Document Detail


Dual targeting of mTOR and aurora-A kinase for the treatment of uterine Leiomyosarcoma.
MedLine Citation:
PMID:  22821997     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated.
EXPERIMENTAL DESIGN: Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo.
RESULTS: Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo.
CONCLUSIONS: mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS.
Authors:
Kari J Brewer Savannah; Elizabeth G Demicco; Kristelle Lusby; Markus Ph Ghadimi; Roman Belousov; Eric Young; Yiqun Zhang; Kai-Lieh Huang; Alexander J Lazar; Kelly K Hunt; Raphael E Pollock; Chad J Creighton; Matthew L Anderson; Dina Lev
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-20
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  18     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-03     Completed Date:  2013-04-09     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4633-45     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
Affiliation:
Department of Cancer Biology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1104, Houston TX 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects
Azepines / administration & dosage
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Gene Expression Regulation, Neoplastic
Humans
Leiomyosarcoma* / drug therapy,  metabolism,  pathology
Mice
Protein-Serine-Threonine Kinases / antagonists & inhibitors*,  metabolism
Pyrimidines / administration & dosage
Signal Transduction
Sirolimus / administration & dosage
TOR Serine-Threonine Kinases / antagonists & inhibitors,  metabolism*
Transplantation, Heterologous
Uterine Neoplasms* / drug therapy,  metabolism,  pathology
Grant Support
ID/Acronym/Agency:
5T32CA009599-21/CA/NCI NIH HHS; R01 CA138345/CA/NCI NIH HHS; R01CA138345/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Azepines; 0/MLN 8237; 0/Pyrimidines; 53123-88-9/Sirolimus; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/aurora kinase
Comments/Corrections

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