title: The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance.
abstract: BACKGROUND
  Dysregulation of the canonical Wnt signaling pathway has been implicated in colorectal cancer (CRC) development as well as incipient stages of malignant transformation. In this study, we investigated the antitumor effects of AZ1366 (a novel tankyrase inhibitor) as a single agent and in combination with irinotecan in our patient derived CRC explant xenograft models.
  
  
  RESULTS
  Six out of 18 CRC explants displayed a significant growth reduction to AZ1366. There was one CRC explant (CRC040) that reached the threshold of sensitivity (TGII ≤ 20%) in this study. In addition, the combination of AZ1366 + irinotecan demonstrated efficacy in 4 out of 18 CRC explants. Treatment effects on the WNT pathway revealed that tankyrase inhibition was ineffective at reducing WNT dependent signaling. However, the anti-tumor effects observed in this study were likely a result of alternative tankyrase effects whereby tankyrase inhibition reduced NuMA levels.
  
  
  METHODS
  Eighteen CRC explants were treated with AZ1366 single agent or in combination for 28 days and treatment responses were assessed. Pharmacokinetic (AZ1366 drug concentrations) and pharmacodynamic effects (Axin2 levels) were investigated over 48 hours. Immunohistochemistry of nuclear β-catenin levels as well as western blot was employed to examine the treatment effects on the WNT pathway as well as NuMA.
  
  
  CONCLUSIONS
  Combination AZ1366 and irinotecan achieved greater anti-tumor effects compared to monotherapy. Activity was limited to CRC explants that displayed irinotecan resistance and increased protein levels of tankyrase and NuMA.
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Quackenbush
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Bagby
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.|Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Wai Meng
authors.initials: WM
authors.lastname: Tai
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Schreiber
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Greene
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Purkey
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Dexiang
authors.initials: D
authors.lastname: Gao
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Blatchford
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Capasso
authors.affiliation: AstraZeneca R & D Boston, Massachusetts, Waltham, Massachusetts, MA, USA.
authors.forename: Alwin G
authors.initials: AG
authors.lastname: Schuller
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060466:Axin Protein / Q000096:biosynthesis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D060466:Axin Protein; D002166:Camptothecin; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D038501:Tankyrases; C491761:AXIN2 protein, human; C418109:TNKS protein, human
keywords: CRC; IRN; NuMA; PDTX; WNT