title: False-negative MRI biomarkers of tumour response to targeted cancer therapeutics.
abstract: BACKGROUND
  Non-invasive quantitative imaging biomarkers are essential for the evaluation of novel targeted therapeutics. Before deployment in clinical trials, such imaging biomarkers require qualification, typically through pre-clinical identification of imaging-pathology correlates.
  
  
  METHODS
  First, in investigating imaging biomarkers of invasion, the response of orthotopic murine PC3 prostate xenografts to the Src inhibitor saracatinib was assessed using susceptibility contrast MRI. Second, the longitudinal response of chemically induced rat mammary adenocarcinomas to the VEGFR2 inhibitor vandetanib was monitored by intrinsic susceptibility MRI, to identify the time window of transient vascular normalisation.
  
  
  RESULTS
  No significant differences in fractional blood volume (%), vessel calibre (μm), native T(1) (ms) or apparent water diffusion coefficient were determined, despite reduced expression of activated Fak and paxillin in the saracatinib cohort. Treatment with vandetanib elicited a 60% antitumour response (P<0.01), 80% inhibition in vessel density (P<0.05) and reduction in hypoxia (P<0.05). There was, however, no significant change in tumour baseline R(2)* (s(-1)) or carbogen-induced ΔR(2)* with treatment.
  
  
  CONCLUSIONS
  Reporting negative imaging biomarker responses is important, to avoid the risk of clinical trials using the same biomarkers being undertaken with a false expectation of success, and the abandonment of promising new therapeutics based on a false-negative imaging biomarker response being mistaken for a true-negative.
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
authors.forename: J K R
authors.initials: JK
authors.lastname: Boult
authors.forename: Y
authors.initials: Y
authors.lastname: Jamin
authors.forename: V
authors.initials: V
authors.lastname: Jacobs
authors.forename: L D
authors.initials: LD
authors.lastname: Gilmour
authors.forename: S
authors.initials: S
authors.lastname: Walker-Samuel
authors.forename: J
authors.initials: J
authors.lastname: Halliday
authors.forename: P
authors.initials: P
authors.lastname: Elvin
authors.forename: A J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: J C
authors.initials: JC
authors.lastname: Waterton
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D005188:False Negative Reactions; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D052117:Benzodioxoles; D014408:Biomarkers, Tumor; D010880:Piperidines; D011799:Quinazolines; C515233:saracatinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D016392:Proto-Oncogene Proteins pp60(c-src); C452423:vandetanib