title: Dual mTORC1/2 inhibition in a preclinical xenograft tumor model of endometrial cancer.
abstract: OBJECTIVE
  Up to 70% of endometrioid endometrial cancers carry PTEN gene deletions that can upregulate mTOR activity. Investigational mTOR kinase inhibitors may provide a novel therapeutic approach for these tumors. Using a xenograft tumor model of endometrial cancer, we assessed the activity of mTOR and downstream effector proteins in the mTOR translational control pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) catalytic inhibitor (PP242) compared to that of an allosteric mTOR complex 1 (mTORC1) inhibitor (everolimus, RAD001).
  
  
  METHODS
  Grade 3 endometrioid endometrial cancer cells (AN3CA) were xenografted into nude mice. Animals were treated with PP242, PP242 and carboplatin, carboplatin, RAD001, and RAD001 and carboplatin. Mean tumor volume was compared across groups by ANOVA. Immunoblot analysis was performed to assess mTORC1/2 activity using P-Akt, P-S6 and P-4E-BP1.
  
  
  RESULTS
  The mean tumor volume of PP242+carboplatin was significantly lower than in all other treatment groups, P < 0.001 (89% smaller). The RAD001+carboplatin group was also smaller, but this did not reach statistical significance (P = 0.097). Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated P-Akt.
  
  
  CONCLUSIONS
  Catalytic mTORC1/2 inhibition demonstrates clear efficacy in tumor growth control that is enhanced by the addition of a DNA damage agent, carboplatin. Targeting mTORC1/2 leads to inhibition of Akt activation and strong downregulation of effectors of mTORC1, resulting in downregulation of protein synthesis. Based on this study, mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for endometrial cancer.
authors: Department Obstetrics and Gynecology, NYU Langone Medical Center, New York, NY 10016, USA.
authors: Sharmilee Bansal
authors: SB
authors: Korets
authors: Department Obstetrics and Gynecology, NYU Langone Medical Center, New York, NY 10016, USA.
authors: Fernanda
authors: F
authors: Musa
authors: Department Obstetrics and Gynecology, NYU Langone Medical Center, New York, NY 10016, USA; NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
authors: John
authors: J
authors: Curtin
authors: Department Obstetrics and Gynecology, NYU Langone Medical Center, New York, NY 10016, USA; NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
authors: Stephanie V
authors: SV
authors: Blank
authors: NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address: Robert.schneider@nyumc.org.
authors: Robert J
authors: RJ
authors: Schneider
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000068338:Everolimus; D005260:Female; D007211:Indoles / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011687:Purines; D000068338:Everolimus; D016190:Carboplatin; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus
keywords: Akt; Endometrial cancer; Preclinical study; Rapamycin; Translational regulation; eIF4E; mTOR pathway; therapeutics