title: Dual targeting of mTOR and aurora-A kinase for the treatment of uterine Leiomyosarcoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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: Department of Cancer Biology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1104, Houston TX 77030, USA.
authors: Kari J
authors: KJ
authors: Brewer Savannah
authors: Elizabeth G
authors: EG
authors: Demicco
authors: Kristelle
authors: K
authors: Lusby
authors: Markus Ph
authors: MP
authors: Ghadimi
authors: Roman
authors: R
authors: Belousov
authors: Eric
authors: E
authors: Young
authors: Yiqun
authors: Y
authors: Zhang
authors: Kai-Lieh
authors: KL
authors: Huang
authors: Alexander J
authors: AJ
authors: Lazar
authors: Kelly K
authors: KK
authors: Hunt
authors: Raphael E
authors: RE
authors: Pollock
authors: Chad J
authors: CJ
authors: Creighton
authors: Matthew L
authors: ML
authors: Anderson
authors: Dina
authors: D
authors: Lev
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; C546842:MTOR protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus