Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216

• Published in: The pharmacogenomics journal 2017-10, Vol.17 (5), p.452-460
• Main Authors: Mohelnikova-Duchonova, B, Kocik, M, Duchonova, B, Brynychova, V, Oliverius, M, Hlavsa, J, Honsova, E, Mazanec, J, Kala, Z, Ojima, I, Hughes, D J, Doherty, J E, Murray, H A, Crockard, M A, Lemstrova, R, Soucek, P
• Format: Article
• Language: English
• Subjects: 38; 631/208/68; 631/67/68; Adenocarcinoma; Aged; Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Care and treatment; Cellular signal transduction; Chemotherapy; Development and progression; Disease-Free Survival; Dosage and administration; Female; Gene Expression; Genes; Genetic aspects; Health aspects; Hedgehog protein; Hedgehog proteins; Hedgehog Proteins - genetics; Human Genetics; Humans; Identification and classification; K-Ras protein; Male; Methods; Mice, Nude; Middle Aged; Mutation; Oncology; original-article; Paclitaxel; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Patient outcomes; Patients; Pharmacotherapy; Polymerase chain reaction; Proto-Oncogene Proteins p21(ras) - genetics; Psychopharmacology; Signal transduction; Taxanes; Taxoids - administration & dosage; Taxoids - therapeutic use; Tissues; Transcription; Transcriptome - drug effects; Treatment Outcome; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2016.55

The Hedgehog pathway is one of the major driver pathways in pancreatic ductal adenocarcinoma. This study investigated prognostic importance of Hedgehog signaling pathway in pancreatic cancer patients who underwent a radical resection. Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified pancreatic cancer. The effect of experimental taxane chemotherapy on the expression of Hedgehog pathway was evaluated in vivo using a mouse xenograft model prepared using pancreatic cancer cell line Paca-44. Mice were treated by experimental Stony Brook Taxane SB-T-1216. The transcript profile of 34 Hedgehog pathway genes in patients and xenografts was assessed using quantitative PCR. The Hedgehog pathway was strongly overexpressed in pancreatic tumors and upregulation of SHH, IHH, HHAT and PTCH1 was associated with a trend toward decreased patient survival. No association of Hedgehog pathway expression with KRAS mutation status was found in tumors. Sonic hedgehog ligand was overexpressed, but all other downstream genes were downregulated by SB-T-1216 treatment in vivo . Suppression of HH pathway expression in vivo by taxane-based chemotherapy suggests a new mechanism of action for treatment of this aggressive tumor.