Leibowitz-Amit Raya, Pintilie Melania, Khoja Leila, Azad Arun A, Berger Raanan, Laird A Douglas, Aftab Dana T, Chi Kim N, Joshua Anthony M
Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel.
Division of Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
J Transl Med. 2016 Jan 13;14:12. doi: 10.1186/s12967-015-0747-y.
Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225).
Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST.
A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib.
Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.
卡博替尼是一种口服可用的酪氨酸激酶抑制剂，包括血管内皮生长因子受体2（VEGFR2）和c-MET。我们进行了一项事后分析，以寻找接受每日100mg卡博替尼治疗的转移性去势抵抗性前列腺癌（mCRPC）患者中特定血浆生物标志物与治疗反应之间的关联，该研究作为2期非随机扩展队列（NCT00940225）的一部分。
收集了81例伴有骨转移的mCRPC患者在基线、6周和最大反应时的血浆样本，其中33例还患有可测量的软组织疾病。使用酶联免疫吸附测定法对27种生物标志物的水平进行了重复测量。根据实体瘤疗效评价标准（RECIST），计算生物标志物水平或其治疗变化与骨扫描反应（BSR）或软组织反应之间关联的Spearman相关系数。
分别在66/81例患者（81%）和6/33例患者（18%）中观察到BSR和RECIST反应。在任何时间点，任何生物标志物与任何一种反应之间均未发现显著关联。无论反应如何，在用卡博替尼治疗期间，血浆中血管内皮生长因子A（VEGFA）、FMS样酪氨酸激酶3配体（FLT3L）、c-MET、AXL、生长停滞特异性蛋白6A（Gas6A）、骨特异性碱性磷酸酶、白细胞介素-8以及缺氧标志物碳酸酐酶9（CA9）和聚集素的浓度均显著增加。在用卡博替尼治疗期间，血浆中VEGFR2、组织金属蛋白酶抑制因子5b（Trap5b）、血管生成素-2、基质金属蛋白酶组织抑制因子2（TIMP-2）和血管内皮生长因子受体酪氨酸激酶2（TIE-2）的浓度显著降低。
我们的数据未揭示与卡博替尼反应相关的血浆生物标志物。在用卡博替尼治疗期间观察到的几种生物标志物的变化可能有助于深入了解卡博替尼对肿瘤细胞和肿瘤微环境的影响，并可能有助于指出潜在的联合靶向治疗方法。
