Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
EBioMedicine. 2018 Jan;27:182-186. doi: 10.1016/j.ebiom.2017.12.024. Epub 2017 Dec 20.
Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents.
雄激素受体 (AR) 通路的失活通过雄激素剥夺疗法 (ADT) 是转移性前列腺癌治疗的主要方法。尽管循环雄激素处于去势水平，但 AR 通路最终仍会被重新激活。因此，即使在去势抵抗性前列腺癌 (CRPC) 中，它也能维持其作用。最近的 STAMPEDE 和 CHAARTED 试验表明，多西他赛联合 ADT 增加了激素敏感前列腺癌患者的生存，这表明 AR 信号和化疗疗效之间存在交叉对话。我们假设，类似的相互作用也可能适用于用卡巴他赛治疗的 CRPC。我们在一种独特的、具有临床相关性的去势抵抗性疾病患者衍生的异种移植模型中研究了雄激素状态对卡巴他赛疗效、药效学和药代动力学的影响。我们发现，卡巴他赛在去势环境下具有高度疗效，AR 激活明显降低，而在 AR 通路活性高的情况下，卡巴他赛抑制肿瘤生长的作用完全被消除。此外，额外的实验表明，与来自雄激素补充动物的肿瘤相比，来自去势小鼠的肿瘤内卡巴他赛水平高 3.5 倍。我们证实卡巴他赛的药代动力学不受睾酮的影响，这表明雄激素状态可能直接影响卡巴他赛的肿瘤摄取。这项研究揭示了雄激素状态对卡巴他赛疗效的影响，并支持将紫杉烷化疗药物与 AR 轴靶向药物联合应用的潜力。
