title: Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma.
abstract: OBJECTIVE
  The hedgehog (HH) signaling pathway is a key regulator in tumorigenesis of pancreatic adenocarcinoma and is upregulated in pancreatic adenocarcinoma cancer stem cells (CSCs). GDC-0449 is an oral small-molecule inhibitor of the HH pathway. This study assessed the effect of GDC-0449-mediated HH inhibition in paired biopsies, followed by combined treatment with gemcitabine, in patients with metastatic pancreatic adenocarcinoma.
  
  
  METHODS
  Twenty-five patients were enrolled of which 23 underwent core biopsies at baseline and following 3 weeks of GDC-0449. On day 29, 23 patients started weekly gemcitabine while continuing GDC-0449. We evaluated GLI1 and PTCH1 inhibition, change in CSCs, Ki-67, fibrosis, and assessed tumor response, survival and toxicity.
  
  
  RESULTS
  On pretreatment biopsy, 75% of patients had elevated sonic hedgehog (SHH) expression. On posttreatment biopsy, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 patients, fibrosis decreased in 45.4% of 22, and Ki-67 in 52.9% of 17 evaluable patients. No significant changes were detected in CSCs pre- and postbiopsy. The median progression-free and overall survival for all treated patients were 2.8 and 5.3 months. The response and disease control rate was 21.7% and 65.2%. No significant correlation was noted between CSCs, fibrosis, SHH, Ki-67, GLI1, PTCH1 (baseline values or relative change on posttreatment biopsy), and survival. Grade ≥ 3 adverse events were noted in 56% of patients.
  
  
  CONCLUSIONS
  We show that GDC-0449 for 3 weeks leads to downmodulation of GLI1 and PTCH1, without significant changes in CSCs compared with baseline. GDC-0449 and gemcitabine were not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer.
authors.affiliation: Work completed at Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI. Currently at University of California at Davis, Sacramento, CA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.|Translational Oncology Program, University of Michigan, Ann Arbor, MI.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Sahai
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, MI.
authors.forename: Ethan V
authors.initials: EV
authors.lastname: Abel
authors.affiliation: Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor.
authors.forename: Kent A
authors.initials: KA
authors.lastname: Griffith
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.affiliation: Work completed at Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI. Currently at Henry Ford Hospital, Detroit, MI.
authors.forename: Gazala N
authors.initials: GN
authors.lastname: Khan
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: John L
authors.initials: JL
authors.lastname: Blau
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Ronald
authors.initials: R
authors.lastname: Craig
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Ulysses G
authors.initials: UG
authors.lastname: Balis
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Zalupski
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, MI.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011725:Pyridines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000813:Anilides; D015415:Biomarkers; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D003841:Deoxycytidine; D000093542:Gemcitabine