title: The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer.
abstract: OBJECTIVE
  To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC).
  
  
  METHODS
  PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined.
  
  
  RESULTS
  In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50) = 9.0-14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013).
  
  
  CONCLUSIONS
  These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.forename: Michael P
authors.initials: MP
authors.lastname: Richardson
authors.forename: Wei Vivian
authors.initials: WV
authors.lastname: Wang
authors.forename: Larissa Georgeon
authors.initials: LG
authors.lastname: Richard
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Erin M
authors.initials: EM
authors.lastname: Coffee
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Sinnamon
authors.forename: Lydia
authors.initials: L
authors.lastname: Lee
authors.forename: Peng-Chieh
authors.initials: PC
authors.lastname: Chen
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Eric S
authors.initials: ES
authors.lastname: Martin
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C484760:PIK3CA protein, human; C531198:dactolisib