Abstract
Aberrant activation of the transcription factor GLI1, a central effector of the Hedgehog (HH) pathway, is associated with several malignancies, including pancreatic ductal adenocarcinoma (PDAC), one of most deadly human cancers. GLI1 has been described as an oncogene in PDAC, making it a promising target for drug therapy. Surprisingly, clinical trials targeting HH/GLI1 axis in advanced PDAC were unsuccessful, leaving investigators questioning the mechanism behind these failures. Recent evidence suggests the loss of GLI1 in the later stages of PDAC may actually accelerate disease. This indicates GLI1 may play a dual role in PDAC, acting as an oncogene in the early stages of disease and a tumor-suppressor in the late stages.
Highlights
The protein GLI1, originally isolated in 1987 due to high levels of amplification in malignant glioma (Kinzler et al, 1987), is a member of the GLI family of transcription factors
Based on work from Fendrich et al on HH signaling and acinar cell differentiation, it might even be provocatively proclaimed that increasing GLI1 levels could drive terminal differentiation and result in lower tumorigenicity (Fendrich et al, 2008). These studies demonstrating GLI1 may act as a tumor suppressor in the late stage of pancreatic ductal adenocarcinoma (PDAC) give insight into the disappointing results of clinical trials testing HH inhibitors in metastatic PDAC patients
While the Olive experiments reported acute administration of IPI-926 increased survival due to decreased stromal content and increased vascularity, the HH inhibitor performed poorly in pancreatic cancer clinical trials in patients. One explanation for this discrepancy may be the short duration of treatment (3 weeks) in the Olive’s experiments, which may have not accurately detected disease progression following HH inhibition. This indicates that as PDAC progresses, the initial positive effects of HH inhibition may be eliminated as GLI1 levels decrease
Summary
The protein GLI1, originally isolated in 1987 due to high levels of amplification in malignant glioma (Kinzler et al, 1987), is a member of the GLI family of transcription factors. Mechanisms included are activation of DYRK1B kinase, which promotes a shift from autocrine to paracrine signaling, which may lead to decreased GLI1 expression. Mills and colleagues using a mouse model for pancreas-specific oncogenic KRAS expression (KC mice) bred on a Gli1 null background (GKO/KC) defined a key role for GLI1 on PDAC initiation through the modulation of the activity of fibroblasts (Mills et al, 2013).
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