title: The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL.
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.
authors.affiliation: Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.forename: Dana A
authors.initials: DA
authors.lastname: Obzut
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cooperman
authors.forename: Junjie
authors.initials: J
authors.lastname: Fang
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Valerie I
authors.initials: VI
authors.lastname: Brown
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus