reduced cyclin dependent kinase 4 and 6 levels. Ultrastructure analysis demonstrated the presence of autophagy and limited apoptosis in cells of RAD001 treated animals. In contrast cleaved PARP suggested apoptosis in cells from animals treated with vincristine or the combination of RAD001 and vincristine, but not in those receiving RAD001 alone. In conclusion, we have demonstrated activity of RAD001 in an in vivo leukemia model supporting further clinical development of mTOR inhibitors for the treatment of patients with ALL.
