title: Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors.
abstract: OBJECTIVE
  Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown.
  
  
  METHODS
  In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice.
  
  
  RESULTS
  Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors.
  
  
  CONCLUSIONS
  Our data provide a rationale for p110α-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. ©2016 AACR.
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Soler
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Figueiredo
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Pau
authors.initials: P
authors.lastname: Castel
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martin
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Erika
authors.initials: E
authors.lastname: Monelli
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo-Urarte
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Milà-Guasch
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.|Departament de Ciències Fisiològiques II, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. mgraupera@idibell.org.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001584:Benzoxepins / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008207:Lymphatic Metastasis / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D001584:Benzoxepins; C000609010:GDC-0326; D007093:Imidazoles; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000068338:Everolimus; D051057:Proto-Oncogene Proteins c-akt