title: A potent combination of the novel PI3K Inhibitor, GDC-0941, with imatinib in gastrointestinal stromal tumor xenografts: long-lasting responses after treatment withdrawal.
abstract: OBJECTIVE
  Oncogenic signaling in gastrointestinal stromal tumors (GIST) is sustained via PI3K/AKT pathway. We used a panel of six GIST xenograft models to assess efficacy of GDC-0941 as single agent or in combination with imatinib (IMA).
  
  
  METHODS
  Nude mice (n = 136) were grafted bilaterally with human GIST carrying diverse KIT mutations. Mice were orally dosed over four weeks, grouped as follows: (A) control; (B) GDC-0941; (C) imatinib, and (D) GDC+IMA treatments. Xenografts regrowth after treatment discontinuation was assessed in groups C and D for an additional four weeks. Tumor response was assessed by volume measurements, micro-PET imaging, histopathology, and immunoblotting. Moreover, genomic alterations in PTEN/PI3K/AKT pathway were evaluated.
  
  
  RESULTS
  In all models, GDC-0941 caused tumor growth stabilization, inhibiting tumor cell proliferation, but did not induce apoptosis. Under GDC+IMA, profound tumor regression, superior to either treatment alone, was observed. This effect was associated with the best histologic response, a nearly complete proliferation arrest and increased apoptosis. Tumor regrowth assays confirmed superior activity of GDC+IMA over imatinib; in three of six models, tumor volume remained reduced and stable even after treatment discontinuation. A positive correlation between response to GDC+IMA and PTEN loss, both on gene and protein levels, was found.
  
  
  CONCLUSIONS
  GDC+IMA has significant antitumor efficacy in GIST xenografts, inducing more substantial tumor regression, apoptosis, and durable effects than imatinib. Notably, after treatment withdrawal, tumor regression was sustained in tumors exposed to GDC+IMA, which was not observed under imatinib. Assessment of PTEN status may represent a useful predictive biomarker for patient selection.
authors.affiliation: Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. giuseppe.floris@uzleuven.be
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Haifu
authors.initials: H
authors.lastname: Li
authors.forename: Lori
authors.initials: L
authors.lastname: Friedman
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Looy
authors.forename: Jasmien
authors.initials: J
authors.lastname: Wellens
authors.forename: Peter
authors.initials: P
authors.lastname: Vermaelen
authors.forename: Christophe M
authors.initials: CM
authors.lastname: Deroose
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D007191:Indazoles / Q000008:administration & dosage; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000008:administration & dosage; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D001549:Benzamides; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D013449:Sulfonamides; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit