Tripathi Manisha, Nandana Srinivas, Billet Sandrine, Cavassani Karen A, Mishra Rajeev, Chung Leland W K, Posadas Edwin M, Bhowmick Neil A
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Department of Research, Greater Los Angeles Veterans Administration, Los Angeles, California 90048, USA.
Oncotarget. 2017 Sep 23;8(50):87891-87902. doi: 10.18632/oncotarget.21248. eCollection 2017 Oct 20.
The tumor microenvironment (TME) is increasingly recognized as the arbiter of metastatic progression and drug resistance in advanced prostate cancer (PCa). Cabozantinib is a potent tyrosine kinase inhibitor (TKI) with reported biological activity in the PCa epithelia, but failed to provide an overall survival benefit in phase 3 clinical trials. However, the promising biologic efficacy of the drug in early trials warranted a better understanding of the mechanism of action, with the goal of improving patient selection for TKI-based therapy such as cabozantinib. We found a 100-fold lower cabozantinib IC in macrophages, PCa associated fibroblasts, and bone marrow fibroblasts compared to PCa epithelia. In PCa mouse models, pre-treatment with cabozantinib potentiated osseous and visceral tumor engraftment, suggesting a pro-tumorigenic host response to the drug. We further found that the host effects of cabozantinib impacted bone turnover, but not necessarily tumor expansion. Cabozantinib affected M1 macrophage polarization in mice. Analogously, circulating monocytes from PCa patients treated with cabozantinib, demonstrated a striking correlation of monocyte reprograming with therapeutic bone responsivity, to support patient selection at early stages of treatment. Thus, a re-evaluation of TKI-based therapeutic strategies in PCa can be considered for suitable patient populations based on TME responses.
肿瘤微环境（TME）越来越被认为是晚期前列腺癌（PCa）转移进展和耐药性的仲裁者。卡博替尼是一种有效的酪氨酸激酶抑制剂（TKI），在PCa上皮细胞中具有报道的生物学活性，但在3期临床试验中未能提供总体生存益处。然而，该药物在早期试验中显示出的有前景的生物学疗效，促使人们更好地理解其作用机制，目标是改善基于TKI的治疗（如卡博替尼）的患者选择。我们发现，与PCa上皮细胞相比，巨噬细胞、PCa相关成纤维细胞和骨髓成纤维细胞中的卡博替尼IC低100倍。在PCa小鼠模型中，用卡博替尼预处理可增强骨和内脏肿瘤的植入，表明宿主对该药物产生了促肿瘤反应。我们进一步发现，卡博替尼的宿主效应影响骨转换，但不一定影响肿瘤扩展。卡博替尼影响小鼠M1巨噬细胞极化。类似地，接受卡博替尼治疗的PCa患者的循环单核细胞显示，单核细胞重编程与治疗性骨反应性之间存在显著相关性，以支持在治疗早期进行患者选择。因此，基于TME反应，对于合适的患者群体，可以考虑重新评估PCa中基于TKI的治疗策略。
