Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients

Abstract

Background:Predictive biomarkers or signature(s) for oesophageal cancer (OC) patients undergoing preoperative therapy could help administration of effective therapy, avoidance of ineffective ones, and establishment new strategies. Since the hedgehog pathway is often upregulated in OC, we examined its transcriptional factor, Gli-1, which confers therapy resistance, we wanted to assess Gli-1 as a predictive biomarker for chemoradiation response and validate it.Methods:Untreated OC tissues from patients who underwent chemoradiation and surgery were assessed for nuclear Gli-1 by immunohistochemistry and labelling indices (LIs) were correlated with pathologic complete response (pathCR) or <pathCR (resistance) and validated in a unique cohort.Results:Initial 60 patients formed the discovery set (TDS) and then unique 167 patients formed the validation set (TVS). 16 (27%) patients in TDS and 40 (24%) patients in TVS achieved a pathCR. Nuclear Gli-1 LIs were highly associated with pathCR based on the fitted logistic regression models (P<0.0001) in TDS and TVS. The areas under the curve (AUCs) for receiver-operating characteristics (ROCs) based on a fitted model were 0.813 (fivefold cross validation (0.813) and bootstrap resampling (0.816) for TDS and 0.902 (fivefold cross validation (0.901) and bootstrap resampling (0.902)) for TVS. Our preclinical (including genetic knockdown) studies with FU or radiation resistant cell lines demonstrated that Gli-1 indeed mediates therapy resistance in OC.Conclusions:Our validated data in OC show that nuclear Gli-1 LIs are predictive of pathCR after chemoradiation with desirable sensitivity and specificity.

Hedgehog pathway proteins SMO and GLI expression as prognostic markers in head and neck squamous cell carcinoma

“…We have demonstrated a correlation between SMO and its downstream target GLI‐1 expression, but not with p53 expression. Previous studies clearly indicated that the HhP is up‐regulated in many types of cancer, including medulloblastoma, pancreatic cancer, prostate cancer and oesophageal cancer . It has been further proposed that the HhP plays a crucial role in cancer development and progression .…”

“…Previous studies clearly indicated that the HhP is up-regulated in many types of cancer, including medulloblastoma, pancreatic cancer, prostate cancer and oesophageal cancer. [10][11][12][13] It has been further proposed that the HhP plays a crucial role in cancer development and progression. 14 In contrast to the findings of Lee et al, 15 we did not find a correlation between GLI-1 expression and lymph node stage.…”

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

“…A monoclonal anti-Shh antibody, 5E1 or LED225 (Novartis) was able to increase the efficacy of radiation treatment in patient-derived xenograft models of cervical and esophageal cancer [ 145 , 146 ]. Clinically, expression of Shh pathway (Gli1 staining) was associated with the efficacy of esophageal patients treated with chemoradiation and surgery, in two cohorts of patients ( n = 60 and n = 167) [ 147 ]. Moreover, activation of Shh pathway is associated with tumor relapse after radiotherapy in patients with head and neck carcinoma and cervical carcinoma [ 148 , 149 ].…”

GLI1 Inhibitor SRI-38832 Attenuates Chemotherapeutic Resistance by Downregulating NBS1 Transcription in BRAFV600E Colorectal Cancer

“…Of the three factors, GLI1 has emerged as a critical oncogene, having transcriptional activity as the distal effector of both the canonical Hh pathway as well as the non-canonical oncogenic KRAS/BRAF pathway (19). Additionally, oncogenic GLI1 activity is often linked to chemo-resistance (20)(21)(22)(23)(24)(25) due in part to GLI1's transcriptional regulation of several oncogenes involved in critical processes at all stages of cellular life ranging from proliferation and survival to cycle checkpoints (26). We have previously reported that GLI inhibition led to significant DNA damage, and subsequent apoptosis in colon carcinoma cells due to an extended pause in DNA replication licensing via down-regulation of CDT1, a critical DNA replication licensing factor and transcriptional target of GLI1 (27).…”