O'Halloran Philip J, Viel Thomas, Murray David W, Wachsmuth Lydia, Schwegmann Katrin, Wagner Stefan, Kopka Klaus, Jarzabek Monika A, Dicker Patrick, Hermann Sven, Faber Cornelius, Klasen Tim, Schäfers Michael, O'Brien David, Prehn Jochen H M, Jacobs Andreas H, Byrne Annette T
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
National Neurosurgical Department, Beaumont Hospital, Dublin 9, Ireland.
Eur J Nucl Med Mol Imaging. 2016 Aug;43(9):1673-83. doi: 10.1007/s00259-016-3343-3. Epub 2016 Mar 15.
Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235.
Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry.
Treatment with BEV resulted in a pronounced decrease in tumour volume (T2-weighted MRI). No additive effect on tumour volume was observed with the BEV/BEZ235 combination compared with BEV monotherapy. The Ki67 proliferation index and [(18)F]FLT uptake studies were used to support the observations. Using ΔR2* and ΔR2 values, respectively, the BEV/BEZ235 combination significantly reduced tumour microvessel volume in comparison to BEV alone. Decreased microvessel density index was further observed in animals treated with the combination, supported by von Willebrand factor (vWF) immunohistochemistry. [(18)F]FET uptake was decreased following treatment with BEV alone, but was not further reduced following treatment with the combination. vWF immunohistochemistry analysis showed that the mean tumour vessel size was increased in all cohorts.
Assessing MR imaging biomarker parameters together with [(18)F]FET and [(18)F]FLT PET provided information on mechanism of action of the drug combination and clues as to potential clinical responses. Following translation to clinical use, treatment with a BEV/BEZ235 combination could reduce peritumoral oedema obviating the requirement for steroids. The use of hypothesis-driven molecular imaging studies facilitates the preclinical evaluation of drug response. Studies of this kind may more accurately predict the clinical potential of the BEV/BEZ235 combination regimen as a novel therapeutic approach in oncology.
胶质母细胞瘤对贝伐单抗（BEV）的耐药性被认为是通过激活包括mTOR/PI3K通路在内的分子网络而发生的。我们采用磁共振/正电子发射断层扫描（MR/PET）分子成像生物标志物方法，研究了BEV与mTOR/PI3K抑制剂BEZ235联合使用的效果。
通过将U87MG-luc2细胞原位植入小鼠体内建立肿瘤模型。动物接受BEZ235和/或BEV治疗，并在注射超顺磁性氧化铁造影剂前后分别使用扩散加权磁共振成像（DWI-MRI）、T2加权和T2加权成像进行扫描。计算弛豫率变化图（ΔR2、ΔR2和表观扩散系数）。得出血管大小指数和微血管密度指数。进一步进行3'-脱氧-3'-[(18)F]氟胸苷（[(18)F]FLT）PET和O-(2-[(18)F]氟乙基)-L-酪氨酸（[(18)F]FET）PET检查，并通过免疫组织化学评估肿瘤内皮/增殖标志物。
BEV治疗导致肿瘤体积显著减小（T2加权MRI）。与BEV单药治疗相比，BEV/BEZ235联合治疗未观察到对肿瘤体积的附加效应。Ki67增殖指数和[(18)F]FLT摄取研究支持了这些观察结果。分别使用ΔR2*和ΔR2值，与单独使用BEV相比，BEV/BEZ235联合治疗显著降低了肿瘤微血管体积。联合治疗的动物中进一步观察到微血管密度指数降低，血管性血友病因子（vWF）免疫组织化学支持了这一结果。单独使用BEV治疗后[(18)F]FET摄取降低，但联合治疗后未进一步降低。vWF免疫组织化学分析显示，所有组的平均肿瘤血管大小均增加。
评估MR成像生物标志物参数以及[(18)F]FET和[(18)F]FLT PET可提供有关药物联合作用机制的信息以及潜在临床反应的线索。转化为临床应用后，BEV/BEZ235联合治疗可减轻瘤周水肿，从而无需使用类固醇。使用假设驱动的分子成像研究有助于药物反应的临床前评估。这类研究可能更准确地预测BEV/BEZ235联合治疗方案作为肿瘤学新型治疗方法的临床潜力。
