The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL.
Publication/Presentation Date
2-1-2006
Abstract
Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheral-blood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy.
Volume
107
Issue
3
First Page
1149
Last Page
1155
ISSN
0006-4971
Published In/Presented At
Teachey, D. T., Obzut, D. A., Cooperman, J., Fang, J., Carroll, M., Choi, J. K., Houghton, P. J., Brown, V. I., & Grupp, S. A. (2006). The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood, 107(3), 1149–1155. https://doi.org/10.1182/blood-2005-05-1935
Disciplines
Medicine and Health Sciences
PubMedID
16195324
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article