title: The significance of Trk receptors in pancreatic cancer.
abstract: This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity. A specific inhibitor of TrkA, B, and C, AstraZeneca 1332, was investigated in vitro and in vivo in combination with radiation. A tissue microarray was constructed from 77 pancreatic ductal adenocarcinoma patients who had undergone neoadjuvant chemoradiation and the Trk receptor, and neurogenic differentiation 1 expression was assessed and correlated with overall survival. A total of 99 genes were identified that were differentially expressed in the chemoradiation patients with neuroendocrine genes and pathways, in particular the neurogenic differentiation 1 and Trk receptor family, being prominent. Fractionated radiation upregulated the expression of neuroendocrine genes, and AstraZeneca 1332 treatment in vitro enhanced radiosensitivity. No added effect of AstraZeneca 1332 was observed in vivo. Trk receptor expression varied between isoforms but did not correlate significantly with clinical outcome. Radiation treatment upregulated neuroendocrine gene expression but the Trk receptor family does not appear to be a promising treatment target.
authors.affiliation: 1 Department of Radiation Oncology, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: 1 Department of Radiation Oncology, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Stone
authors.affiliation: 2 Beaumont BioBank, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Thibodeau
authors.affiliation: 3 Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Baschnagel
authors.affiliation: 1 Department of Radiation Oncology, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Galoforo
authors.affiliation: 2 Beaumont BioBank, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fortier
authors.affiliation: 2 Beaumont BioBank, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Billie
authors.initials: B
authors.lastname: Ketelsen
authors.affiliation: 2 Beaumont BioBank, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Samreen
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: 2 Beaumont BioBank, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Zakiya
authors.initials: Z
authors.lastname: Kelley
authors.affiliation: 1 Department of Radiation Oncology, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Alaa
authors.initials: A
authors.lastname: Hana
authors.affiliation: 1 Department of Radiation Oncology, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Wilson
authors.affiliation: 1 Department of Radiation Oncology, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Robertson
authors.affiliation: 4 Department of General Surgery, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jury
authors.affiliation: 1 Department of Radiation Oncology, William Beaumont Hospital, Beaumont Health System, Royal Oak, MI, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Wilson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D020794:Receptor Protein-Tyrosine Kinases
keywords: AstraZeneca 1332; Neuroendocrine gene expression; Trk receptors; radiation