Journal article
Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma
Clinical cancer research, Vol.20(23), pp.5937-5945
12/01/2014
DOI: 10.1158/1078-0432.CCR-14-1269
PMCID: PMC4254161
PMID: 25278454
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma
- Creators
- Edward J Kim - University of Michigan–Ann ArborVaibhav Sahai - Translational Oncology Program, University of Michigan, Ann Arbor, MIEthan V Abel - Translational Oncology Program, University of Michigan, Ann Arbor, MIKent A Griffith - Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann ArborJoel K Greenson - Department of Pathology, University of Michigan, Ann Arbor, MINaoko Takebe - Division of Cancer Treatment and Diagnosis, National Cancer InstituteGazala N Khan - Work completed at Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI. Currently at Henry Ford Hospital, Detroit, MIJohn L Blau - Department of Pathology, University of Michigan, Ann Arbor, MIRonald Craig - Department of Pathology, University of Michigan, Ann Arbor, MIUlysses G Balis - Department of Pathology, University of Michigan, Ann Arbor, MIMark M Zalupski - Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MIDiane M Simeone - Translational Oncology Program, University of Michigan, Ann Arbor, MI
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.20(23), pp.5937-5945
- Publisher
- United States
- DOI
- 10.1158/1078-0432.CCR-14-1269
- PMID
- 25278454
- PMCID
- PMC4254161
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- ULRR024986 / PHS HHS 5 P30 CA046592 / NCI NIH HHS P30 CA046592 / NCI NIH HHS UL1 RR024986 / NCRR NIH HHS
- Language
- English
- Date published
- 12/01/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984047875102771
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