title: Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer.
abstract: OBJECTIVE
  Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model.
  
  
  METHODS
  NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C+BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation.
  
  
  RESULTS
  In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p<0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p<0.05). Synergistic tumor growth suppression (p<0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels.
  
  
  CONCLUSIONS
  Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Bradford
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rauh-Hain
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Clark
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jolijn W
authors.initials: JW
authors.lastname: Groeneweg
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Darrell
authors.initials: D
authors.lastname: Borger
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Zukerberg
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: brueda@partners.org.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism*; D002296:Carcinosarcoma / Q000235:genetics / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D016190:Carboplatin; D058534:Class I Phosphatidylinositol 3-Kinases; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D058539:Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C571178:NVP-BKM120; C484760:PIK3CA protein, human; C494929:PTEN protein, human
keywords: Endometrial cancer; PI3K inhibitor; PI3K/AKT/mTOR pathway