title: Preclinical FLT-PET and FDG-PET imaging of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901.
abstract: BACKGROUND
  The Aurora kinases play a key role in mitosis and have recently been identified as attractive targets for therapeutic intervention in cancer. The aim of this study was therefore to investigate the utility of 3'-[(18)F]fluoro-3'-deoxythymidine (FLT) and 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) for assessment of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901.
  
  
  METHODS
  Balb/c nude mice bearing HCT116 colorectal xenografts were treated with up to 30mg/kg TAK 901 or vehicle intravenously twice daily for two days on a weekly cycle. Tumor growth was monitored by calliper measurements and PET imaging was performed at baseline, day 4, 8, 11 and 15. Tumors were harvested at time points corresponding to days of PET imaging for analysis of ex vivo markers of cell proliferation and metabolism together with markers of Aurora B kinase inhibition including phospho-histone H3 (pHH3) and senescence associated β-galactosidase.
  
  
  RESULTS
  Tumor growth was inhibited by 60% on day 12 of 30mg/kg TAK-901 therapy. FLT uptake was significantly reduced by day 4 of treatment and this corresponded with reduction in bromodeoxyuridine and pHH3 staining by immunohistochemistry. All biomarkers rebounded towards baseline levels by the commencement of the next treatment cycle, consistent with release of Aurora B kinase suppression. TAK-901 therapy had no impact on glucose metabolism as assessed by FDG uptake and GLUT1 staining by immunohistochemistry.
  
  
  CONCLUSIONS
  FLT-PET, but not FDG-PET, is a robust non-invasive imaging biomarker of early HCT116 tumor response to the on-target effects of the multi-targeted Aurora B kinase inhibitor, TAK-901.
  
  
  CONCLUSIONS
  This is the first report to demonstrate the impact of the multi-targeted Aurora B kinase inhibitor, TAK-901 on tumor FLT uptake. The findings provide a strong rationale for the evaluation of FLT-PET as an early biomarker of tumor response in the early phase clinical development of this compound.
authors: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: carleen.cullinane@petermac.org.
authors: Carleen
authors: C
authors: Cullinane
authors: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Kelly L
authors: KL
authors: Waldeck
authors: Centre for Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: David
authors: D
authors: Binns
authors: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Ekaterina
authors: E
authors: Bogatyreva
authors: Millennium Pharmaceuticals, Cambridge, MA.
authors: Daniel P
authors: DP
authors: Bradley
authors: Takeda California, San Diego, CA.
authors: Ron
authors: R
authors: de Jong
authors: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Department of Medicine, St Vincent's Hospital, The University of Melbourne, Parkville, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Grant A
authors: GA
authors: McArthur
authors: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Centre for Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Department of Medicine, St Vincent's Hospital, The University of Melbourne, Parkville, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Rodney J
authors: RJ
authors: Hicks
mesh_terms: D000818:Animals; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D001692:Biological Transport / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015224:Dideoxynucleosides / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D002243:Carbolines; D015224:Dideoxynucleosides; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C583854:TAK-901; D019788:Fluorodeoxyglucose F18; D064107:Aurora Kinase B; C002854:alovudine
keywords: Aurora B kinase; FDG-PET; FLT-PET; TAK-901