The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance
| Autor: | Kevin Quackenbush, Jihye Kim, Wells A. Messersmith, Justin Greene, S. Gail Eckhardt, Alicia Purkey, Patrick J. Blatchford, Guoliang Wang, Dexiang Gao, Alwin Schuller, Stacey M. Bagby, Wai Meng Tai, Anna R Schreiber, Anna Capasso, John J. Arcaroli, Todd M. Pitts, Anna Nguyen |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Oncology medicine.medical_specialty Colorectal cancer Mice Nude Antineoplastic Agents Irinotecan Malignant transformation WNT Mice 03 medical and health sciences Axin Protein Internal medicine medicine AXIN2 Animals Humans Enzyme Inhibitors Aged Tankyrases business.industry Wnt signaling pathway Cancer Middle Aged medicine.disease Xenograft Model Antitumor Assays digestive system diseases CRC 030104 developmental biology NuMA Drug Resistance Neoplasm PDTX IRN Immunohistochemistry Camptothecin Female Colorectal Neoplasms business Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.8626 |
| Popis: | // Kevin S. Quackenbush 1 , Stacey Bagby 1 , Wai Meng Tai 1, 2 , Wells A. Messersmith 1 , Anna Schreiber 1 , Justin Greene 1 , Jihye Kim 1 , Guoliang Wang 1 , Alicia Purkey 1 , Todd M. Pitts 1 , Anna Nguyen 1 , Dexiang Gao 1 , Patrick Blatchford 1 , Anna Capasso 1 , Alwin G. Schuller 3 , S. Gail Eckhardt 1 , John J. Arcaroli 1 1 Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA 2 Division of Medical Oncology, National Cancer Centre Singapore, Singapore 3 AstraZeneca R & D Boston, Massachusetts, Waltham, Massachusetts, MA, USA Correspondence to: John J. Arcaroli, email: john.arcaroli@ucdenver.edu Keywords: CRC, WNT, IRN, NuMA, PDTX Received: December 30, 2015 Accepted: February 28, 2016 Published: April 07, 2016 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. Materials and 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. |
| Databáze: | OpenAIRE |
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