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Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in
combination with gemcitabine in patients with metastatic pancreatic
adenocarcinoma
#MMPMID25278454
Kim EJ
; Sahai V
; Abel EV
; Griffith KA
; Greenson JK
; Takebe N
; Khan GN
; Blau JL
; Craig R
; Balis UG
; Zalupski MM
; Simeone DM
Clin Cancer Res
2014[Dec]; 20
(23
): 5937-5945
PMID25278454
show ga
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. CONCLUSION:
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.
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