Preclinical Evaluation of Imaging Biomarkers for Prostate Cancer Bone Metastasis and Response to Cabozantinib
Preclinical Evaluation of Imaging Biomarkers for Prostate Cancer Bone Metastasis and Response to Cabozantinib
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DOI：
10.1093/jnci/dju033
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发表时间：
2014-04-01
影响因子：
10.3
通讯作者：
Robinson, Simon P.
中科院分区：
文献类型：
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作者：
Graham, Timothy J.;Box, Gary;Robinson, Simon P.
背景前列腺癌一旦转移到骨就无法治愈。缺乏适当的临床前模型。多激酶抑制剂卡博替尼的治疗效果进行了评估，在原位异种移植模型去势抵抗性前列腺癌（CRPC）骨转移使用非侵入性，多模态功能imaging.Methods NOD/SCID小鼠胫骨内注射表达ERG（v-ets禽成红细胞增多症病毒E26癌基因同源物）重排VCaP人前列腺癌细胞。使用生物发光成像以及解剖学和扩散加权磁共振成像研究VCaP异种移植物（每组n = 7）对卡博替尼的响应。这使得能够定量肿瘤体积和表观扩散系数（ADC）。用单光子发射计算机断层扫描评估锝-亚甲基二膦酸盐（Tc-99 m-MDP）的骨摄取。体外微型计算机断层扫描用于定量骨体积，并与适当的组织病理学相关。统计学显著性采用双侧Mann-Whitney检验或Wilcoxon符号秩和检验。结果VCaP异种移植物主要是具有一定溶骨性活性的骨形成。荧光原位杂交分析证实保留ERG癌基因重排。治疗15天后，卡博替尼诱导肿瘤亮度统计学显著降低52%（P = 0.02）和肿瘤体积停滞。卡博替尼组肿瘤ADC在统计学上显著增加，并与广泛坏死相关（10天后，平均肿瘤ADC +/- SD = 556 +/- 43 x 10（-6）mm（2）/s vs治疗前ADC = 485 +/- 43 x 10（-6）mm（2）/s; P = .02）。治疗3天后，肿瘤相关的Tc-99 m-MDP摄取在统计学上显著降低（P =.02），持续超过15天的治疗，并与统计学显著性相关。（P = 0.048）胫骨皮质骨生长减少，但在统计学上，结论胫骨内VCaP模型忠实地模拟了临床疾病。卡博替尼对肿瘤和肿瘤诱导的骨基质重塑都发挥有效作用，ADC的定量为CRPC骨转移中治疗反应的早期敏感评估提供了临床可转化的成像生物标志物。
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 (Tc-99m-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 x 10(-6) mm(2)/s vs pretreatment ADC = 485 +/- 43 x 10(-6) mm(2)/s; P = .02). Tumor-associated uptake of Tc-99m-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.