title: Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216.
abstract: 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.
authors: Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.|Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors: B
authors: B
authors: Mohelnikova-Duchonova
authors: Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine, Prague, Czech Republic.
authors: M
authors: M
authors: Kocik
authors: Palacky University, Olomouc, Czech Republic.
authors: B
authors: B
authors: Duchonova
authors: Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.|Charles University in Prague, Prague, Czech Republic.
authors: V
authors: V
authors: Brynychova
authors: Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine, Prague, Czech Republic.
authors: M
authors: M
authors: Oliverius
authors: Department of Surgery, University Hospital and Medical Faculty, Masaryk University, Brno, Czech Republic.
authors: J
authors: J
authors: Hlavsa
authors: Department of Clinical and Transplantation Pathology, Institute of Clinical and Experimental Medicine, Prague, Czech Republic.
authors: E
authors: E
authors: Honsova
authors: Department of Pathology, University Hospital and Medical Faculty, Masaryk University, Brno, Czech Republic.
authors: J
authors: J
authors: Mazanec
authors: Department of Surgery, University Hospital and Medical Faculty, Masaryk University, Brno, Czech Republic.
authors: Z
authors: Z
authors: Kala
authors: Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA.
authors: I
authors: I
authors: Ojima
authors: Department of Physiology &Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: D J
authors: DJ
authors: Hughes
authors: Randox Laboratories, Crumlin, UK.
authors: J E
authors: JE
authors: Doherty
authors: Randox Laboratories, Crumlin, UK.
authors: H A
authors: HA
authors: Murray
authors: Randox Laboratories, Crumlin, UK.
authors: M A
authors: MA
authors: Crockard
authors: Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors: R
authors: R
authors: Lemstrova
authors: Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.
authors: P
authors: 0000-0002-4294-6799
authors: P
authors: Soucek
mesh_terms: D000368:Aged; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D059467:Transcriptome / Q000187:drug effects*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D053823:Hedgehog Proteins; C117307:KRAS protein, human; D043823:Taxoids; D016283:Proto-Oncogene Proteins p21(ras)