title: Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib.
abstract: BACKGROUND
  Prostate cancer is incurable once it has metastasized to the bone. Appropriate preclinical models are lacking. The therapeutic efficacy of the multikinase inhibitor cabozantinib was assessed in an orthotopic xenograft model of castration-resistant prostate cancer (CRPC) bone metastasis using noninvasive, multimodality functional imaging.
  
  
  METHODS
  NOD/SCID mice were injected intratibially with luciferase-expressing ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) rearranged VCaP human prostate carcinoma cells. The response of VCaP xenografts (n = 7 per group) to cabozantinib was investigated using bioluminescence imaging and anatomical and diffusion weighted magnetic resonance imaging. This enabled quantitation of tumor volume and apparent diffusion coefficient (ADC). Bone uptake of technetium-methylene diphosphonate ((99m)Tc-MDP) was assessed by single-photon emission computed tomography. Ex vivo micro computed tomography was used to quantify bone volume and correlated with appropriate histopathology. Statistical significance was determined using the two-sided Mann-Whitney test or Wilcoxon signed rank test.
  
  
  RESULTS
  VCaP xenografts were predominantly osteosclerotic with some osteolytic activity. Fluorescent in situ hybridization analysis confirmed retention of ERG oncogene rearrangements. Cabozantinib induced a statistically significant 52% reduction in tumor luminance (P = .02) and stasis in tumor volume after 15 days of treatment. Tumor ADC statistically significantly increased with cabozantinib and was associated with extensive necrosis (after 10 days, mean tumor ADC ± SD = 556±43×10(-6) mm(2)/s vs pretreatment ADC = 485±43×10(-6) mm(2)/s; P = .02 ). Tumor-associated uptake of (99m)Tc-MDP was statistically significantly reduced after 3 days of treatment (P = .02), sustained over 15 days treatment, and associated with a statistically significant (P = .048) reduction in bone growth on the tibial cortex, yet a highly statistically significant (P = .001) increase in trabecular bone volume.
  
  
  CONCLUSIONS
  The intratibial VCaP model faithfully emulates clinical disease. Cabozantinib exerts potent effects on both tumor and tumor-induced bone matrix remodeling, and quantitation of ADC provides a clinically translatable imaging biomarker for early, sensitive assessment of treatment response in CRPC bone metastasis.
authors.affiliation: Affiliations of authors: Division of Radiotherapy and Imaging (TJG, NT, TJS, SPR), Cancer Research UK Cancer Therapeutics Unit (GB, MC, SM, GA, JdB, SAE, FED), and Molecular Pathology (FED), Institute of Cancer Research and Royal Marsden NHS Trust, Surrey, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Graham
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Nina
authors.initials: N
authors.lastname: Tunariu
authors.forename: Mateus
authors.initials: M
authors.lastname: Crespo
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Spinks
authors.forename: Susana
authors.initials: S
authors.lastname: Miranda
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D000368:Aged; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D001859:Bone Neoplasms / Q000556:secondary*; D016723:Bone Remodeling / Q000187:drug effects*; D038524:Diffusion Magnetic Resonance Imaging; D006801:Humans; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D008875:Middle Aged; D010014:Osteolysis / Q000188:drug therapy; D010026:Osteosclerosis / Q000188:drug therapy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013669:Technetium Tc 99m Medronate / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011725:Pyridines; D019275:Radiopharmaceuticals; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases; D013669:Technetium Tc 99m Medronate